@unpublished{dinh_meta_analysis_2026,
title = {Meta-analysis of over 8,000 individuals from {Hawai}‘i and {Samoa} for genetic associations to cardiometabolic phenotypes},
copyright = {© 2026, Posted by openRxiv. This pre-print is available under a Creative Commons License (Attribution-NonCommercial-NoDerivs 4.0 International), CC BY-NC-ND 4.0, as described at http://creativecommons.org/licenses/by-nc-nd/4.0/},
url = {https://www.medrxiv.org/content/10.64898/2026.05.08.26352761v1},
doi = {10.64898/2026.05.08.26352761},
language = {en},
urldate = {2026-05-19},
publisher = {medRxiv},
author = {Dinh, Bryan L. and Wang, Xinran and Sheng, Xin and Wan, Peggy and Srivastava, Amit Kumar and Naseri, Take and Viali, Satupa‘itea and Wilkens, Lynne and Marchand, Loïc Le and Haiman, Christopher and Weeks, Daniel E. and Chiang, Charleston W. K. and Carlson, Jenna C.},
month = may,
year = {2026},
note = {ISSN: 3067-2007
Pages: 2026.05.08.26352761},
file = {Full Text PDF:/Users/dweeks/Zotero/storage/6IEHVN9T/Dinh et al. - 2026 - Meta-analysis of over 8,000 individuals from Hawai‘i and Samoa for genetic associations to cardiomet.pdf:application/pdf}
}
Although genome-wide association studies (GWAS) now routinely reveal genetic associations and biological insights in millions of individuals, underrepresentation of global populations, such as those from Polynesia, continue to persist. These exclusions, often driven by logistical challenges and lack of data, prevent systematic identification of population-enriched associations, such as the association of the missense variant at the CREBRF locus to BMI and type 2 diabetes discovered commonly occurring in Polynesian populations due to its rarity in global populations. Armed with the recently updated TOPMed imputation panel that could benefit studies in diverse populations that previously had poorer imputation performance, we performed the first GWAS of Native Hawaiians and largest to date of Polynesian-ancestry populations (combined N up to 8,461) to identify population-enriched associations for 13 adiposity and cardiometabolic traits available across both cohorts: BMI, fasting glucose, fasting insulin, HDL, height, hip circumference, HOMA-IR, LDL, T2D, total cholesterol, triglycerides, waist circumference, and waist-hip ratio. We found 25 trait-loci associations that met genome-wide significance: 20 previously reported or known associations and 5 associations newly confirmed via meta-analysis. In particular, with improved statistical power, we were able to confirm the suspected association between the missense CREBRF variant with fasting glucose levels. The remaining 4 potentially novel loci-trait associations for BMI, LDL, and waist-hip ratio, however, were not replicated in multi-ethnic datasets from All-of-Us despite having reasonable power to replicate. The lack of Polynesian-enriched findings outside of the CREBRF locus informs the bounds of the effect sizes or frequency of any enriched variants, and suggests that further expansion of cohort sizes from this region of the world and improved imputation references specific to these populations are needed to identify more population-enriched associations.
@unpublished{lee_incorporating_2025,
title = {Incorporating {Dietary} {Information} to {Enhance} {Polygenic} {Prediction} {Models} with {Applications} to {Body} {Mass} {Index} and {Type} 2 {Diabetes}},
copyright = {© 2025, Posted by openRxiv. The copyright holder for this pre-print is the author. All rights reserved. The material may not be redistributed, re-used or adapted without the author's permission.},
url = {https://www.medrxiv.org/content/10.1101/2025.10.03.25337287v2},
doi = {10.1101/2025.10.03.25337287},
language = {en},
urldate = {2026-03-10},
publisher = {medRxiv},
author = {Lee, Eunice Y. and @unpublished, Bryan L. and Tang, Ji and Streicher, Samantha and Wang, Xinran and Biswas, Subarna and Tian, He and Yu, Xian and Tappara, Kekoa and Naseri, Take and Viali, Satupa‘itea and Weeks, Daniel E. and Carlson, Jenna C. and Haiman, Christopher A. and Marchand, Loic Le and Maskarinec, Gertraud and Wilkens, Lynne R. and Park, Song-Yi and Chiang, Charleston W. K.},
month = dec,
year = {2025},
pmid = {41378348},
pmcid = {PMC12687799},
note = {ISSN: 3067-2007
Pages: 2025.10.03.25337287}
}
Polygenic predictors can enhance screening for biomedical conditions, such as metabolism-related traits and diseases, but explain limited phenotypic variance and face implementation challenges in non-European populations. On the other hand, dietary quality and other sociocultural factors are well established metabolic risk factors that remain under-investigated in risk stratification models. In this study, we developed and evaluated risk stratification model combining polygenic predictors and diet-based models for body mass index (BMI) and type 2 diabetes (T2D). Using 5,368 Native Hawaiians from the Multiethnic Cohort (MEC-NH) with genetic data, we integrated large-scale cross-ancestry GWAS summary statistics to develop polygenic score (PGS) models with better prediction accuracies (partial-R2 [SE] = 0.12 [0.04] for BMI; liability-R2 [SE] = 0.09 [0.04] and AUC = 0.65 for T2D) than using GWAS information from single ancestry (partial-R2 = 0.03-0.09 for BMI and liability-R2 = 0.01-0.07 and AUC = 0.52-0.63 for T2D) or in combination with GWAS from MEC-NH (partial-R2 = 0.04-0.07 for BMI and liability-R2 = 0.01-0.04 and AUC = 0.53-0.62). Moreover, machine learning models trained on 520 dietary variables available from 14,344 MEC-NH individuals substantially explained BMI variation (partial-R2 [SE] = 0.12 [0.01]) and enhanced prediction when combined with PGS (adjusted-R2 = 0.29). The best performing diet score model for BMI was associated with multiple chronic diseases in the same cohort, potentially mediated via inflammatory and lipid pathways. Both PGS and dietary scores provided significant, complementary information for predicting BMI and T2D. For populations with limited genetic studies like Native Hawaiians, integrating external GWAS data or non-genetic dietary information can improve risk stratification models.
@unpublished{heinsberg_study_2025,
title = {Study {Protocol} for the {Health} {Outcomes} in {Pregnancy} and {Early} {Childhood} ({HOPE}) {Study}: {A} {Mother}-{Infant} {Study} in {American} {Samoa}},
shorttitle = {Study {Protocol} for the {Health} {Outcomes} in {Pregnancy} and {Early} {Childhood} ({HOPE}) {Study}},
doi = {10.1101/2025.06.04.25329013},
language = {eng},
journal = {medRxiv},
author = {Heinsberg, Lacey W. and Loia, Miracle and Tasele, Susie and Faasalele-Savusa, Kima and Carlson, Jenna C. and Anesi, Scott and Desobry, Katie and Yuchongco, Efren and Guevara, Brian Fortuno and Sesaga, Aigaeiva and Iloilo, Alice and Tofaeono, Va'atausili and Bryan, Kaylynn and Tauasosi-Posiulai, Tina and Kershaw, Erin E. and Conley, Yvette P. and Weeks, Daniel E. and Hawley, Nicola L. and Muasau-Howard, Bethel},
month = jun,
year = {2025},
pmid = {40502564},
pmcid = {PMC12155048}
}
INTRODUCTION: Pacific Islanders, including those in American Samoa, face a disproportionately high burden of gestational diabetes mellitus (GDM) and related sequalae of metabolic conditions. The CREBRF rs373863828 genetic variant, which is uniquely common among Pacific Islanders, has been paradoxically associated with higher body mass index (BMI) but lower risk of type 2 diabetes. While emerging evidence suggests this variant may influence both maternal metabolic outcomes and infant growth, studies in pregnancy and early life remain limited. The purpose of this paper is to describe the protocol for a study designed to address these gaps. METHODS AND ANALYSIS: The Health Outcomes in Pregnancy and Early Childhood (HOPE) Study is an observational, longitudinal cohort study that will enroll up to 180 Samoan pregnant women and their infants (target n=150 dyads completing study protocols) in American Samoa, with follow-up through six months postpartum/postnatal. The study includes questionnaires, anthropometric measurements, and biospecimen collection. Genetic and epigenetic analyses will examine associations between maternal and infant CREBRF rs373863828 genotype, gestational diabetes status, infant body size, and cord blood DNA methylation. ETHICS AND DISSEMINATION: The study is approved by the Institutional Review Boards at the University of Pittsburgh, Yale University, and the American Samoa Department of Health, as well as the Lyndon B. Johnson Tropical Medical Center (American Samoa) Research Oversight Committee. Findings will be disseminated through peer-reviewed publications, conference presentations, and community reports.
@unpublished{heinsberg_differential_2025,
title = {Differential {DNA} {Methylation} of the {Brain}-{Derived} {Neurotrophic} {Factor} {Gene} is {Observed} after {Pediatric} {Traumatic} {Brain} {Injury} {Compared} to {Orthopedic} {Injury}},
copyright = {© 2025, Posted by Cold Spring Harbor Laboratory. This pre-print is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), CC BY-NC 4.0, as described at http://creativecommons.org/licenses/by-nc/4.0/},
url = {https://www.medrxiv.org/content/10.1101/2025.06.16.25329571v1},
doi = {10.1101/2025.06.16.25329571},
language = {en},
urldate = {2025-06-17},
journal = {medRiv},
author = {Heinsberg, Lacey W. and Kesbhat, Aboli and Petersen, Bailey and Kaseman, Lauren and Stec, Zachary and Anton, Nivinthiga and Kochanek, Patrick M. and Yeates, Keith Owen and Weeks, Daniel E. and Conley, Yvette and Treble-Barna, Amery},
month = jun,
year = {2025}
}
Importance: Pediatric traumatic brain injury (TBI) triggers biological changes that may differ from those observed in non-brain injuries. BDNF DNA methylation (DNAm) may serve as a novel, dynamic biomarker of the brain’s response and help identify TBI-specific epigenetic patterns relevant to later recovery. Objective: To determine whether BDNF DNAm differed between children with TBI and those with orthopedic injury (OI, comparison group) acutely and over time. Design: The Epigenetic Effects on TBI Recovery (EETR) study is a prospective, longitudinal, cohort study with phenotype data and peripheral blood collection at approximately 24 hours, 6 months, and 12 months post-injury. Setting: Single-site study conducted at UPMC Children’s Hospital of Pittsburgh. Participants: Consecutive sampling of children aged 3-18 years hospitalized for a minimum of overnight for complicated mild to severe non-penetrating TBI (n=189) or OI without evidence of head trauma (n=105). Participants were excluded for pre-existing neurological or psychiatric conditions, sensory or motor impairments precluding study participation, and prior hospitalization for TBI. Exposure: The primary exposure was injury type (TBI vs. OI), with severity examined as a secondary exposure within the TBI group. Main outcomes and measures: The primary outcome was BDNF DNAm measured via pyrosequencing at seven sites (five retained for analysis) acutely (mean=31.6 hours post-injury) and 6 (mean=216.9 days) and 12 months (mean=405.9 days post-injury). Primary covariates included age, sex, and race; secondary covariates included age-adjusted body mass index, non-head injury severity score, pubertal status, socioeconomic status, and psychosocial adversity. Outcomes, covariates, and hypotheses were prespecified. Results: Participants were 66.3% male, 82.3% White, and had a mean age of 11.7 (+/-4.2) years. Acutely, children with TBI showed significantly lower DNAm at three of five sites (1.8%-8.7% lower; p=0.0042 to 5.76E-06). One site remained significantly lower at 12 months (p=0.0038); no significant differences were observed at 6 months. TBI severity (measured via Glasgow Coma Scale) was not associated with DNAm at any time point. Conclusions and relevance: BDNF DNAm appears to differ in children with TBI vs OI, particularly in the acute period. BDNF DNAm differences may reflect early biological responses that are specific to TBI.
@unpublished{heinsberg_study_2026,
title = {Study {Protocol} for the {Health} {Outcomes} in {Pregnancy} and {Early} {Childhood} ({HOPE}) {Study}: {A} {Mother}-{Infant} {Study} in {American} {Samoa}},
shorttitle = {Study {Protocol} for the {Health} {Outcomes} in {Pregnancy} and {Early} {Childhood} ({HOPE}) {Study}},
doi = {10.1101/2025.06.04.25329013},
language = {eng},
journal = {medRxiv},
author = {Heinsberg, Lacey W. and Loia, Miracle and Tasele, Susie and Faasalele-Savusa, Kima and Carlson, Jenna C. and Anesi, Scott and Desobry, Katie and Yuchongco, Efren and Guevara, Brian Fortuno and Sesaga, Aigaeiva and Iloilo, Alice and Tofaeono, Va'atausili and Bryan, Kaylynn and Tauasosi-Posiulai, Tina and Kershaw, Erin E. and Conley, Yvette P. and Weeks, Daniel E. and Hawley, Nicola L. and Muasau-Howard, Bethel},
month = jun,
year = {2025},
file = {Full Text PDF:/Users/dweeks/Zotero/storage/AMHPCEYS/Heinsberg et al. - 2025 - Study Protocol for the Health Outcomes in Pregnancy and Early Childhood (HOPE) Study A Mother-Infan.pdf:application/pdf}
}
INTRODUCTION: Pacific Islanders, including those in American Samoa, face a disproportionately high burden of gestational diabetes mellitus (GDM) and related sequalae of metabolic conditions. The CREBRF rs373863828 genetic variant, which is uniquely common among Pacific Islanders, has been paradoxically associated with higher body mass index (BMI) but lower risk of type 2 diabetes. While emerging evidence suggests this variant may influence both maternal metabolic outcomes and infant growth, studies in pregnancy and early life remain limited. The purpose of this paper is to describe the protocol for a study designed to address these gaps. METHODS AND ANALYSIS: The Health Outcomes in Pregnancy and Early Childhood (HOPE) Study is an observational, longitudinal cohort study that will enroll up to 180 Samoan pregnant women and their infants (target n=150 dyads completing study protocols) in American Samoa, with follow-up through six months postpartum/postnatal. The study includes questionnaires, anthropometric measurements, and biospecimen collection. Genetic and epigenetic analyses will examine associations between maternal and infant CREBRF rs373863828 genotype, gestational diabetes status, infant body size, and cord blood DNA methylation. ETHICS AND DISSEMINATION: The study is approved by the Institutional Review Boards at the University of Pittsburgh, Yale University, and the American Samoa Department of Health, as well as the Lyndon B. Johnson Tropical Medical Center (American Samoa) Research Oversight Committee. Findings will be disseminated through peer-reviewed publications, conference presentations, and community reports.
@unpublished{heinsberg_differential_2026,
title = {Differential {DNA} {Methylation} of the {Brain}-{Derived} {Neurotrophic} {Factor} {Gene} is {Observed} after {Pediatric} {Traumatic} {Brain} {Injury} {Compared} to {Orthopedic} {Injury}},
copyright = {© 2025, Posted by Cold Spring Harbor Laboratory. This pre-print is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), CC BY-NC 4.0, as described at http://creativecommons.org/licenses/by-nc/4.0/},
url = {https://www.medrxiv.org/content/10.1101/2025.06.16.25329571v1},
doi = {10.1101/2025.06.16.25329571},
language = {en},
urldate = {2025-06-17},
journal = {medRiv},
author = {Heinsberg, Lacey W. and Kesbhat, Aboli and Petersen, Bailey and Kaseman, Lauren and Stec, Zachary and Anton, Nivinthiga and Kochanek, Patrick M. and Yeates, Keith Owen and Weeks, Daniel E. and Conley, Yvette and Treble-Barna, Amery},
month = jun,
year = {2025},
pages = {2025.06.16.25329571},
file = {Full Text PDF:/Users/dweeks/Zotero/storage/A338F495/Heinsberg et al. - 2025 - Differential DNA Methylation of the Brain-Derived Neurotrophic Factor Gene is Observed after Pediatr.pdf:application/pdf}
}
Importance: Pediatric traumatic brain injury (TBI) triggers biological changes that may differ from those observed in non-brain injuries. BDNF DNA methylation (DNAm) may serve as a novel, dynamic biomarker of the brain’s response and help identify TBI-specific epigenetic patterns relevant to later recovery. Objective: To determine whether BDNF DNAm differed between children with TBI and those with orthopedic injury (OI, comparison group) acutely and over time. Design: The Epigenetic Effects on TBI Recovery (EETR) study is a prospective, longitudinal, cohort study with phenotype data and peripheral blood collection at approximately 24 hours, 6 months, and 12 months post-injury. Setting: Single-site study conducted at UPMC Children’s Hospital of Pittsburgh. Participants: Consecutive sampling of children aged 3-18 years hospitalized for a minimum of overnight for complicated mild to severe non-penetrating TBI (n=189) or OI without evidence of head trauma (n=105). Participants were excluded for pre-existing neurological or psychiatric conditions, sensory or motor impairments precluding study participation, and prior hospitalization for TBI. Exposure: The primary exposure was injury type (TBI vs. OI), with severity examined as a secondary exposure within the TBI group. Main outcomes and measures: The primary outcome was BDNF DNAm measured via pyrosequencing at seven sites (five retained for analysis) acutely (mean=31.6 hours post-injury) and 6 (mean=216.9 days) and 12 months (mean=405.9 days post-injury). Primary covariates included age, sex, and race; secondary covariates included age-adjusted body mass index, non-head injury severity score, pubertal status, socioeconomic status, and psychosocial adversity. Outcomes, covariates, and hypotheses were prespecified. Results: Participants were 66.3% male, 82.3% White, and had a mean age of 11.7 (+/-4.2) years. Acutely, children with TBI showed significantly lower DNAm at three of five sites (1.8%-8.7% lower; p=0.0042 to 5.76E-06). One site remained significantly lower at 12 months (p=0.0038); no significant differences were observed at 6 months. TBI severity (measured via Glasgow Coma Scale) was not associated with DNAm at any time point. Conclusions and relevance: BDNF DNAm appears to differ in children with TBI vs OI, particularly in the acute period. BDNF DNAm differences may reflect early biological responses that are specific to TBI.
@unpublished{erdoganyildirim_genomewide_2024,
title = {A genome-wide association study of anti-{Müllerian} hormone ({AMH}) levels in {Samoan} women},
copyright = {© 2024, Posted by Cold Spring Harbor Laboratory. The copyright holder for this pre-print is the author. All rights reserved. The material may not be redistributed, re-used or adapted without the author's permission.},
url = {https://www.medrxiv.org/content/10.1101/2024.12.05.24318457v1},
doi = {10.1101/2024.12.05.24318457},
language = {en},
urldate = {2024-12-09},
journal = {medRxiv},
author = {Erdogan-Yildirim, Zeynep and Carlson, Jenna C. and Krishnan, Mohanraj and Zhang, Jerry Z. and Lambert-Messerlian, Geralyn and Naseri, Take K. and Viali, Satupaitea and Hawley, Nicola L. and McGarvey, Stephen T. and Weeks, Daniel E. and Minster, Ryan L.},
month = dec,
year = {2024}
}
Study question: Can a genome–wide association study (GWAS) and transcriptome–wide association study (TWAS) help identify genetic variation or genes associated with circulating anti–Müllerian hormone (AMH) levels in Samoan women? Summary answer: We identified eleven genome–wide suggestive loci (strongest association signal in ARID3A 19–946163–G–C [p = 2.32 × 10⁻⁷]) and seven transcriptome–wide significant genes (GINS2, SENP3, USP7, TUSC3, MAFA, METTL4, NDFIP1 [all with a p \textless 2.50 × 10⁻⁶]) associated with circulating AMH levels in Samoan women. What is known already: Three prior GWASs of AMH levels identified eight loci in premenopausal women of European ancestry (AMH, MCM8, TEX41, CHECK2, CDCA7, EIF4EBP1, BMP4 and an uncharacterized non–coding RNA gene CTB–99A3.1), among which the MCM8 locus was shared among all three studies. Study design, size, duration: We included a sample of 1,185 women from two independently recruited samples: a family study (n = 212; age: 18 to 40 years) recruited in 2002–03 from Samoa and American Samoa; and the Soifua Manuia Study (n = 973; age: 25 to 51 years), a cross–sectional population–based study recruited in 2010 from Samoa. Participants/materials, setting, methods: Serum AMH levels were measured using enzyme linked immunosorbent assays (ELISA). We performed GWASs in the two participant samples using a Cox mixed–effects model to account for AMH levels below detectable limits and adjusted for centered age, centered age2, polity, and kinship via kinship matrix. The summary statistics were then meta–analyzed using a fixed–effect model. We annotated the variants with p \textless 1 × 10⁻⁵ and calculated posterior probability of causality for prioritization. We further annotated variants using FUMA and performed colocalization and transcriptome–wide association analysis. We also assessed whether any previously reported loci were replicated in our GWAS. Main results and the role of chance: We identified eleven novel genome–wide suggestive loci (p \textless 1 × 10⁻⁵) associated with AMH levels and replicated EIF4EBP1, a previously reported AMH locus, in the GWAS. The lead variant in ARID3A, 19–946163–G–C is in high linkage disequilibrium (r2 = 0.79) with the known age–at–menopause variant 19–950694–G–A. Nearby KISS1R is a bio-logically plausibility causal gene in the region; kisspeptin regulates ovarian follicle development and has been linked to AMH levels. Further investigation of the ARID3A locus is warranted. Limitations, reasons for caution: The main limitations of our study are the small sample size for a GWAS and the use of the transcription model trained on mostly European samples from the Genotype Tissue Expression (GTEx) project, which may have led to reduced power to detect genotype–expression associations. Our findings need to be validated in larger Polynesian cohorts. Wider implications of the findings: In addition to replicating one of the eight previously discovered AMH loci, we identified new suggestive associations. It is known that the inclusion of founder populations aids in the discovery of novel loci. These findings could enhance our understanding of AMH and AMH–related reproductive phenotypes (ovarian reserve, age at menopause, premature ovarian failure, and polycystic ovary syndrome) and help build a screening approach for women at risk for these phenotypes using genetically predicted AMH levels. Study funding/competing interest(s): This work was funded by NIH grants R01–HL093093 (PI: S.T.M.), R01–HL133040 (PI: R.L.M.), and T90–DE030853 (PI: C.S. Sfeir). Molecular data for the Trans–Omics in Precision Medicine (TOPMed) Program was supported by the National Heart, Lung and Blood Institute (NHLBI). The content is solely the responsibility of the authors and does not represent the official views of the National Institutes of Health.
@unpublished{erdogan_yildirim_genome_wide_2024,
title = {A genome-wide association study of anti-{Müllerian} hormone ({AMH}) levels in {Samoan} women},
copyright = {© 2024, Posted by Cold Spring Harbor Laboratory. The copyright holder for this pre-print is the author. All rights reserved. The material may not be redistributed, re-used or adapted without the author's permission.},
url = {https://www.medrxiv.org/content/10.1101/2024.12.05.24318457v1},
doi = {10.1101/2024.12.05.24318457},
language = {en},
urldate = {2024-12-09},
journal = {medRxiv},
author = {Erdogan-Yildirim, Zeynep and Carlson, Jenna C. and Krishnan, Mohanraj and Zhang, Jerry Z. and Lambert-Messerlian, Geralyn and Naseri, Take K. and Viali, Satupaitea and Hawley, Nicola L. and McGarvey, Stephen T. and Weeks, Daniel E. and Minster, Ryan L.},
month = dec,
year = {2024},
file = {Full Text PDF:/Users/dweeks/Zotero/storage/8PMCGYWG/Erdogan-Yildirim et al. - 2024 - A genome-wide association study of anti-Müllerian hormone (AMH) levels in Samoan women.pdf:application/pdf}
}
Study question: Can a genome–wide association study (GWAS) and transcriptome–wide association study (TWAS) help identify genetic variation or genes associated with circulating anti–Müllerian hormone (AMH) levels in Samoan women? Summary answer: We identified eleven genome–wide suggestive loci (strongest association signal in ARID3A 19–946163–G–C [p = 2.32 × 10⁻⁷]) and seven transcriptome–wide significant genes (GINS2, SENP3, USP7, TUSC3, MAFA, METTL4, NDFIP1 [all with a p \textless 2.50 × 10⁻⁶]) associated with circulating AMH levels in Samoan women. What is known already: Three prior GWASs of AMH levels identified eight loci in premenopausal women of European ancestry (AMH, MCM8, TEX41, CHECK2, CDCA7, EIF4EBP1, BMP4 and an uncharacterized non–coding RNA gene CTB–99A3.1), among which the MCM8 locus was shared among all three studies. Study design, size, duration: We included a sample of 1,185 women from two independently recruited samples: a family study (n = 212; age: 18 to 40 years) recruited in 2002–03 from Samoa and American Samoa; and the Soifua Manuia Study (n = 973; age: 25 to 51 years), a cross–sectional population–based study recruited in 2010 from Samoa. Participants/materials, setting, methods: Serum AMH levels were measured using enzyme linked immunosorbent assays (ELISA). We performed GWASs in the two participant samples using a Cox mixed–effects model to account for AMH levels below detectable limits and adjusted for centered age, centered age2, polity, and kinship via kinship matrix. The summary statistics were then meta–analyzed using a fixed–effect model. We annotated the variants with p \textless 1 × 10⁻⁵ and calculated posterior probability of causality for prioritization. We further annotated variants using FUMA and performed colocalization and transcriptome–wide association analysis. We also assessed whether any previously reported loci were replicated in our GWAS. Main results and the role of chance: We identified eleven novel genome–wide suggestive loci (p \textless 1 × 10⁻⁵) associated with AMH levels and replicated EIF4EBP1, a previously reported AMH locus, in the GWAS. The lead variant in ARID3A, 19–946163–G–C is in high linkage disequilibrium (r2 = 0.79) with the known age–at–menopause variant 19–950694–G–A. Nearby KISS1R is a bio-logically plausibility causal gene in the region; kisspeptin regulates ovarian follicle development and has been linked to AMH levels. Further investigation of the ARID3A locus is warranted. Limitations, reasons for caution: The main limitations of our study are the small sample size for a GWAS and the use of the transcription model trained on mostly European samples from the Genotype Tissue Expression (GTEx) project, which may have led to reduced power to detect genotype–expression associations. Our findings need to be validated in larger Polynesian cohorts. Wider implications of the findings: In addition to replicating one of the eight previously discovered AMH loci, we identified new suggestive associations. It is known that the inclusion of founder populations aids in the discovery of novel loci. These findings could enhance our understanding of AMH and AMH–related reproductive phenotypes (ovarian reserve, age at menopause, premature ovarian failure, and polycystic ovary syndrome) and help build a screening approach for women at risk for these phenotypes using genetically predicted AMH levels. Study funding/competing interest(s): This work was funded by NIH grants R01–HL093093 (PI: S.T.M.), R01–HL133040 (PI: R.L.M.), and T90–DE030853 (PI: C.S. Sfeir). Molecular data for the Trans–Omics in Precision Medicine (TOPMed) Program was supported by the National Heart, Lung and Blood Institute (NHLBI). The content is solely the responsibility of the authors and does not represent the official views of the National Institutes of Health.
@unpublished{liu_associations_2024,
title = {Associations between {DNA} methylation and cognitive function in early-stage hormone receptor-positive breast cancer patients},
copyright = {© 2024, Posted by Cold Spring Harbor Laboratory. The copyright holder for this pre-print is the author. All rights reserved. The material may not be redistributed, re-used or adapted without the author's permission.},
url = {https://www.medrxiv.org/content/10.1101/2024.11.17.24317299v1},
doi = {10.1101/2024.11.17.24317299},
language = {en},
urldate = {2024-11-19},
publisher = {medRxiv},
author = {Liu, Shuwei and Liu, Dongjing and Bender, Catherine M. and Erickson, Kirk I. and Sereika, Susan M. and Shaffer, John R. and Weeks, Daniel E. and Conley, Yvette P.},
month = nov,
year = {2024}
}
Background: Approximately one-third of breast cancer (BC) patients show poorer cognitive function (CF) before receiving adjuvant therapy compared with age-matched healthy controls. However, the biological mechanisms driving CF variation in the context of BC remain unclear. In this study, we aimed to identify genes and biological pathways associated with CF in postmenopausal women with early-stage hormone receptor-positive (HR+) BC using DNA methylation (DNAm) data, a dynamic regulator of gene activity. Methods: Epigenome-wide association studies (EWAS) and differentially methylated region analyses were performed for each CF phenotype (seven objective domains and one subjective phenotype) using DNAm data from whole blood samples (n=109) taken at time of enrollment. Post-EWAS functional analyses were performed to enhance the understanding of the CF-related cytosine-phosphate-guanine (CpG) sites. Results: When adjusting for age, verbal IQ scores, and global DNAm signature, cg10331779 near CTNND2 (p-value=9.65×10-9)) and cg25906741 in MLIP (p-value=2.01×10-8) were associated with processing speed and subjective CF, respectively, while regions in/near SLC6A11, PRKG1/CSTF2T, and FAM3B for processing speed, and regions in/near PI4KB and SGCE/PEG10 for mental flexibility were differentially methylated. In addition, beta-estradiol was identified as a common upstream regulator for all the CF phenotypes, suggesting an essential role of estrogen in explaining variation in CF of HR+ BC patients. Conclusions: In our EWAS of 8 CF phenotypes, we found two epigenome-wide significant signals, one at cg10331779 near CTNND2 with processing speed and the other at cg25906741 in MLIP with subjective CF. We also found three differentially methylated regions associated with processing speed and two associated with mental flexibility. These findings need replication in larger cohorts.
@unpublished{liu_associations_2025,
title = {Associations between {DNA} methylation and cognitive function in early-stage hormone receptor-positive breast cancer patients},
copyright = {© 2024, Posted by Cold Spring Harbor Laboratory. The copyright holder for this pre-print is the author. All rights reserved. The material may not be redistributed, re-used or adapted without the author's permission.},
url = {https://www.medrxiv.org/content/10.1101/2024.11.17.24317299v1},
doi = {10.1101/2024.11.17.24317299},
language = {en},
urldate = {2024-11-19},
journal = {medRxiv},
author = {Liu, Shuwei and Liu, Dongjing and Bender, Catherine M. and Erickson, Kirk I. and Sereika, Susan M. and Shaffer, John R. and Weeks, Daniel E. and Conley, Yvette P.},
month = nov,
year = {2024},
pages = {2024.11.17.24317299},
file = {Full Text PDF:/Users/dweeks/Zotero/storage/AG255CBT/Liu et al. - 2024 - Associations between DNA methylation and cognitive function in early-stage hormone receptor-positive.pdf:application/pdf}
}
Background: Approximately one-third of breast cancer (BC) patients show poorer cognitive function (CF) before receiving adjuvant therapy compared with age-matched healthy controls. However, the biological mechanisms driving CF variation in the context of BC remain unclear. In this study, we aimed to identify genes and biological pathways associated with CF in postmenopausal women with early-stage hormone receptor-positive (HR+) BC using DNA methylation (DNAm) data, a dynamic regulator of gene activity. Methods: Epigenome-wide association studies (EWAS) and differentially methylated region analyses were performed for each CF phenotype (seven objective domains and one subjective phenotype) using DNAm data from whole blood samples (n=109) taken at time of enrollment. Post-EWAS functional analyses were performed to enhance the understanding of the CF-related cytosine-phosphate-guanine (CpG) sites. Results: When adjusting for age, verbal IQ scores, and global DNAm signature, cg10331779 near CTNND2 (p-value=9.65×10-9)) and cg25906741 in MLIP (p-value=2.01×10-8) were associated with processing speed and subjective CF, respectively, while regions in/near SLC6A11, PRKG1/CSTF2T, and FAM3B for processing speed, and regions in/near PI4KB and SGCE/PEG10 for mental flexibility were differentially methylated. In addition, beta-estradiol was identified as a common upstream regulator for all the CF phenotypes, suggesting an essential role of estrogen in explaining variation in CF of HR+ BC patients. Conclusions: In our EWAS of 8 CF phenotypes, we found two epigenome-wide significant signals, one at cg10331779 near CTNND2 with processing speed and the other at cg25906741 in MLIP with subjective CF. We also found three differentially methylated regions associated with processing speed and two associated with mental flexibility. These findings need replication in larger cohorts.
@unpublished{carlson_improving_2023,
title = {Improving imputation quality in {Samoans} through the integration of population-specific sequences into existing reference panels},
doi = {10.1101/2023.10.31.23297835},
language = {eng},
journal = {medRxiv},
author = {Carlson, Jenna C. and Krishnan, Mohanraj and Liu, Shuwei and Anderson, Kevin J. and Zhang, Jerry Z. and Yapp, Toni-Ann J. and Chiyka, Elizabeth A. and Dikec, Devin A. and Cheng, Hong and Naseri, Take and Reupena, Muagututi'a Sefuiva and Viali, Satupa'itea and Deka, Ranjan and Hawley, Nicola L. and McGarvey, Stephen T. and Weeks, Daniel E. and Minster, Ryan L.},
month = oct,
year = {2023},
pmid = {37961708},
pmcid = {PMC10635250}
}
Genotype imputation is fundamental to association studies, and yet even gold standard panels like TOPMed are limited in the populations for which they yield good imputation. Specifically, Pacific Islanders are poorly represented in extant panels. To address this, we constructed an imputation reference panel using 1,285 Samoan individuals with whole-genome sequencing, combined with 1000 Genomes (1000G) samples, to create a reference panel that better represents Pacific Islander, specifically Samoan, genetic variation. We compared this panel to 1000G and TOPMed panels based on imputed variants using genotyping array data for 1,834 Samoan participants who were not part of the panels. The 1000G + 1285 Samoan panel yielded up to 2.25-2.76 times more well-imputed (r 2 ≥ 0.80) variants than TOPMed and 1000G. There was improved imputation accuracy across the minor allele frequency (MAF) spectrum, although it was more pronounced for variants with 0.01 ≤ MAF ≤ 0.05. Imputation accuracy (r 2 ) was greater for population-specific variants (high fixation index, F ST ) and those from larger haplotypes (high LD score). The gain in imputation accuracy over TOPMed was largest for small haplotypes (low LD score), reflecting the Samoan panel’s ability to capture population-specific variation not well tagged by other panels. We also augmented the 1000G reference panel with varying numbers of Samoan samples and found that panels with 48 or more Samoans included outperformed TOPMed for all variants with MAF ≥ 0.001. This study identifies variants with improved imputation using population-specific reference panels and provides a framework for constructing other population-specific reference panels.
@unpublished{shan_bayesrb_2022,
title = {{BayesRB}: a {Markov} chain {Monte} {Carlo}-based polygenic genetic risk score algorithm for dichotomous traits},
copyright = {© 2022, Posted by Cold Spring Harbor Laboratory. The copyright holder for this pre-print is the author. All rights reserved. The material may not be redistributed, re-used or adapted without the author's permission.},
shorttitle = {{BayesRB}},
url = {https://www.biorxiv.org/content/10.1101/2022.02.27.482193v1},
doi = {10.1101/2022.02.27.482193},
language = {en},
urldate = {2022-03-03},
journal = {bioRxiv},
author = {Shan, Ying and Weeks, Daniel E.},
month = mar,
year = {2022}
}
Identifying high-risk individuals with diseases through reliable prediction models guides screening and preventive treatment. Most complex diseases have a genetic basis influenced by multiple genes and so disease risk can be estimated using polygenic risk score (PRS) algorithms. Many PRS algorithms have been developed so far. Among them, BayesR shows good characteristics of unbiasedness, accuracy, sparseness, and robustness. It detects the associated SNPs, estimates the SNP effects, and makes prediction of disease risks based on all SNPs simultaneously. However, this method assumes that the phenotypes follow a Gaussian distribution, which cannot be met in case-control studies. Here, we made an extension of the BayesR method, called BayesRB, by adding auxiliary variables to the BayesR model. We explored the characteristics, efficacy, and accuracy of BayesRB when estimating SNP effects and predicting disease risks compared with three traditional algorithms under different conditions using both simulated data and real data from the Welcome Trust Case Control Consortium (WTCCC). For SNP effect estimation, BayesRB shows unbiasedness and sparseness for big and small effect SNPs, respectively. For disease risk prediction, BayesRB had the best performance among the methods. This study provides a theoretical basis for complex disease risk prediction and disease prevention.
@article{ray_allostatic_2026,
title = {Allostatic {Load} {Mediates} {Associations} {Between} {Race} and {Ethnicity} and {Hypertensive} {Disorders} of {Pregnancy}},
volume = {147},
issn = {0029-7844},
url = {http://doi.org/10.1097/AOG.0000000000006062},
doi = {10.1097/AOG.0000000000006062},
language = {en-US},
number = {2},
urldate = {2026-05-19},
journal = {Obstetrics \& Gynecology},
author = {Ray, Mitali and Heinsberg, Lacey W. and McNeil, Rebecca B. and Grobman, William A. and Lueth, Amir and Silver, Robert M. and Bairey Merz, C. Noel and Levine, Lisa D. and Yee, Lynn M. and Weeks, Daniel E. and Conley, Yvette P. and Catov, Janet M.},
month = feb,
year = {2026},
pmid = {40907023},
pmcid = {PMC12412905},
pages = {242},
file = {PDF:/Users/dweeks/Zotero/storage/VXHSF4Q4/Ray et al. - 2026 - Allostatic Load Mediates Associations Between Race and Ethnicity and Hypertensive Disorders of Pregn.pdf:application/pdf}
}
OBJECTIVE:
To evaluate whether chronic stress exposure, measured by allostatic load (a biological measure of chronic stress embodiment, including stressors exacerbated by structural inequities [eg, structural racism]) and patient-reported perceived stress in the first trimester of pregnancy, mediates the association between self-identified race and ethnicity and hypertensive disorders of pregnancy (HDP).
METHODS:
This was a secondary analysis of data from nuMoM2b (Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be), a large prospective cohort study. We evaluated self-identified race and ethnicity as an independent variable (non-Hispanic Black, Hispanic, Asian, non-Hispanic White), and our outcome of interest was HDP (ie, gestational hypertension, preeclampsia or eclampsia). Allostatic load was operationalized with regression- and count-based approaches. Perceived stress was collected with the Cohen perceived stress scale. We investigated allostatic load and perceived stress and used causal mediation analyses with a counterfactual approach to evaluate whether they mediated the association between self-identified race and ethnicity and HDP, adjusting for age and tobacco use. Mediation analyses were conducted for each minoritized racial and ethnic group compared with non-Hispanic White participants.
RESULTS:
The sample included 645 participants who developed HDP and 2,438 participants without HDP or other adverse pregnancy outcome. Allostatic load and perceived stress varied by race and ethnicity; HDP varied by allostatic load but not perceived stress. Allostatic load was a partial mediator exclusively in the comparison of non-Hispanic Black and non-Hispanic White participants (0.027, 95% CI, 0.013–0.040, P\textless.001; 28.9%). Perceived stress was not a significant mediator.
CONCLUSION:
First-trimester allostatic load mediated the association between self-identified race and ethnicity and HDP for non-Hispanic Black and non-Hispanic White participants. This mediation effect was not observed in other racial and ethnic comparisons. These results demonstrate a physiologic pathway through which racism may contribute to adverse pregnancy outcomes and suggest that interventions targeting allostatic load reduction could help address racial and ethnic disparities in HDP.
@article{heinsberg_differential_2025_1,
title = {Differential {DNA} {Methylation} of the {Brain}-{Derived} {Neurotrophic} {Factor} {Gene} is {Observed} after {Pediatric} {Traumatic} {Brain} {Injury} {Compared} with {Orthopedic} {Injury}},
issn = {0897-7151},
url = {https://doi.org/10.1177/08977151251400737},
doi = {10.1177/08977151251400737},
language = {EN},
urldate = {2026-01-16},
journal = {Journal of Neurotrauma},
publisher = {SAGE Publications},
author = {Heinsberg, Lacey W. and Kesbhat, Aboli and Petersen, Bailey and Kaseman, Lauren and Stec, Zachary and Anton, Nivinthiga and Kochanek, Patrick M. and Yeates, Keith Owen and Weeks, Daniel E. and Conley, Yvette P. and Treble-Barna, Amery},
month = dec,
year = {2025},
pmid = {41376515},
pmcid = {PMC12990021},
keywords = {BDNF, biomarkers, epigenetics, precision medicine},
pages = {08977151251400737},
file = {SAGE PDF Full Text:/Users/dweeks/Zotero/storage/5IC77JNF/Heinsberg et al. - 2025 - Differential DNA Methylation of the Brain-Derived Neurotrophic Factor Gene is Observed after Pediatr.pdf:application/pdf}
}
Pediatric traumatic brain injury (TBI) triggers biological changes that may differ from those observed in non-brain injuries. Brain-derived neurotrophic factor (BDNF) DNA methylation (DNAm) may serve as a novel, dynamic biomarker of the brain’s response and help identify TBI-specific epigenetic patterns relevant to later recovery. Therefore, the purpose of this study was to examine whether BDNF DNAm differed between children with TBI and those with orthopedic injury (OI, comparison group) acutely and over time. Data were derived from the Epigenetic Effects on TBI Recovery study, a prospective, longitudinal cohort study conducted at UPMC Children’s Hospital of Pittsburgh. Children aged 3–18 years hospitalized at a minimum of overnight for complicated mild-to-severe TBI or OI without head trauma were enrolled. Exclusion criteria included prior hospitalization for TBI, pre-existing neurological or psychiatric conditions, or sensory or motor impairments precluding study participation. Blood samples were collected during hospitalization (mean = 31.6 h post-injury) and at 6 (mean = 216.9 days) and 12 months (mean = 405.9 days) post-injury. The primary outcome variable was DNAm assessed via pyrosequencing at five quality-controlled CpG sites in the BDNF gene (chromosome 11, Genome Reference Consortium Human Build 38 positions 27722033, 27722036, 27722047, 27701612, and 27701614). The primary exposure was injury type (TBI vs. OI), with severity (measured via Glasgow Coma Scale [GCS]) examined as a secondary exposure within the TBI group. Primary covariates included age, sex, and race; secondary covariates included pubertal status, age-adjusted body mass index, non-head injury severity, socioeconomic status, and psychosocial adversity. The final analysis sample included n = 189 participants with TBI and n = 105 participants with OI. Participants were 66.3% male, 83.2% White, and had a mean age of 10.6 (±4.3) years at the time of enrollment. Acutely, children with TBI showed significantly lower DNAm at three of five sites (3.17–5.83% lower; p = 0.0044 to 6.48E-06) while controlling for age, sex, and race. One site remained significantly lower at 12 months (8.56% lower; p = 0.0045); no significant differences were observed at 6 months. Observed differences remained robust across sensitivity models adjusting for secondary covariates. GCS-measured TBI severity was not associated with DNAm at any time point. These findings suggest that BDNF DNAm differs between children with TBI and those with OI, particularly in the acute period. BDNF DNAm differences may reflect early biological responses that are specific to TBI.
@article{heinsberg_study_2025_1,
title = {Study protocol for the {Health} {Outcomes} in {Pregnancy} and {Early} {Childhood} ({HOPE}) {Study}: {A} mother-infant study in {American} {Samoa}},
volume = {20},
issn = {1932-6203},
shorttitle = {Study protocol for the {Health} {Outcomes} in {Pregnancy} and {Early} {Childhood} ({HOPE}) {Study}},
url = {https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0326644},
doi = {10.1371/journal.pone.0326644},
language = {en},
number = {9},
urldate = {2025-09-20},
journal = {PLOS ONE},
publisher = {Public Library of Science},
author = {Heinsberg, Lacey W. and Loia, Miracle and Tasele, Susie and Faasalele-Savusa, Kima and Carlson, Jenna C. and Anesi, Scott and Desobry, Katie and Yuchongco, Efren and Guevara, Brian Fortuno and Sesaga, Aigaeiva and Iloilo, Alice and Tofaeono, Va’atausili and Bryan, Kaylynn and Tauasosi-Posiulai, Tina and Kershaw, Erin E. and Conley, Yvette P. and Weeks, Daniel E. and Hawley, Nicola L. and Muasau-Howard, Bethel T.},
month = sep,
year = {2025},
keywords = {Genetics, DNA methylation, Blood, Infants, Socioeconomic aspects of health, Birth, Questionnaires},
pages = {e0326644},
file = {Full Text PDF:/Users/dweeks/Zotero/storage/H289A9IW/Heinsberg et al. - 2025 - Study protocol for the Health Outcomes in Pregnancy and Early Childhood (HOPE) Study A mother-infan.pdf:application/pdf}
}
Pacific Islanders, including those in American Samoa, face a disproportionately high burden of gestational diabetes mellitus (GDM) and related sequalae of metabolic conditions. The CREBRF rs373863828 genetic variant, which is uniquely common among Pacific Islanders, has been paradoxically associated with higher body mass index (BMI) but lower risk of type 2 diabetes. While emerging evidence suggests this variant may influence both maternal metabolic outcomes and infant growth, studies in pregnancy and early life remain limited. The purpose of this paper is to describe the protocol for a study designed to address these gaps. The Health Outcomes in Pregnancy and Early Childhood (HOPE) Study is an observational, longitudinal cohort study that will enroll up to 180 Samoan pregnant women and their infants (target n = 150 dyads completing study protocols) in American Samoa, with follow-up through six months postpartum/postnatal. The study includes questionnaires, anthropometric measurements, and biospecimen collection. Genetic and epigenetic analyses will examine associations between maternal and infant CREBRF rs373863828 genotype, gestational diabetes status, infant body size, and cord blood DNA methylation. The study is approved by the Institutional Review Boards at the University of Pittsburgh, Yale University, and the American Samoa Department of Health, as well as the Lyndon B. Johnson Tropical Medical Center (American Samoa) Research Oversight Committee. Findings will be disseminated through peer-reviewed publications, conference presentations, and community reports.
@article{erdogan_yildirim_genome_wide_2025,
title = {A {Genome}-{Wide} {Association} {Study} of {Anti}-{Müllerian} {Hormone} ({AMH}) {Levels} in {Samoan} {Women}},
volume = {16},
copyright = {http://creativecommons.org/licenses/by/3.0/},
issn = {2073-4425},
url = {https://www.mdpi.com/2073-4425/16/7/793},
doi = {10.3390/genes16070793},
language = {en},
number = {7},
urldate = {2025-07-02},
journal = {Genes},
publisher = {Multidisciplinary Digital Publishing Institute},
author = {Erdogan-Yildirim, Zeynep and Carlson, Jenna C. and Krishnan, Mohanraj and Zhang, Jerry Z. and Lambert-Messerlian, Geralyn and Naseri, Take and Viali, Satupaitea and Hawley, Nicola L. and McGarvey, Stephen T. and Weeks, Daniel E. and Minster, Ryan L.},
month = jul,
year = {2025},
note = {Number: 7},
keywords = {genome-wide association study, Pacific Island People, AMH, anti-Müllerian hormone, reproductive health},
pages = {793},
file = {Full Text PDF:/Users/dweeks/Zotero/storage/A3K8YFPP/Erdogan-Yildirim et al. - 2025 - A Genome-Wide Association Study of Anti-Müllerian Hormone (AMH) Levels in Samoan Women.pdf:application/pdf}
}
Background/Objectives: The anti-Müllerian hormone (AMH) is a key biomarker of the ovarian reserve, correlating with ovarian follicle count, fertility outcomes, and menopause timing. Understanding its genetic determinants has broad implications for female reproductive health. However, prior genome-wide association studies (GWASs) have focused exclusively on women of European ancestry, limiting insights into diverse populations. Methods: We conducted a GWAS to identify genetic loci associated with circulating AMH levels in a sample of 1185 Samoan women from two independently recruited samples. Using a Cox mixed-effects model we accounted for AMH levels below detectable limits and meta-analysed the summary statistics using a fixed-effect model. To prioritize variants and genes, we used FUMA and performed colocalization and transcriptome-wide association analysis (TWAS). We also assessed whether any previously reported loci were replicated in our GWAS. Results: We identified eleven genome-wide suggestive loci, with the strongest signal at ARID3A (19-946163-G-C; p = 2.32 × 10−7) and replicated rs10093345 near EIF4EBP1. The gene-based testing revealed ARID3A and R3HDM4 as significant genes. Integrating GWAS results with expression quantitative trait loci via TWAS, we detected seven transcriptome-wide significant genes. The lead variant in ARID3A is in high linkage disequilibrium (r2 = 0.79) with the known age-at-menopause variant 19-950694-G-A. Nearby KISS1R is a biologically plausible candidate gene that encodes the kisspeptin receptor, a regulator of ovarian follicle development linked to AMH levels. Conclusions: This study expands our understandings of AMH genetics by focusing on Samoan women. While these findings may be particularly relevant to Pacific Islanders, they hold broader implications for reproductive phenotypes such as the ovarian reserve, menopause timing, and polycystic ovary syndrome.
@article{heinsberg_multivariate_2025,
title = {Multivariate {Bayesian} {Analyses} in {Nursing} {Research}: {An} {Introductory} {Guide}},
volume = {27},
issn = {1552-4175},
shorttitle = {Multivariate {Bayesian} {Analyses} in {Nursing} {Research}},
doi = {10.1177/10998004241292644},
language = {eng},
number = {2},
journal = {Biological Research for Nursing},
author = {Heinsberg, Lacey W. and Davis, Tara S. and Maher, Dylan and Bender, Catherine M. and Conley, Yvette P. and Weeks, Daniel E.},
month = apr,
year = {2025},
pmid = {39413351},
keywords = {Bayes Theorem, bnlearn, data science, genomics, Humans, Multivariate Analysis, mvBIMBAM, nurse scientists, Nursing Research, omics, Research Design},
pages = {316--325}
}
In the era of precision health, nursing research has increasingly focused on the analysis of large, multidimensional data sets containing multiple correlated phenotypes (e.g., symptoms). This presents challenges for statistical analyses, especially in genetic association studies. For example, the inclusion of multiple symptoms within a single model can raise concerns about multicollinearity, while individual SNP-symptom analyses may obscure complex relationships. As such, many traditional statistical approaches often fall short in providing a comprehensive understanding of the complexity inherent in many nursing-focused research questions. Multivariate Bayesian approaches offer the unique advantage of allowing researchers to ask questions that are not feasible with traditional approaches. Specifically, these methods support the simultaneous exploration of multiple phenotypes, accounting for the underlying correlational structure between variables, and allow for formal incorporation of existing knowledge into the statistical model. By doing so, they may provide a more realistic view of statistical relationships within a biological system, potentially uncovering new insights into well-established and undiscovered connections, such as the probabilities of association and direct versus indirect effects. This valuable information can help us better understand our phenotypes of interest, leading to more effective nurse-led intervention and prevention programs. To illustrate these concepts, this paper includes an application section covering two specific multivariate Bayesian analysis software programs, bnlearn and mvBIMBAM, with an emphasis on interpretation and extension to nursing research. To complement the paper, we provide access to a detailed online tutorial, including executable R code and a synthetic data set, so the concepts can be more easily extended to other research questions.
@article{liu_dna_2025,
title = {{DNA} methylation associations with cognitive function in early-stage hormone receptor-positive breast cancer patients},
volume = {17},
issn = {1750-1911},
url = {https://doi.org/10.1080/17501911.2025.2542116},
doi = {10.1080/17501911.2025.2542116},
number = {13},
urldate = {2025-08-07},
journal = {Epigenomics},
author = {Liu, Shuwei and Liu, Dongjing and Bender, Catherine M. and Erickson, Kirk I. and Sereika, Susan M. and Shaffer, John R. and Weeks, Daniel E. and Conley, Yvette P.},
year = {2025},
keywords = {DNA methylation, epigenome-wide association study, Randomized Controlled Trials as Topic, Humans, Genome-Wide Association Study, Aged, Female, Middle Aged, Breast cancer, DNA Methylation, cognitive function, Breast Neoplasms, Cognition, Epigenesis, Genetic, Receptors, Estrogen, Receptors, Progesterone, estrogen},
pages = {879--889},
file = {PDF:/Users/dweeks/Zotero/storage/QIQ7YHAE/Liu et al. - 2025 - DNA methylation associations with cognitive function in early-stage hormone receptor-positive breast.pdf:application/pdf;Supplemental_Material-1:/Users/dweeks/Zotero/storage/XTNRLZZG/Supplemental_Material-1.pdf:application/pdf}
}
Approximately one-third of breast cancer (BC) patients show poorer cognitive function (CF). Using DNA methylation (DNAm) data, here we aimed to identify genes and biological pathways associated with CF in postmenopausal women with early-stage hormone receptor-positive (HR+) BC. Epigenome-wide association studies (EWAS) and differentially methylated region analyses were performed for each CF phenotype (seven objective domains and one subjective phenotype) using DNAm data from whole blood samples (n = 109) taken at the time of enrollment. When adjusting for age, verbal IQ scores, and global DNAm signature, cg10331779 near CTNND2 (p-value = 9.65×10−9) and cg25906741 in MLIP (p-value = 2.01×10−8) were associated with processing speed and subjective CF, respectively, while regions in/near SLC6A11, PRKG1/CSTF2T, and FAM3B for processing speed, and regions in/near PI4KB and SGCE/PEG10 for mental flexibility were differentially methylated. In addition, beta-estradiol was identified as a common upstream regulator for all the CF phenotypes, suggesting an essential role of estrogen in explaining variation in CF of HR+ BC patients. In our EWAS of 8 CF phenotypes, we found two epigenome-wide significant signals, one for processing speed and the other for subjective CF. We also found three differentially methylated regions associated with processing speed and two associated with mental flexibility. www.clinicaltrials.gov identifier is NCT02793921. Many breast cancer patients experience problems remembering things, thinking clearly, or paying attention. Our study looked at how a chemical change called ‘DNA methylation’ – which controls how genes work without actually changing the genetic code itself – is related to these thought problems in 109 women with early-stage breast cancer. We found that methylation levels near the CTNND2 gene were related to how quickly the brain processes information. Methylation levels near the MLIP gene were related to patients’ reports of their thought problems. We also discovered that beta-estradiol, a type of estrogen hormone, seemed to be a key player in all the thought problems we looked at. Our results give us new clues about why some breast cancer patients have thinking problems and point to other opportunities for future research.
@article{heinsberg_char_2024,
title = {Characterization of sleep apnea among a sample of adults from {Samoa}},
issn = {2667-3436},
url = {https://www.sciencedirect.com/science/article/pii/S2667343624000258},
doi = {10.1016/j.sleepe.2024.100099},
urldate = {2024-09-30},
journal = {Sleep Epidemiology},
author = {Heinsberg, Lacey W. and Pomer, Alysa and Cade, Brian E. and Carlson, Jenna C. and Naseri, Take and Reupena, Muagututia Sefuiva and Viali, Satupa'itea and Weeks, Daniel E. and McGarvey, Stephen T. and Redline, Susan and Hawley, Nicola L.},
month = sep,
year = {2024},
keywords = {Pacific Islander, Sleep apnea, sleep epidemiology, Sleep health},
pages = {100099}
}
Sleep apnea is a global public health concern, but little research has examined this issue in low- and middle-income countries, including Samoa. The purpose of this study was to examine the sample prevalence and characteristics of sleep apnea using a validated home sleep apnea device (WatchPAT, Itamar) and explore factors that may influence sleep health in the Samoan setting. This study used data collected through the Soifua Manuia (“Good Health”) study, which investigated the impact of the body mass index (BMI)-associated genetic variant rs373863828 in CREBRF on metabolic traits in Samoan adults (sampled to overrepresent the obesity-risk allele of interest). A total of 330 participants had sleep data available. Participants (53.3% female) had a mean (SD) age of 52.0 (9.9) years and BMI of 35.5 (7.5) kg/m2, and 36.3% of the sample had type 2 diabetes. Based on the 3% and 4% apnea hypopnea indices (AHI) and the 4% oxygen desaturation index (ODI), descriptive analyses revealed moderate to severe sleep apnea (defined as >=15 events/hr) in 54.9%, 31.5%, and 34.5% of the sample, respectively. Sleep apnea was more severe in men (e.g., AHI 3% ≥15 in 61.7% of men and 48.9% of women). Correction for non-representational sampling related to the CREBRF obesity-risk allele resulted in only slightly lower estimates. Multiple linear regression linked a higher number of events/hr to higher age, male sex, higher BMI, higher abdominal-hip circumference ratio, and geographic region of residence. Further research and an increased focus on equitable and affordable diagnosis and access to treatment are crucial to addressing sleep apnea in Samoa and globally.
@article{rivara_associations_2024,
title = {Associations between fasting glucose rate-of-change and the missense variant, rs373863828, in an adult {Samoan} cohort},
volume = {19},
issn = {1932-6203},
url = {https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0302643},
doi = {10.1371/journal.pone.0302643},
language = {en},
number = {6},
urldate = {2024-08-26},
journal = {PLOS ONE},
author = {Rivara, Anna C. and Russell, Emily M. and Carlson, Jenna C. and Pomer, Alysa and Naseri, Take and Reupena, Muagututia Seifuiva and Manna, Samantha L. and Viali, Satupaitea and Minster, Ryan L. and Weeks, Daniel E. and DeLany, James P. and Kershaw, Erin E. and McGarvey, Stephen T. and Hawley, Nicola L.},
month = jun,
year = {2024},
keywords = {Type 2 diabetes, Genome-wide association studies, Glucose, Adults, Diabetes mellitus, Variant genotypes, Physical activity, Census},
pages = {e0302643}
}
Background The A allele of rs373863828 in CREB3 regulatory factor is associated with high Body Mass Index, but lower odds of type 2 diabetes. These associations have been replicated elsewhere, but to date all studies have been cross-sectional. Our aims were (1) to describe the development of type 2 diabetes and change in fasting glucose between 2010 and 2018 among a longitudinal cohort of adult Samoans without type 2 diabetes or who were not using diabetes medications at baseline, and (2) to examine associations between fasting glucose rate-of-change (mmol/L per year) and the A allele of rs373863828. Methods We describe and test differences in fasting glucose, the development of type 2 diabetes, body mass index, age, smoking status, physical activity, urbanicity of residence, and household asset scores between 2010 and 2018 among a cohort of n = 401 adult Samoans, selected to have a ~2:2:1 ratio of GG:AG: AA rs373863828 genotypes. Multivariate linear regression was used to test whether fasting glucose rate-of-change was associated with rs373863828 genotype, and other baseline variables. Results By 2018, fasting glucose and BMI significantly increased among all genotype groups, and a substantial portion of the sample developed type 2 diabetes mellitus. The A allele was associated with a lower fasting glucose rate-of-change (β = −0.05 mmol/L/year per allele, p = 0.058 among women; β = −0.004 mmol/L/year per allele, p = 0.863 among men), after accounting for baseline variables. Mean fasting glucose and mean BMI increased over an eight-year period and a substantial number of individuals developed type 2 diabetes by 2018. However, fasting glucose rate-of-change, and type 2 diabetes development was lower among females with AG and AA genotypes. Conclusions Further research is needed to understand the effect of the A allele on fasting glucose and type 2 diabetes development. Based on our observations that other risk factors increased over time, we advocate for the continued promotion for diabetes prevention and treatment programming, and the reduction of modifiable risk factors, in this setting.
@article{heinsberg_characterization_2024,
title = {Characterization of per- and polyfluoroalkyl substances ({PFAS}) concentrations in a community-based sample of infants from {Samoa}},
volume = {353},
issn = {1879-1298},
doi = {10.1016/j.chemosphere.2024.141527},
language = {eng},
journal = {Chemosphere},
author = {Heinsberg, Lacey W. and Niu, Shan and Arslanian, Kendall J. and Chen, Ruiwen and Bedi, Megha and Unasa-Apelu, Folla and Fidow, Ulai T. and Soti-Ulberg, Christina and Conley, Yvette P. and Weeks, Daniel E. and Ng, Carla A. and Hawley, Nicola L.},
month = apr,
year = {2024},
pmid = {38401869},
pmcid = {PMC10997188},
keywords = {Humans, Male, Female, Cord blood, Samoa, Pacific Islands, Infant, Infant, Newborn, Alkanesulfonic Acids, Environmental Pollutants, Fluorocarbons, Dried blood spots, Environmental health, Exposure science, Infant exposure, Pacific Islander},
pages = {141527}
}
Per- and polyfluoroalkyl substances (PFAS) are persistent contaminants with documented harmful health effects. Despite increasing research, little attention has been given to studying PFAS contamination in low- and middle-income countries, including Samoa. Using data and biosamples collected through the Foafoaga o le Ola ("Beginning of Life") Study, which recruited a sample of mothers and infants from Samoa, we conducted an exploratory study to describe concentrations of 40 PFAS analytes in infant cord blood collected at birth (n = 66) and infant dried blood spots (DBS) collected at 4 months post-birth (n = 50). Of the 40 PFAS analytes tested, 19 were detected in cord blood, with 10 detected in \textgreater50% of samples (PFBA, PFPeA, PFOA, PFNA, PFDA, PFUnA, PFTrDA, PFHxS, PFOS, and 9Cl-PF3ONS); and 12 analytes were detected in DBS, with 3 detected in \textgreater50% of samples (PFBA, PFHxS, and PFOS). PFAS concentrations were generally lower than those reported in existing literature, with the exception of PFHxS, which was detected at higher concentrations. In cord blood, we noted suggestive (p \textless 0.05) or significant (p \textless 0.006) associations between higher PFHxS and male sex; higher PFPeA and residence in Northwest ’Upolu (NWU) compared to the Apia Urban Area (AUA); lower PFUnA and 9Cl-PF3ONS and greater socioeconomic resources; lower PFOA and higher parity; higher PFDA and higher maternal age; and lower PFUnA, PFTrDA, and 9Cl-PF3ONS and higher maternal BMI. In DBS, we found suggestive (p \textless 0.05) or significant (p \textless 0.025) associations between lower PFBA and residence in NWU versus AUA; lower PFBA and PFHxS and higher maternal age; and higher PFBA and higher maternal BMI. Finally, we observed associations between nutrition source at 4 months and DBS PFBA and PFHxS, with formula- or mixed-fed infants having higher concentrations compared to exclusively breastfed infants. This study represents the first characterization of PFAS contamination in Samoa. Additional work in larger samples is needed to identify potentially modifiable determinants of PFAS concentrations, information that is critical for informing environmental and health policy measures.
@article{moors_polynesian_2023,
title = {A {Polynesian}-specific missense {CETP} variant alters the lipid profile},
volume = {4},
issn = {2666-2477},
doi = {10.1016/j.xhgg.2023.100204},
language = {eng},
number = {3},
journal = {HGG advances},
author = {Moors, Jaye and Krishnan, Mohanraj and Sumpter, Nick and Takei, Riku and Bixley, Matt and Cadzow, Murray and Major, Tanya J. and Phipps-Green, Amanda and Topless, Ruth and Merriman, Marilyn and Rutledge, Malcolm and Morgan, Ben and Carlson, Jenna C. and Zhang, Jerry Z. and Russell, Emily M. and Sun, Guangyun and Cheng, Hong and Weeks, Daniel E. and Naseri, Take and Reupena, Muagututi'a Sefuiva and Viali, Satupa'itea and Tuitele, John and Hawley, Nicola L. and Deka, Ranjan and McGarvey, Stephen T. and de Zoysa, Janak and Murphy, Rinki and Dalbeth, Nicola and Stamp, Lisa and Taumoepeau, Mele and King, Frances and Wilcox, Phillip and Rapana, Nuku and McCormick, Sally and Minster, Ryan L. and Merriman, Tony R. and Leask, Megan},
month = jul,
year = {2023},
pmid = {37250494},
pmcid = {PMC10209881},
keywords = {Humans, Lipids, genetics, HDL-C, Māori, Pacific, Polymorphism, Genetic, Cholesterol, LDL, Cholesterol Ester Transfer Proteins, Cholesterol, HDL, Association analyses, CETP, equity, Maori People, Pacific Island People},
pages = {100204}
}
Identifying population-specific genetic variants associated with disease and disease-predisposing traits is important to provide insights into the genetic determinants of health and disease between populations, as well as furthering genomic justice. Various common pan-population polymorphisms at CETP associate with serum lipid profiles and cardiovascular disease. Here, sequencing of CETP identified a missense variant rs1597000001 (p.Pro177Leu) specific to Māori and Pacific people that associates with higher HDL-C and lower LDL-C levels. Each copy of the minor allele associated with higher HDL-C by 0.236 mmol/L and lower LDL-C by 0.133 mmol/L. The rs1597000001 effect on HDL-C is comparable with CETP Mendelian loss-of-function mutations that result in CETP deficiency, consistent with our data, which shows that rs1597000001 lowers CETP activity by 27.9%. This study highlights the potential of population-specific genetic analyses for improving equity in genomics and health outcomes for population groups underrepresented in genomic studies.
@article{treblebarna_brainderived_2023,
title = {Brain-derived neurotrophic factor ({BDNF}) epigenomic modifications and brain-related phenotypes in humans: {A} systematic review},
volume = {147},
issn = {1873-7528},
shorttitle = {Brain-derived neurotrophic factor ({BDNF}) epigenomic modifications and brain-related phenotypes in humans},
doi = {10.1016/j.neubiorev.2023.105078},
language = {eng},
journal = {Neuroscience and Biobehavioral Reviews},
author = {Treble-Barna, Amery and Heinsberg, Lacey W. and Stec, Zachary and Breazeale, Stephen and Davis, Tara S. and Kesbhat, Aboli A. and Chattopadhyay, Ansuman and VonVille, Helena M. and Ketchum, Andrea M. and Yeates, Keith Owen and Kochanek, Patrick M. and Weeks, Daniel E. and Conley, Yvette P.},
month = apr,
year = {2023},
pmid = {36764636},
pmcid = {PMC10164361},
keywords = {DNA methylation, Humans, Phenotype, DNA Methylation, Epigenomics, Brain, BDNF, Brain-Derived Neurotrophic Factor, Trauma, Histone modifications, Neurodevelopmental, Neurological, Non-coding RNA, Psychiatric},
pages = {105078}
}
Epigenomic modifications of the brain-derived neurotrophic factor (BDNF) gene have been postulated to underlie the pathogenesis of neurodevelopmental, psychiatric, and neurological conditions. This systematic review summarizes current evidence investigating the association of BDNF epigenomic modifications (DNA methylation, non-coding RNA, histone modifications) with brain-related phenotypes in humans. A novel contribution is our creation of an open access web-based application, the BDNF DNA Methylation Map, to interactively visualize specific positions of CpG sites investigated across all studies for which relevant data were available. Our literature search of four databases through September 27, 2021 returned 1701 articles, of which 153 met inclusion criteria. Our review revealed exceptional heterogeneity in methodological approaches, hindering the identification of clear patterns of robust and/or replicated results. We summarize key findings and provide recommendations for future epigenomic research. The existing literature appears to remain in its infancy and requires additional rigorous research to fulfill its potential to explain BDNF-linked risk for brain-related conditions and improve our understanding of the molecular mechanisms underlying their pathogenesis.
@article{heinsberg_dbgapcheckup_2023,
title = {{dbGaPCheckup}: pre-submission checks of {dbGaP}-formatted subject phenotype files},
volume = {24},
issn = {1471-2105},
shorttitle = {{dbGaPCheckup}},
doi = {10.1186/s12859-023-05200-8},
language = {eng},
number = {1},
journal = {BMC bioinformatics},
author = {Heinsberg, Lacey W. and Weeks, Daniel E.},
month = mar,
year = {2023},
pmid = {36869285},
pmcid = {PMC9985192},
keywords = {Reproducibility of Results, Phenotype, Databases, Factual, Information Dissemination, Biotechnology, Data distribution, Data quality control, Data sharing, Database architecture, Database of genotypes and phenotypes, Repository},
pages = {77}
}
BACKGROUND: Data archiving and distribution are essential to scientific rigor and reproducibility of research. The National Center for Biotechnology Information’s Database of Genotypes and Phenotypes (dbGaP) is a public repository for scientific data sharing. To support curation of thousands of complex data sets, dbGaP has detailed submission instructions that investigators must follow when archiving their data. RESULTS: We developed dbGaPCheckup, an R package which implements a series of check, awareness, reporting, and utility functions to support data integrity and proper formatting of the subject phenotype data set and data dictionary prior to dbGaP submission. For example, as a tool, dbGaPCheckup ensures that the data dictionary contains all fields required by dbGaP, and additional fields required by dbGaPCheckup; the number and names of variables match between the data set and data dictionary; there are no duplicated variable names or descriptions; observed data values are not more extreme than the logical minimum and maximum values stated in the data dictionary; and more. The package also includes functions that implement a series of minor/scalable fixes when errors are detected (e.g., a function to reorder the variables in the data dictionary to match the order listed in the data set). Finally, we also include reporting functions that produce graphical and textual descriptives of the data to further reduce the likelihood of data integrity issues. The dbGaPCheckup R package is available on CRAN ( https://CRAN.R-project.org/package=dbGaPCheckup ) and developed on GitHub ( https://github.com/lwheinsberg/dbGaPCheckup ). CONCLUSION: dbGaPCheckup is an innovative assistive and timesaving tool that fills an important gap for researchers by making dbGaP submission of large and complex data sets less error prone.
@article{krishnan_association_2023,
title = {Association of rs9939609 in {FTO} with {BMI} among {Polynesian} peoples living in {Aotearoa} {New} {Zealand} and other {Pacific} nations},
issn = {1435-232X},
doi = {10.1038/s10038-023-01141-5},
language = {eng},
journal = {Journal of Human Genetics},
author = {Krishnan, Mohanraj and Phipps-Green, Amanda and Russell, Emily M. and Major, Tanya J. and Cadzow, Murray and Stamp, Lisa K. and Dalbeth, Nicola and Hindmarsh, Jennie Harré and Qasim, Muhammad and Watson, Huti and Liu, Shuwei and Carlson, Jenna C. and Minster, Ryan L. and Hawley, Nicola L. and Naseri, Take and Reupena, Muagututi'a Sefuiva and Deka, Ranjan and McGarvey, Stephen T. and Merriman, Tony R. and Murphy, Rinki and Weeks, Daniel E.},
month = mar,
year = {2023},
pmid = {36864286},
pmcid = {PMC10313811}
}
The fat mass and obesity associated (FTO) locus consistently associates with higher body mass index (BMI) across diverse ancestral groups. However, previous small studies of people of Polynesian ancestries have failed to replicate the association. In this study, we used Bayesian meta-analysis to test rs9939609, the most replicated FTO variant, for association with BMI with a large sample (n = 6095) of Aotearoa New Zealanders of Polynesian (Māori and Pacific) ancestry and of Samoan people living in the Independent State of Samoa and in American Samoa. We did not observe statistically significant association within each separate Polynesian subgroup. Bayesian meta-analysis of the Aotearoa New Zealand Polynesian and Samoan samples resulted in a posterior mean effect size estimate of +0.21 kg/m2, with a 95% credible interval [+0.03 kg/m2, +0.39 kg/m2]. While the Bayes Factor (BF) of 0.77 weakly favors the null, the BF = 1.4 Bayesian support interval is [+0.04, +0.20]. These results suggest that rs9939609 in FTO may have a similar effect on mean BMI in people of Polynesian ancestries as previously observed in other ancestral groups.
@article{zhang_multivariate_2023,
title = {Multivariate analysis of a missense variant in {CREBRF} reveals associations with measures of adiposity in people of {Polynesian} ancestries},
volume = {47},
issn = {0741-0395, 1098-2272},
url = {https://onlinelibrary.wiley.com/doi/10.1002/gepi.22508},
doi = {10.1002/gepi.22508},
language = {en},
number = {1},
urldate = {2022-11-10},
journal = {Genetic Epidemiology},
author = {Zhang, Jerry Z. and Heinsberg, Lacey W. and Krishnan, Mohanraj and Hawley, Nicola L. and Major, Tanya J. and Carlson, Jenna C. and Harré Hindmarsh, Jennie and Watson, Huti and Qasim, Muhammad and Stamp, Lisa K. and Dalbeth, Nicola and Murphy, Rinki and Sun, Guangyun and Cheng, Hong and Naseri, Take and Reupena, Muagututi'a S. and Kershaw, Erin E. and Deka, Ranjan and McGarvey, Stephen T. and Minster, Ryan L. and Merriman, Tony R. and Weeks, Daniel E.},
month = feb,
year = {2023},
pmcid = {PMC9892232},
pmid = {36352773},
keywords = {mvBIMBAM},
pages = {105--118}
}
The minor allele of rs373863828, a missense variant in CREB3 Regulatory Factor, is associated with several cardiometabolic phenotypes in Polynesian peoples. To better understand the variant, we tested the association of rs373863828 with a panel of correlated phenotypes (body mass index [BMI], weight, height, HDL cholesterol, triglycerides, and total cholesterol) using multivariate Bayesian association and network analyses in a Samoa cohort (n = 1632), Aotearoa New Zealand cohort (n = 1419), and combined cohort (n = 2976). An expanded set of phenotypes (adding estimated fat and fat-free mass, abdominal circumference, hip circumference, and abdominal-hip ratio) was tested in the Samoa cohort (n = 1496). In the Samoa cohort, we observed significant associations (log10 Bayes Factor [BF] ≥ 5.0) between rs373863828 and the overall phenotype panel (8.81), weight (8.30), and BMI (6.42). In the Aotearoa New Zealand cohort, we observed suggestive associations (1.5 < log10 BF < 5) between rs373863828 and the overall phenotype panel (4.60), weight (3.27), and BMI (1.80). In the combined cohort, we observed concordant signals with larger log10 BFs. In the Samoa-specific expanded phenotype analyses, we also observed significant associations between rs373863828 and fat mass (5.65), abdominal circumference (5.34), and hip circumference (5.09). Bayesian networks provided evidence for a direct association of rs373863828 with weight and indirect associations with height and BMI.
@article{carlson_stopgain_2023,
title = {A stop-gain variant in {BTNL9} is associated with atherogenic lipid profiles},
volume = {4},
issn = {26662477},
url = {https://linkinghub.elsevier.com/retrieve/pii/S2666247722000720},
doi = {10.1016/j.xhgg.2022.100155},
language = {en},
number = {1},
urldate = {2023-02-02},
journal = {Human Genetics and Genomics Advances},
author = {Carlson, Jenna C. and Krishnan, Mohanraj and Rosenthal, Samantha L. and Russell, Emily M. and Zhang, Jerry Z. and Hawley, Nicola L. and Moors, Jaye and Cheng, Hong and Dalbeth, Nicola and de Zoysa, Janak R. and Watson, Huti and Qasim, Muhammad and Murphy, Rinki and Naseri, Take and Reupena, Muagututi’a Sefuiva and Viali, Satupa‘itea and Stamp, Lisa K. and Tuitele, John and Kershaw, Erin E. and Deka, Ranjan and McGarvey, Stephen T. and Merriman, Tony R. and Weeks, Daniel E. and Minster, Ryan L.},
month = jan,
year = {2023},
pmcid = {PMC9630829},
pmid = {36340932},
pages = {100155}
}
Current understanding of lipid genetics has come mainly from studies in European-ancestry populations; limited effort has focused on Polynesian populations, whose unique population history and high prevalence of dyslipidemia may provide insight into the biological foundations of variation in lipid levels. Here, we performed an association study to fine map a suggestive association on 5q35 with high-density lipoprotein cholesterol (HDL-C) seen in Micronesian and Polynesian populations. Fine-mapping analyses in a cohort of 2,851 Samoan adults highlighted an association between a stop-gain variant (rs200884524; c.652C>T, p.R218∗; posterior probability = 0.9987) in BTNL9 and both lower HDL-C and greater triglycerides (TGs). Meta-analysis across this and several other cohorts of Polynesian ancestry from Samoa, American Samoa, and Aotearoa New Zealand confirmed the presence of this association (βHDL-C = -1.60 mg/dL, p HDL-C = 7.63 × 10-10; βTG = 12.00 mg/dL, p TG = 3.82 × 10-7). While this variant appears to be Polynesian specific, there is also evidence of association from other multiancestry analyses in this region. This work provides evidence of a previously unexplored contributor to the genetic architecture of lipid levels and underscores the importance of genetic analyses in understudied populations.
@article{liu_longitudinal_2023,
title = {A longitudinal epigenome-wide association study of preeclamptic and normotensive pregnancy},
volume = {3},
issn = {2730-7034},
url = {https://epicom.biomedcentral.com/articles/10.1186/s43682-022-00014-w},
doi = {10.1186/s43682-022-00014-w},
language = {en},
number = {1},
urldate = {2023-03-21},
journal = {Epigenetics Communications},
author = {Liu, Shuwei and Fu, Haoyi and Ray, Mitali and Heinsberg, Lacey W. and Conley, Yvette P. and Anderson, Cindy M. and Hubel, Carl A. and Roberts, James M. and Jeyabalan, Arun and Weeks, Daniel E. and Schmella, Mandy J.},
month = jan,
year = {2023},
pmcid = {PMC10101051},
pmid = {37063698},
pages = {1}
}
Background
While preeclampsia (PE) is a leading cause of pregnancy-related morbidity/mortality, its underlying mechanisms are not fully understood. DNA methylation (DNAm) is a dynamic regulator of gene expression that may offer insight into PE pathophysiology and/or serve as a biomarker (e.g., risk, subtype, a therapeutic response). This study’s purpose was to evaluate for differences in blood-based DNAm across all trimesters between individuals eventually diagnosed with PE (cases) and individuals who remained normotensive throughout pregnancy, did not develop proteinuria, and birthed a normally grown infant (controls).
Results
In the discovery phase, longitudinal, genome-wide DNAm data were generated across three trimesters of pregnancy in 56 participants (n=28 cases, n=28 controls) individually matched on self-identified race, pre-pregnancy body mass index, smoking, and gestational age at sample collection. An epigenome-wide association study (EWAS) was conducted, using surrogate variable analysis to account for unwanted sources of variation. No CpGs met the genome-wide significance p value threshold of 9×10^-8, but 16 CpGs (trimester 1: 5; trimester 2: 1; trimester 3: 10) met the suggestive significance threshold of 1×10^-5. DNAm data were also evaluated for differentially methylated regions (DMRs) by PE status. Three DMRs in each trimester were significant after Bonferonni-adjustment. Since only third-trimester samples were available from an independent replication sample (n=64 cases,n=50 controls), the top suggestive hits from trimester 3 (cg16155413 and cg21882990 associated with TRAF3IP2-AS1/TRAF3IP2 genes, which also made up the top DMR) were carried forward for replication. During replication, DNAm data were also generated for validation purposes from discovery phase third trimester samples. While significant associations between DNAm and PE status were observed at both sites in the validation sample, no associations between DNAm and PE status were observed in the independent replication sample.
Conclusions
The discovery phase findings for cg16155413/cg21882990 (TRAF3IP2-AS1/TRAF3IP2) were validated with a new platform but were not replicated in an independent sample. Given the differences in participant characteristics between the discovery and replication samples, we cannot rule out important signals for these CpGs. Additional research is warranted for cg16155413/cg21882990, as well as top hits in trimesters 1–2 and significant DMRs that were not examined in the replication phase.
@article{heinsberg_correlates_2022,
title = {Correlates of daytime sleepiness and insomnia among adults in {Samoa}},
volume = {2},
issn = {26673436},
url = {https://linkinghub.elsevier.com/retrieve/pii/S2667343622000233},
doi = {10.1016/j.sleepe.2022.100042},
language = {en},
urldate = {2022-09-21},
journal = {Sleep Epidemiology},
author = {Heinsberg, Lacey W. and Carlson, Jenna C. and Pomer, Alysa and Cade, Brian E. and Naseri, Take and Reupena, Muagututia Sefuiva and Weeks, Daniel E. and McGarvey, Stephen T. and Redline, Susan and Hawley, Nicola L.},
month = dec,
year = {2022},
pmcid = {PMC9635619},
pmid = {36338277},
pages = {100042}
}
Objective: To describe daytime sleepiness and insomnia among adults in Samoa and identify modifiable factors associated with these measures.
Design/setting: Cross-sectional analysis of data from the Soifua Manuia ("Good Health") study (n = 519, 55.1% female); Upolu island, Samoa.
Methods: Daytime sleepiness and insomnia were assessed with the Epworth Sleepiness Scale (ESS) and the Women’s Health Initiative Insomnia Rating Scale (WHIIRS), respectively. Detailed physical, sociodemographic, and behavioral factors were collected. Sleep measures were characterized using multiple linear regression with backwards elimination and a bootstrap stability investigation.
Results: Excessive daytime sleepiness (ESS>10) and insomnia (WHIIRS>10) were reported by 20% and 6.3% of the sample, respectively. ESS scores were higher in individuals reporting more physical activity (Estimate=1.88; 95% CI=1.12 to 2.75), higher material wealth (0.18; 0.09 to 0.28), and asthma (2.85; 1.25 to 4.51). ESS scores were lower in individuals residing in periurban versus urban regions (-1.43; -2.39 to -0.41), reporting no work versus day shift work (-2.26; -3.07 to -1.41), and reporting greater perceived stress (-0.14; -0.23 to -0.06). WHIIRS scores were lower in individuals reporting "other" shift work (split/irregular/on-call/rotating) versus day shift work (-1.96; -2.89 to -1.14) and those who perceived their village’s wealth to be poor/average versus wealthy (-0.94; -1.50 to -0.34).
Conclusions: Participants had a generally higher prevalence of excessive daytime sleepiness, but lower prevalence of insomnia, compared with individuals from high-income countries. Factors associated with sleep health differed compared with prior studies, emphasizing potential cultural/environmental differences and the need for targeted interventions to improve sleep health in this setting.
@article{hawley_protective_2022,
title = {The protective effect of rs373863828 on type 2 diabetes does not operate through a body composition pathway in adult {Samoans}},
volume = {30},
issn = {1930-739X},
doi = {10.1002/oby.23559},
language = {eng},
number = {12},
journal = {Obesity (Silver Spring, Md.)},
author = {Hawley, Nicola L. and Duckham, Rachel L. and Carlson, Jenna C. and Naseri, Take and Reupena, Muagututia Sefuiva and Lameko, Viali and Pomer, Alysa and Wetzel, Abigail and Selu, Melania and Lupematisila, Vaimoana and Unasa, Folla and Vesi, Lupesina and Fatu, Tracy and Unasa, Seipepa and Faasalele-Savusa, Kima and Rivara, Anna C. and Russell, Emily and Delany, James P. and Viali, Satupaitea and Kershaw, Erin E. and Minster, Ryan L. and Weeks, Daniel E. and McGarvey, Stephen T.},
month = dec,
year = {2022},
pmid = {36284436},
keywords = {Humans, Male, Adult, Female, Body Mass Index, Obesity, Glucose, Diabetes Mellitus, Type 2, Body Composition, Native Hawaiian or Other Pacific Islander, Absorptiometry, Photon},
pages = {2468--2476}
}
OBJECTIVE: The aim of this study was to understand whether the paradoxical association of missense variant rs373863828 in CREB3 regulatory factor (CREBRF) with higher BMI but lower odds of diabetes is explained by either metabolically favorable body fat distribution or greater fat-free mass. METHODS: This study explored the association of the minor allele with dual-energy x-ray absorptiometry-derived body composition in n = 421 Samoans and used path analysis to examine the mediating role of fat and fat-free mass on the relationship between rs373863828 and fasting glucose. RESULTS: Among females, the rs373863828 minor A allele was associated with greater BMI. There was no association of genotype with percent body fat, visceral adiposity, or fat distribution in either sex. In both females and males, lean mass was greater with each A allele: 2.16 kg/copy (p = 0.0001) and 1.73 kg/copy (p = 0.02), respectively. Path analysis showed a direct negative effect of rs373863828 genotype on fasting glucose (p = 0.004) consistent with previous findings, but also an indirect positive effect on fasting glucose operating through fat-free mass (p = 0.027). CONCLUSIONS: The protective effect of rs373863828 in CREBRF, common among Pacific Islanders, on type 2 diabetes does not operate through body composition. Rather, the variant’s effects on body size/composition and fasting glucose likely operate via different, tissue-specific mechanisms.
@article{heinsberg_validity_2022,
title = {Validity of anthropometric equation-based estimators of fat mass in {Samoan} adults},
issn = {1520-6300},
doi = {10.1002/ajhb.23838},
language = {eng},
journal = {American Journal of Human Biology: The Official Journal of the Human Biology Council},
author = {Heinsberg, Lacey W. and Hawley, Nicola L. and Duckham, Rachel L. and Pomer, Alysa and Rivara, Anna C. and Naseri, Take and Reupena, Muagututi'a Sefuiva and Weeks, Daniel E. and McGarvey, Stephen T. and Minster, Ryan L.},
month = nov,
year = {2022},
pmid = {36428275},
pmcid = {PMC10023273},
pages = {e23838}
}
INTRODUCTION: In 1999, a set of highly accurate Polynesian-specific equations to estimate adult body fat from non-invasive field measures of age, sex, height, and weight (Equation 1), age, sex, height, weight, and bioelectrical impedance analysis (BIA) resistance (Equation 2), and age, sex, height, weight, and the sum of two skinfold thicknesses (Equation 3) were published. The purpose of this study was to evaluate the performance of the equation-based estimators in a sample of Samoan adults recruited 20 years later between 2017 and 2019. METHODS: Age, sex, height, weight, BIA resistance, skinfold thickness, and fat mass as measured using dual energy x-ray absorptiometry (DXA) were available for 432 Samoan adults (mean age 50.9 years, 56% female) seen in 2017/2019. We compared equation-derived fat mass and DXA-derived fat mass using scatterplots and Pearson correlation coefficients. We then updated the equation coefficient estimates in a training set (2/3 of the sample) and evaluated the performance of the updated equations in a testing set (the remaining 1/3 of the sample). RESULTS: Equation-derived fat mass was strongly correlated with DXA-derived fat mass for Equation (1) (r2 = 0.95, n = 432), Equation (2) (r2 = 0.97, n = 425), and Equation (3) (r2 = 0.95, n = 426). Updating the equation coefficient estimates resulted in mostly similar coefficients and nearly identical testing set performance for Equation (1) (r2 = 0.96, n = 153), Equation (2) (r2 = 0.98, n = 150), and Equation (3) (r2 = 0.96, n = 150). CONCLUSIONS: The Polynesian-specific body fat estimation equations remained stable despite changing social and environmental factors and marked increase in obesity prevalence in Samoa.
@article{blobner_rare_2022,
title = {Rare {Variants} in {Genes} {Encoding} {Subunits} of the {Epithelial} {Na}+ {Channel} {Are} {Associated} {With} {Blood} {Pressure} and {Kidney} {Function}},
volume = {79},
issn = {1524-4563},
doi = {10.1161/HYPERTENSIONAHA.121.18513},
language = {eng},
number = {11},
journal = {Hypertension},
author = {Blobner, Brandon M. and Kirabo, Annet and Kashlan, Ossama B. and Sheng, Shaohu and Arnett, Donna K. and Becker, Lewis C. and Boerwinkle, Eric and Carlson, Jenna C. and Gao, Yan and Gibbs, Richard A. and He, Jiang and Irvin, Marguerite R. and Kardia, Sharon L. R. and Kelly, Tanika N. and Kooperberg, Charles and McGarvey, Stephen T. and Menon, Vipin K. and Montasser, May E. and Naseri, Take and Redline, Susan and Reiner, Alexander P. and Reupena, Muagututi'a S. and Smith, Jennifer A. and Sun, Xiao and Vaidya, Dhananjay and Viaud-Martinez, Karine A. and Weeks, Daniel E. and Yanek, Lisa R. and Zhu, Xiaofeng and {NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium*} and Minster, Ryan L. and Kleyman, Thomas R.},
month = nov,
year = {2022},
pmid = {36193739},
pmcid = {PMC9669116},
keywords = {arterial pressure, blood pressure, ENaC (epithelial Na+ channel), glomerular filtration rate, kidney, stroke},
pages = {2573--2582}
}
BACKGROUND: The epithelial Na+ channel (ENaC) is intrinsically linked to fluid volume homeostasis and blood pressure. Specific rare mutations in SCNN1A, SCNN1B, and SCNN1G, genes encoding the α, β, and γ subunits of ENaC, respectively, are associated with extreme blood pressure phenotypes. No associations between blood pressure and SCNN1D, which encodes the δ subunit of ENaC, have been reported. A small number of sequence variants in ENaC subunits have been reported to affect functional transport in vitro or blood pressure. The effects of the vast majority of rare and low-frequency ENaC variants on blood pressure are not known. METHODS: We explored the association of low frequency and rare variants in the genes encoding ENaC subunits, with systolic blood pressure, diastolic blood pressure, mean arterial pressure, and pulse pressure. Using whole-genome sequencing data from 14 studies participating in the Trans-Omics in Precision Medicine Whole-Genome Sequencing Program, and sequence kernel association tests. RESULTS: We found that variants in SCNN1A and SCNN1B were associated with diastolic blood pressure and mean arterial pressure (P\textless0.00625). Although SCNN1D is poorly expressed in human kidney tissue, SCNN1D variants were associated with systolic blood pressure, diastolic blood pressure, mean arterial pressure, and pulse pressure (P\textless0.00625). ENaC variants in 2 of the 4 subunits (SCNN1B and SCNN1D) were also associated with estimated glomerular filtration rate (P\textless0.00625), but not with stroke. CONCLUSIONS: Our results suggest that variants in extrarenal ENaCs, in addition to ENaCs expressed in kidneys, influence blood pressure and kidney function.
@article{heinsberg_post_2022,
title = {Post hoc power is not informative},
volume = {46},
issn = {1098-2272},
url = {http://onlinelibrary.wiley.com/doi/abs/10.1002/gepi.22464},
doi = {10.1002/gepi.22464},
language = {en},
number = {7},
urldate = {2022-06-01},
journal = {Genetic Epidemiology},
author = {Heinsberg, Lacey W. and Weeks, Daniel E.},
month = oct,
year = {2022},
pmcid = {PMC9452450},
pmid = {35642557},
keywords = {exploratory data analysis, achieved power, observed power, postexperiment power, retrospective power},
pages = {390--394}
}
Post hoc power estimates are often requested by reviewers and/or performed by researchers after a study has been conducted. The purpose of this commentary is to provide a heuristic explanation of why post hoc power should not be used. To illustrate our point, we provide a detailed simulation study of two essentially identical research experiments hypothetically conducted in parallel at two separate universities. The simulation demonstrates that post hoc power calculations are misleading and simply not informative for data interpretation. As such, we encourage authors and peer-reviewers to avoid using or requesting post hoc power calculations.
@article{heinsberg_advancing_2022,
title = {Advancing {Nursing} {Research} {Through} {Interactive} {Data} {Visualization} {With} {R} {Shiny}},
issn = {1099-8004, 1552-4175},
url = {http://journals.sagepub.com/doi/10.1177/10998004221121109},
doi = {10.1177/10998004221121109},
language = {en},
urldate = {2022-08-27},
journal = {Biological Research For Nursing},
author = {Heinsberg, Lacey W. and Koleck, Theresa A. and Ray, Mitali and Weeks, Daniel E. and Conley, Yvette P.},
month = aug,
year = {2022},
pages = {109980042211211},
file = {Heinsberg et al. - 2022 - Advancing Nursing Research Through Interactive Dat.pdf:/Users/dweeks/Zotero/storage/P5EE7N85/Heinsberg et al. - 2022 - Advancing Nursing Research Through Interactive Dat.pdf:application/pdf}
}
Scientific data visualization is a critical aspect of fully understanding data patterns and trends. To date, the majority of data visualizations in nursing research – as with other biomedical fields – have been static. The availability of electronic scientific journal articles (which are quickly becoming the norm) has created new opportunities for dynamic and interactive data visualization which carry added cognitive benefits and support the ability to understand data more fully. Therefore, here we highlight the benefits of R, an open-source programming language, for scientific data visualization, with a specific focus on creating dynamic, interactive figures using the R shiny package. For R users, we have included a tutorial with example code to create three increasingly complex shiny applications. For individuals more interested in understanding the potential of R shiny as an innovative tool to interact with research data, we have included links to online versions of the examples that do not require any programming or R experience. We believe that widespread adoption of dynamic and interactive scientific data visualization will further support nurse scientists’ higher-level mission of advancing our understanding of health and wellness of individuals and communities.
@article{fu_missense_2022,
title = {The missense variant, rs373863828, in {CREBRF} plays a role in longitudinal changes in body mass index in {Samoans}},
issn = {1871-403X},
url = {https://www.sciencedirect.com/science/article/pii/S1871403X22000370},
doi = {10.1016/j.orcp.2022.04.004},
language = {en},
urldate = {2022-05-20},
journal = {Obesity Research \& Clinical Practice},
author = {Fu, Haoyi and Hawley, Nicola L. and Carlson, Jenna C. and Russell, Emily M. and Pomer, Alysa and Cheng, Hong and Naseri, Take and Reupena, Muagututi‘a Sefuiva and Deka, Ranjan and Choy, Courtney C. and McGarvey, Stephen T. and Minster, Ryan L. and Weeks, Daniel E.},
month = may,
year = {2022},
pmcid = {PMC9373717},
pmid = {35606300},
keywords = {CREBRF, Body mass index, Longitudinal changes, Samoans},
file = {Fu et al. - 2022 - The missense variant, rs373863828, in CREBRF plays.pdf:/Users/dweeks/Zotero/storage/Z4DUWJ43/Fu et al. - 2022 - The missense variant, rs373863828, in CREBRF plays.pdf:application/pdf}
}
Objective A missense variant, rs373863828, in CREBRF is associated with obesity in Polynesians. We investigate whether rs373863828 and other factors are associated with body mass index (BMI) rate-of-change between 2010 and 2017–19 in Samoans. Methods We used sex-stratified models to test whether BMI rate-of-change was associated with rs373863828, baseline BMI, age, residence, physical activity, and household asset score in a cohort study of 480 Samoan adults measured in both 2010 (mean age 43.8 years) and 2017–19. Results Mean BMI increased from 32.1 to 33.5 kg/m2 in males (n = 220, p = 1.3 ×10−8) and from 35.9 to 37.8 kg/m2 in females (n = 260, p = 1.2 ×10−13). In females, the A allele was associated with a higher rate-of-change (0.150 kg/m2/year/allele, p = 1.7 ×10−4). Across 10-year age groups, mean BMI rate-of-change was lower in older participants. The BMI rate of change differed by genotype: it was, in females with AA genotype, approximately half that seen in GG and AG participants. In females lower baseline household asset scores were associated with a higher rate-of-change (p = 0.002). Conclusions In Samoans, the minor A allele of rs373863828 is associated with an increased rate-of-change in BMI in females. On average, BMI of females with the AA genotype increased 0.30 kg/m2/year more than of those with the GG genotype.
@article{bastard_lossfunction_2022,
title = {A loss-of-function {IFNAR1} allele in {Polynesia} underlies severe viral diseases in homozygotes},
volume = {219},
issn = {0022-1007},
url = {https://doi.org/10.1084/jem.20220028},
doi = {10.1084/jem.20220028},
number = {6},
urldate = {2022-04-21},
journal = {Journal of Experimental Medicine},
author = {Bastard, Paul and Hsiao, Kuang-Chih and Zhang, Qian and Choin, Jeremy and Best, Emma and Chen, Jie and Gervais, Adrian and Bizien, Lucy and Materna, Marie and Harmant, Christine and Roux, Maguelonne and Hawley, Nicola L. and Weeks, Daniel E. and McGarvey, Stephen T. and Sandoval, Karla and Barberena-Jonas, Carmina and Quinto-Cortés, Consuelo D. and Hagelberg, Erika and Mentzer, Alexander J. and Robson, Kathryn and Coulibaly, Boubacar and Seeleuthner, Yoann and Bigio, Benedetta and Li, Zhi and Uzé, Gilles and Pellegrini, Sandra and Lorenzo, Lazaro and Sbihi, Zineb and Latour, Sylvain and Besnard, Marianne and Adam de Beaumais, Tiphaine and Jacqz Aigrain, Evelyne and Béziat, Vivien and Deka, Ranjan and Esera Tulifau, Litara and Viali, Satupa‘itea and Reupena, Muagututi‘a Sefuiva and Naseri, Take and McNaughton, Peter and Sarkozy, Vanessa and Peake, Jane and Blincoe, Annaliesse and Primhak, Sarah and Stables, Simon and Gibson, Kate and Woon, See-Tarn and Drake, Kylie Marie and Hill, Adrian V.S. and Chan, Cheng-Yee and King, Richard and Ameratunga, Rohan and Teiti, Iotefa and Aubry, Maite and Cao-Lormeau, Van-Mai and Tangye, Stuart G. and Zhang, Shen-Ying and Jouanguy, Emmanuelle and Gray, Paul and Abel, Laurent and Moreno-Estrada, Andrés and Minster, Ryan L. and Quintana-Murci, Lluis and Wood, Andrew C. and Casanova, Jean-Laurent},
month = apr,
year = {2022},
pmcid = {PMC9026234},
pmid = {35442418},
pages = {e20220028},
file = {Bastard et al. - 2022 - A loss-of-function IFNAR1 allele in Polynesia unde.pdf:/Users/dweeks/Zotero/storage/CV9Q8NED/Bastard et al. - 2022 - A loss-of-function IFNAR1 allele in Polynesia unde.pdf:application/pdf}
}
Globally, autosomal recessive IFNAR1 deficiency is a rare inborn error of immunity underlying susceptibility to live attenuated vaccine and wild-type viruses. We report seven children from five unrelated kindreds of western Polynesian ancestry who suffered from severe viral diseases. All the patients are homozygous for the same nonsense IFNAR1 variant (p.Glu386*). This allele encodes a truncated protein that is absent from the cell surface and is loss-of-function. The fibroblasts of the patients do not respond to type I IFNs (IFN-α2, IFN-ω, or IFN-β). Remarkably, this IFNAR1 variant has a minor allele frequency >1% in Samoa and is also observed in the Cook, Society, Marquesas, and Austral islands, as well as Fiji, whereas it is extremely rare or absent in the other populations tested, including those of the Pacific region. Inherited IFNAR1 deficiency should be considered in individuals of Polynesian ancestry with severe viral illnesses.
@article{russell_crebrf_2022,
title = {{CREBRF} missense variant rs373863828 has both direct and indirect effects on type 2 diabetes and fasting glucose in {Polynesian} peoples living in {Samoa} and {Aotearoa} {New} {Zealand}},
volume = {10},
issn = {2052-4897},
doi = {10.1136/bmjdrc-2021-002275},
language = {eng},
number = {1},
journal = {BMJ open diabetes research \& care},
author = {Russell, Emily M. and Carlson, Jenna C. and Krishnan, Mohanraj and Hawley, Nicola L. and Sun, Guangyun and Cheng, Hong and Naseri, Take and Reupena, Muagututi'a Sefuiva and Viali, Satupa'itea and Tuitele, John and Major, Tanya J. and Miljkovic, Iva and Merriman, Tony R. and Deka, Ranjan and Weeks, Daniel E. and McGarvey, Stephen T. and Minster, Ryan L.},
month = feb,
year = {2022},
pmid = {35144939},
pmcid = {PMC8845200},
keywords = {genetics, obesity, BMI, glucose},
pages = {e002275}
}
INTRODUCTION: The minor allele of a missense variant, rs373863828, in CREBRF is associated with higher body mass index (BMI), lower fasting glucose, and lower odds of type 2 diabetes. rs373863828 is common in Pacific Island populations (minor allele frequency (MAF) 0.096-0.259) but rare in non-Pacific Island populations (MAF \textless0.001). We examined the cross-sectional associations between BMI and rs373863828 in type 2 diabetes and fasting glucose with a large sample of adults of Polynesian ancestries from Samoa, American Samoa, and Aotearoa New Zealand, and estimated the direct and indirect (via BMI) effects of rs373863828 on type 2 diabetes and fasting glucose. RESEARCH DESIGN AND METHODS: We regressed type 2 diabetes and fasting glucose on BMI and rs373863828 stratified by obesity, regressed type 2 diabetes and fasting glucose on BMI stratified by rs373863828 genotype, and assessed the effects of rs373863828 on type 2 diabetes and fasting glucose with path analysis. The regression analyses were completed separately in four samples that were recruited during different time periods between 1990 and 2010 and then the results were meta-analyzed. All samples were pooled for the path analysis. RESULTS: Association of BMI with type 2 diabetes and fasting glucose may be greater in those without obesity (OR=7.77, p=0.015 and β=0.213, p=9.53×10-5, respectively) than in those with obesity (OR=5.01, p=1.12×10-9 and β=0.162, p=5.63×10-6, respectively). We did not observe evidence of differences in the association of BMI with type 2 diabetes or fasting glucose by genotype. In the path analysis, the minor allele has direct negative (lower odds of type 2 diabetes and fasting glucose) and indirect positive (higher odds of type 2 diabetes and fasting glucose) effects on type 2 diabetes risk and fasting glucose, with the indirect effects mediated through a direct positive effect of rs373863828 on BMI. CONCLUSIONS: There may be a stronger effect of BMI on fasting glucose in Polynesian individuals without obesity than in those with obesity. Carrying the rs373863828 minor allele does not decouple higher BMI from higher odds of type 2 diabetes.
@article{liu_decreased_2022,
title = {Decreased {DNA} {Methylation} of {RGMA} is {Associated} with {Intracranial} {Hypertension} {After} {Severe} {Traumatic} {Brain} {Injury}: {An} {Exploratory} {Epigenome}-{Wide} {Association} {Study}},
issn = {1556-0961},
shorttitle = {Decreased {DNA} {Methylation} of {RGMA} is {Associated} with {Intracranial} {Hypertension} {After} {Severe} {Traumatic} {Brain} {Injury}},
doi = {10.1007/s12028-021-01424-9},
language = {eng},
journal = {Neurocritical Care},
author = {Liu, Dongjing and Zusman, Benjamin E. and Shaffer, John R. and Li, Yunqi and Arockiaraj, Annie I. and Liu, Shuwei and Weeks, Daniel E. and Desai, Shashvat M. and Kochanek, Patrick M. and Puccio, Ava M. and Okonkwo, David O. and Conley, Yvette P. and Jha, Ruchira M.},
month = jan,
year = {2022},
pmid = {35028889},
keywords = {DNA methylation, Epigenome-wide association study (EWAS), Intracranial hypertension, Repulsive guidance molecule A (RGMA), Traumatic brain injury},
file = {Liu et al. - 2022 - Decreased DNA Methylation of RGMA is Associated wi.pdf:/Users/dweeks/Zotero/storage/CK9LD7E3/Liu et al. - 2022 - Decreased DNA Methylation of RGMA is Associated wi.pdf:application/pdf}
}
BACKGROUND: Cerebral edema and intracranial hypertension are major contributors to unfavorable prognosis in traumatic brain injury (TBI). Local epigenetic changes, particularly in DNA methylation, may influence gene expression and thus host response/secondary injury after TBI. It remains unknown whether DNA methylation in the central nervous system is associated with cerebral edema severity or intracranial hypertension post TBI. We sought to identify epigenome-wide DNA methylation patterns associated with these forms of secondary injury after TBI. METHODS: We obtained genome-wide DNA methylation profiles of DNA extracted from ventricular cerebrospinal fluid samples at three different postinjury time points from a prospective cohort of patients with severe TBI (n = 89 patients, 254 samples). Cerebral edema and intracranial pressure (ICP) measures were clustered to generate composite end points of cerebral edema and ICP severity. We performed an unbiased epigenome-wide association study (EWAS) to test associations between DNA methylation at 419,895 cytosine-phosphate-guanine (CpG) sites and cerebral edema/ICP severity categories. Given inflated p values, we conducted permutation tests for top CpG sites to filter out potential false discoveries. RESULTS: Our data-driven hierarchical clustering across six cerebral edema and ICP measures identified two groups differing significantly in ICP based on the EWAS-identified CpG site cg22111818 in RGMA (Repulsive guidance molecule A, permutation p = 4.20 × 10-8). At 3-4 days post TBI, patients with severe intracranial hypertension had significantly lower levels of methylation at cg22111818. CONCLUSIONS: We report a novel potential relationship between intracranial hypertension after TBI and an acute, nonsustained reduction in DNA methylation at cg22111818 in the RGMA gene. To our knowledge, this is the largest EWAS in severe TBI. Our findings are further strengthened by previous findings that RGMA modulates axonal repair in other central nervous system disorders, but a role in intracranial hypertension or TBI has not been previously identified. Additional work is warranted to validate and extend these findings, including assessment of its possible role in risk stratification, identification of novel druggable targets, and ultimately our ability to personalize therapy in TBI.
@article{heinsberg_iron_2021,
title = {Iron homeostasis pathway {DNA} methylation trajectories reveal a role for {STEAP3} metalloreductase in patient outcomes after aneurysmal subarachnoid hemorrhage},
volume = {1},
copyright = {All rights reserved},
issn = {2730-7034},
url = {https://epicom.biomedcentral.com/articles/10.1186/s43682-021-00003-5},
doi = {10.1186/s43682-021-00003-5},
language = {en},
number = {1},
urldate = {2021-12-20},
journal = {Epigenetics Communications},
author = {Heinsberg, Lacey W. and Weeks, Daniel E. and Alexander, Sheila A. and Minster, Ryan L. and Sherwood, Paula R. and Poloyac, Samuel M. and Deslouches, Sandra and Crago, Elizabeth A. and Conley, Yvette P.},
month = dec,
year = {2021},
pages = {4},
file = {Heinsberg et al. - 2021 - Iron homeostasis pathway DNA methylation trajector.pdf:/Users/dweeks/Zotero/storage/688P5FXX/Heinsberg et al. - 2021 - Iron homeostasis pathway DNA methylation trajector.pdf:application/pdf}
}
Abstract
Background
Following aneurysmal subarachnoid hemorrhage (aSAH), the brain is susceptible to ferroptosis, a type of iron-dependent cell death. Therapeutic intervention targeting the iron homeostasis pathway shows promise for mitigating ferroptosis and improving recovery in animal models, but little work has been conducted in humans. DNA methylation (DNAm) plays a key role in gene expression and brain function, plasticity, and injury recovery, making it a potentially useful biomarker of outcomes or therapeutic target for intervention. Therefore, in this longitudinal, observational study, we examined the relationships between trajectories of DNAm in candidate genes related to iron homeostasis and acute (cerebral vasospasm and delayed cerebral ischemia) and long-term (Glasgow Outcome Scale [GOS, unfavorable = 1–3] and death) patient outcomes after aSAH.
Results
Longitudinal, genome-wide DNAm data were generated from DNA extracted from post-aSAH cerebrospinal fluid (
n
= 260 participants). DNAm trajectories of 637 CpG sites in 36 candidate genes related to iron homeostasis were characterized over 13 days post-aSAH using group-based trajectory analysis, an unsupervised clustering method. Significant associations were identified between inferred DNAm trajectory groups at several CpG sites and acute and long-term outcomes. Among our results, cg25713625 in the STEAP3 metalloreductase gene (
STEAP3
) stood out. Specifically, in comparing the highest cg25713625 DNAm trajectory group with the lowest, we observed significant associations (i.e., based on
p
-values less than an empirical significance threshold) with unfavorable GOS at 3 and 12 months (
OR
= 11.7,
p
= 0.0006 and
OR
= 15.6,
p
= 0.0018, respectively) and death at 3 and 12 months (
OR
= 19.1,
p
= 0.0093 and
OR
= 12.8,
p
= 0.0041, respectively). These results were replicated in an independent sample (
n
= 100 participants) observing significant associations with GOS at 3 and 12 months (
OR
= 8.2,
p
= 0.001 and
OR
= 6.3,
p
= 0.0.0047, respectively) and death at 3 months (
OR
= 2.3,
p
= 0.008) and a suggestive association (i.e.,
p
-value \textless 0.05 not meeting an empirical significance threshold) with death at 12 months (
OR
= 2.0,
p
= 0.0272). In both samples, an additive effect of the DNAm trajectory group was observed as the percentage of participants with unfavorable long-term outcomes increased substantially with higher DNAm trajectory groups.
Conclusion
Our results support a role for DNAm of cg25713625/
STEAP3
in recovery following aSAH. Additional research is needed to further explore the role of DNAm of cg25713625/
STEAP3
as a biomarker of unfavorable outcomes, or therapeutic target to improve outcomes, to translate these findings clinically.
@article{liu_angpt1_2021,
title = {{ANGPT1} methylation and delayed cerebral ischemia in aneurysmal subarachnoid hemorrhage patients},
volume = {1},
copyright = {All rights reserved},
issn = {2730-7034},
url = {https://epicom.biomedcentral.com/articles/10.1186/s43682-021-00001-7},
doi = {10.1186/s43682-021-00001-7},
language = {en},
number = {1},
urldate = {2021-12-21},
journal = {Epigenetics Communications},
author = {Liu, Dongjing and Arockiaraj, Annie I. and Shaffer, John R. and Poloyac, Samuel M. and Sherwood, Paula R. and Alexander, Sheila A. and Crago, Elizabeth A. and Weeks, Daniel E. and Conley, Yvette P.},
month = dec,
year = {2021},
pages = {3},
file = {Liu et al. - 2021 - ANGPT1 methylation and delayed cerebral ischemia i.pdf:/Users/dweeks/Zotero/storage/HY8PPTSC/Liu et al. - 2021 - ANGPT1 methylation and delayed cerebral ischemia i.pdf:application/pdf}
}
Abstract
Background
Delayed cerebral ischemia (DCI) is a common secondary complication and an important cause of disability and mortality among patients who survive aneurysmal subarachnoid hemorrhage (aSAH). Knowledge on DCI pathogenesis, risk factors, and biomarkers are essential for early detection and improved prognosis. To investigate the role of DNA methylation in DCI risk, we conducted an epigenome-wide association study (EWAS) in 68 patients followed up to 1 year after the initial aneurysm rupture. Blood samples were collected within 48 h post hemorrhage and used for DNA methylation profiling at ~ 450k CpG sites. A separate cohort of 175 patients was sequenced for the top CpG sites from the discovery analysis for a replication of the EWAS findings.
Results
EWAS did not identify any epigenome-wide significant CpGs. The top signal, cg18031596, was annotated to
ANGPT1
, a gene with critical functions in angiogenesis after vascular injury. Post hoc power calculations indicated a well-powered discovery analysis for cg18031596. Analysis of the replication cohort showed that four out of the five CpG sites sequenced at the
ANGPT1
locus passed a Bonferroni-adjusted significance threshold. In a pooled analysis of the entire sample, three out of five yielded a significant
p
-value, and the top association signal (
p
-value = 0.004) was seen for a CpG that was not originally measured in the discovery EWAS. However, four
ANGPT1
CpG sites had an opposite effect direction in the replication analysis compared to the discovery EWAS, marking a failure of replication. We carefully examined this observed flip in directions and propose several possible explanations in addition to that it was a random chance that
ANGPT1
ranked at the top in the discovery EWAS.
Conclusions
We failed to demonstrate a significant and consistent effect of
ANGPT1
methylation in DCI risk in two cohorts. Though the replication attempt to weaken the overall support of this gene, given its relevant function and top rank of significance in the EWAS, our results call for future studies of larger aSAH cohorts to determine its relevance for the occurrence of DCI.
@article{ray_exploratory_2021,
title = {An exploratory study of white blood cell proportions across preeclamptic and normotensive pregnancy by self-identified race in individuals with overweight or obesity},
volume = {40},
issn = {1064-1955},
url = {https://doi.org/10.1080/10641955.2021.1987453},
doi = {10.1080/10641955.2021.1987453},
number = {4},
urldate = {2022-11-04},
journal = {Hypertension in Pregnancy},
author = {Ray, Mitali and Heinsberg, Lacey W. and Conley, Yvette P. and Roberts, James M. and Jeyabalan, Arun and Hubel, Carl A. and Weeks, Daniel E. and Schmella, Mandy J.},
month = oct,
year = {2021},
pmid = {34697971},
pmcid = {PMC8740522},
keywords = {DNA methylation, Preeclampsia, hypertension in pregnancy, WBC count, white blood cell},
pages = {312--321},
file = {Ray et al. - 2021 - An exploratory study of white blood cell proportio.pdf:/Users/dweeks/Zotero/storage/87ZYS9EG/Ray et al. - 2021 - An exploratory study of white blood cell proportio.pdf:application/pdf}
}
Objective: Examine white blood cell (WBC) proportions across preeclamptic (n = 28 cases) and normotensive (n = 28 controls) pregnancy in individuals with overweight/obesity.Methods: WBC proportions were inferred from genome-wide DNA methylation data and compared by case/control status and self-identified race.Results: In Trimester 1, ean B cell proportions were suggestively lower in cases in the overall sample and significantly lower in White participants but not in Black participants. More significant WBC proportion changes were observed across normotensive than preeclamptic pregnancy.Conclusions: These findings in a small sample demonstrate need for additional studies investigating the relationship between self-identified race and WBCs in pregnancy.
@article{yan_chit_2021,
title = {{CHIT}: an allele-specific method for testing the association between molecular quantitative traits and phenotype-genotype interaction},
copyright = {All rights reserved},
issn = {1367-4811},
shorttitle = {{CHIT}},
doi = {10.1093/bioinformatics/btab554},
language = {eng},
journal = {Bioinformatics (Oxford, England)},
author = {Yan, Qi and Forno, Erick and Celedón, Juan C. and Chen, Wei and Weeks, Daniel E.},
month = jul,
year = {2021},
pmid = {34323937},
pmcid = {PMC8711119},
pages = {btab554}
}
MOTIVATION: Allele specific differences in molecular traits can be obtained from next generation sequencing data and could potentially improve testing power, but such information is usually overlooked in association studies. Furthermore, the variation of molecular quantitative traits (e.g., gene expression) could result from the interaction effect of genotypes and phenotypes, but it is challenging to identify such interaction signals in complex disease studies in humans due to small genetic effect sizes and/or small sample sizes. RESULTS: We develop a novel statistical method, the combined haplotype interaction test (CHIT), which tests for association between molecular quantitative traits and phenotype-genotype interactions by modeling the total read counts and allele-specific reads in a target region. CHIT can be used as a supplementary analysis to the regular linear interaction regression. In our simulations, CHIT obtains non-inflated type I error rates, and it has higher power than a standard interaction quantitative trait locus approach based on linear regression models. Finally, we illustrate CHIT by testing associations between gene expression obtained by RNA-seq and the interaction of SNPs and atopy status from a study of childhood asthma in Puerto Ricans, and results demonstrate that CHIT could be more powerful than a standard linear interaction expression quantitative trait loci (eQTL) approach. AVAILABILITY: The CHIT algorithm has been implemented in Python. The source code and documentation are available and can be downloaded from https://github.com/QiYanPitt/CHIT. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Daniel E. Weeks, Ph.D.
Department of Human Genetics
School of Public Health
University of Pittsburgh
Public Health 3119
130 DeSoto Street
Pittsburgh, PA 15261
© 2026 Daniel E. Weeks