A large-scale genome-wide study of gene-sleep duration interactions for blood pressure in 811,405 individuals from diverse populations. - Nagarajan, Pavithra; Winkler, Thomas W; Bentley, Amy R; Miller, Clint L; Kraja, Aldi T; Schwander, Karen; Lee, Songmi; Wang, Wenyi; Brown, Michael R; Morrison, John L; Giri, Ayush; O'Connell, Jeffrey R; et al. (Mol Psychiatry, 2025)
Although both short and long sleep duration are associated with elevated hypertension risk, our understanding of their interplay with biological pathways governing blood pressure remains limited. To address this, we carried out genome-wide cross-population gene-by-short-sleep and long-sleep duration interaction analyses for three blood pressure traits (systolic, diastolic, and pulse pressure) in 811,405 individuals from diverse population groups. We discovered 22 novel gene-sleep duration interaction loci for blood pressure, mapped to 23 genes. Investigating these genes' functional implications shed light on neurological, thyroidal, bone metabolism, and hematopoietic pathways that necessitate future investigation for blood pressure management that caters to sleep health lifestyle. Non-overlap between short sleep (12) and long sleep (10) interactions underscores the plausible nature of distinct influences of both sleep duration extremes in cardiovascular health. Several of our loci are specific towards a particular population background or sex, emphasizing the importance of addressing heterogeneity entangled in gene-environment interactions, when considering precision medicine design approaches for blood pressure management.

Meta-analysis of genome-wide associations and polygenic risk prediction for atrial fibrillation in more than 180,000 cases. - Roselli, Carolina; Surakka, Ida; Olesen, Morten S; Sveinbjornsson, Gardar; Marston, Nicholas A; Choi, Seung Hoan; Holm, Hilma; Chaffin, Mark; Gudbjartsson, Daniel; Hill, Matthew C; Aegisdottir, Hildur; Albert, Christine M; et al. (Nat Genet, 2025)
Atrial fibrillation (AF) is the most common heart rhythm abnormality and is a leading cause of heart failure and stroke. This large-scale meta-analysis of genome-wide association studies increased the power to detect single-nucleotide variant associations and found more than 350 AF-associated genetic loci. We identified candidate genes related to muscle contractility, cardiac muscle development and cell-cell communication at 139 loci. Furthermore, we assayed chromatin accessibility using assay for transposase-accessible chromatin with sequencing and histone H3 lysine 4 trimethylation in stem cell-derived atrial cardiomyocytes. We observed a marked increase in chromatin accessibility for our sentinel variants and prioritized genes in atrial cardiomyocytes. Finally, a polygenic risk score (PRS) based on our updated effect estimates improved AF risk prediction compared to the CHARGE-AF clinical risk score and a previously reported PRS for AF. The doubling of known risk loci will facilitate a greater understanding of the pathways underlying AF.
Keywords: Atrial Fibrillation; Chromatin; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Male; Multifactorial Inheritance; Myocytes, Cardiac; Polymorphism, Single Nucleotide; Risk Factors

Methylome-wide association analyses of lipids and modifying effects of behavioral factors in diverse race and ethnicity participants. - Hu, Yao; Haessler, Jeff; Lundin, Jessica I; Darst, Burcu F; Whitsel, Eric A; Grove, Megan; Guan, Weihua; Xia, Rui; Szeto, Mindy; Raffield, Laura M; Ratliff, Scott; Wang, Yuxuan; et al. (Clin Epigenetics, 2025)
Circulating lipid concentrations are clinically associated with cardiometabolic diseases. The phenotypic variance explained by identified genetic variants remains limited, highlighting the importance of searching for additional factors beyond genetic sequence variants. DNA methylation has been linked to lipid concentrations in previous studies, although most of the studies harbored moderate sample sizes and exhibited underrepresentation of non-European ancestry populations. In addition, knowledge of nongenetic factors on lipid profiles is extremely limited. In the Population Architecture Using Genomics and Epidemiology (PAGE) Study, we performed methylome-wide association analysis on 9,561 participants from diverse race and ethnicity backgrounds for HDL-c, LDL-c, TC, and TG levels, and also tested interactions between smoking or alcohol intake and methylation in their association with lipid levels. We identified novel CpG sites at 16 loci (P < 1.18E-7) with successful replication on 3,215 participants. One additional novel locus was identified in the self-reported White participants (P = 4.66E-8). Although no additional CpG sites were identified in the genome-wide interaction analysis, 13 reported CpG sites showed significant heterogeneous association across smoking or alcohol intake strata. By mapping novel and reported CpG sites to genes, we identified enriched pathways directly linked to lipid metabolism as well as ones spanning various biological functions. These findings provide new insights into the regulation of lipid concentrations.
Keywords: Adult; Aged; Alcohol Drinking; CpG Islands; DNA Methylation; Ethnicity; Female; Genome-Wide Association Study; Humans; Lipids; Male; Middle Aged; Racial Groups; Smoking; White People

Plasma Proteomic Assessment of Calcific Aortic Valve Disease in Older Adults. - Bortnick, Anna E; Austin, Thomas R; Hamerton, Emily; Gudmundsdottir, Valborg; Emilsson, Valur; Jennings, Lori L; Gudnason, Vilmundur; Owens, David S; Massera, Daniele; Dufresne, Line; Yang, Ta-Yu; Engert, James C; et al. (J Am Heart Assoc, 2025)
BACKGROUND: Calcific aortic valve disease (CAVD), and ensuing severe aortic stenosis (AS), is the foremost valvular disorder of aging, yet preventive therapies are lacking. A better understanding of the molecular underpinnings of aortic valve calcification (AVC) is necessary to develop pharmacologic interventions. METHODS AND RESULTS: We undertook large-scale plasma proteomics in a cohort study of adults ≥65 years old, the CHS (Cardiovascular Health Study), to identify individual proteins associated with echocardiographic AVC and incident moderate/severe AS. Proteomics measurements were performed with the aptamer-based SomaLogic platform of ~5000 proteins. Significant proteins were validated in a second cohort, the AGES-RS (Age, Gene/Environment Susceptibility-Reykjavik Study), which assessed AVC and AS by computed tomography. The potential causal associations of replicated proteins were tested in 2-sample Mendelian randomization using identified cis protein quantitative trait loci in consortia having computed tomography-quantified AVC or AS as outcomes. Six proteins showed Bonferroni-corrected significant relationships with AVC in CHS. Three of these, CXCL-12 (C-X-C chemokine ligand 12), KLKB1 (kallikrein), and leptin, replicated in AGES-RS, of which the former 2 are novel. Only 1 protein, CXCL6, which showed a near-significant association with AS in the replication cohort, was significantly (positively) associated with incident AS. Mendelian randomization analysis was conducted for KLKB1, CXCL12, and CXCL6, which supported a causal relationship for higher KLKB1 with lower AVC (beta=-0.25, =0.009). CONCLUSIONS: This study of older adults newly identified and largely replicated associations of 3 circulating proteins with calcific aortic valve disease, of which the relationship of plasma KLKB1 may have a causal basis. Additional investigation is necessary to determine if KLKB1 could be harnessed for calcific aortic valve disease therapeutics.
Keywords: Age Factors; Aged; Aged, 80 and over; Aortic Valve; Aortic Valve Stenosis; Biomarkers; Blood Proteins; Calcinosis; Chemokine CXCL12; Echocardiography; Female; Humans; Male; Mendelian Randomization Analysis; Proteomics; Severity of Illness Index

Plasma TAR DNA-binding protein 43 (TDP-43) levels in a population-based cohort of older adults: The cardiovascular health study. - Fohner, Alison E; Sitlani, Colleen M; Jayadev, Suman; Bis, Joshua C; Trittschuh, Emily H; Lopez, Oscar L; Tracy, Russel P; Psaty, Bruce M; Longstreth, W T; Seshadri, Sudha (J Alzheimers Dis, 2025)
Brain deposition of transactive response DNA-binding protein 43 (TDP-43) is a feature of neurodegenerative syndromes. We evaluated TDP-43 plasma concentrations in 1058 participants in the Cardiovascular Health Study (CHS), a population-based longitudinal cohort. The cohort was 38% male, 11% Black, had a mean age 75 years, and 261 people developed dementia over a mean of 5.5 years of follow up. Median TDP-43 levels were 211.0 pg/mL (IQR: 134.0-341.0 pg/mL). TDP-43 levels were not associated with cross-sectional or longitudinal change in cognitive scores, with plasma AD biomarkers, with brain MRI volumes, with incident dementia, or with demographic characteristics.

Polygenic scores for obstructive sleep apnoea reveal pathways contributing to cardiovascular disease. - Kurniansyah, Nuzulul; Strausz, Satu J; Chittoor, Geetha; Gupta, Shreyash; Justice, Anne E; Hrytsenko, Yana; Keenan, Brendan T; Cade, Brian E; Spitzer, Brian W; Wang, Heming; Huffman, Jennifer; Moll, Matthew R; et al. (EBioMedicine, 2025)
BACKGROUND: Obstructive sleep apnoea (OSA) is a common chronic condition, with obesity its strongest risk factor. Polygenic scores (PGSs) summarise the genetic liability to phenotype and can provide insights into relationships between phenotypes. Recently, large datasets that include genetic data and OSA status became available, providing an opportunity to utilise PGS approaches to study the genetic relationship between OSA and other phenotypes, while differentiating OSA-specific from obesity-specific genetic factors. METHODS: Using race/ethnic diverse samples from over 1.2 million individuals from the Million Veteran Program, FinnGen, TOPMed, All of Us (AoU), Geisinger's MyCode, MGB Biobank, and the Human Phenotype Project, we developed and assessed PGSs for OSA, both without (BMIunadjOSA-PGS) and with adjustment for the genetic contributions of BMI (BMIadjOSA-PGS). FINDINGS: Adjusted odds ratios (ORs) for OSA per 1 standard deviation of the PGSs ranged from 1.38 to 2.75. The associations of BMIadjOSA- and BMIunadjOSA-PGSs with CVD outcomes in AoU shared both common and distinct patterns. Only BMIunadjOSA-PGS was associated with type 2 diabetes, heart failure, and coronary artery disease, while both BMIadjOSA- and BMIunadjOSA-PGSs were associated with hypertension and stroke. Sex stratified analyses revealed that BMIadjOSA-PGS association with hypertension was driven by females (OR = 1.1, p-value = 0.002, OR = 1.01 p-value = 0.2 in males). OSA PGSs were also associated with body fat measures with some sex-specific associations. INTERPRETATION: Distinct components of OSA genetic risk are related and independent of obesity. Sex-specific associations with body fat distribution measures may explain differing OSA risks and associations with cardiometabolic morbidities between sexes. FUNDING: R01AG080598.
Keywords: Aged; Body Mass Index; Cardiovascular Diseases; Female; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Multifactorial Inheritance; Obesity; Odds Ratio; Phenotype; Polymorphism, Single Nucleotide; Risk Factors; Sleep Apnea, Obstructive

Rare damaging CCR2 variants are associated with lower lifetime cardiovascular risk. - Georgakis, Marios K; Malik, Rainer; Bounkari, Omar El; Hasbani, Natalie R; Li, Jiang; Huffman, Jennifer E; Shakt, Gabrielle; Tack, Reinier W P; Kimball, Tamara N; Asare, Yaw; Morrison, Alanna C; Tsao, Noah L; et al. (Genome Med, 2025)
BACKGROUND: Previous work has shown a role of CCL2, a key chemokine governing monocyte trafficking, in atherosclerosis. However, it remains unknown whether targeting CCR2, the cognate receptor of CCL2, provides protection against human atherosclerotic cardiovascular disease. METHODS: Computationally predicted damaging or loss-of-function (REVEL > 0.5) variants within CCR2 were detected in whole-exome-sequencing data from 454,775 UK Biobank participants and tested for association with cardiovascular endpoints in gene-burden tests. Given the key role of CCR2 in monocyte mobilization, variants associated with lower monocyte count were prioritized for experimental validation. The response to CCL2 of human cells transfected with these variants was tested in migration and cAMP assays. Validated damaging variants were tested for association with cardiovascular endpoints, atherosclerosis burden, and vascular risk factors. Significant associations were replicated in six independent datasets (n = 1,062,595). RESULTS: Carriers of 45 predicted damaging or loss-of-function CCR2 variants (n = 787 individuals) were at lower risk of myocardial infarction and coronary artery disease. One of these variants (M249K, n = 585, 0.15% of European ancestry individuals) was associated with lower monocyte count and with both decreased downstream signaling and chemoattraction in response to CCL2. While M249K showed no association with conventional vascular risk factors, it was consistently associated with a lower risk of myocardial infarction (odds ratio [OR]: 0.66, 95% confidence interval [CI]: 0.54-0.81, p = 6.1 × 10) and coronary artery disease (OR: 0.74, 95%CI: 0.63-0.87, p = 2.9 × 10) in the UK Biobank and in six replication cohorts. In a phenome-wide association study, there was no evidence of a higher risk of infections among M249K carriers. CONCLUSIONS: Carriers of an experimentally confirmed damaging CCR2 variant are at a lower lifetime risk of myocardial infarction and coronary artery disease without carrying a higher risk of infections. Our findings provide genetic support for the translational potential of CCR2-targeting as an atheroprotective approach.
Keywords: Aged; Cardiovascular Diseases; Chemokine CCL2; Female; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Monocytes; Receptors, CCR2

Robust Automated Harmonization of Heterogeneous Data Through Ensemble Machine Learning: Algorithm Development and Validation Study. - Yang, Doris; Zhou, Doudou; Cai, Steven; Gan, Ziming; Pencina, Michael; Avillach, Paul; Cai, Tianxi; Hong, Chuan (JMIR Med Inform, 2025)
BACKGROUND: Cohort studies contain rich clinical data across large and diverse patient populations and are a common source of observational data for clinical research. Because large scale cohort studies are both time and resource intensive, one alternative is to harmonize data from existing cohorts through multicohort studies. However, given differences in variable encoding, accurate variable harmonization is difficult. OBJECTIVE: We propose SONAR (Semantic and Distribution-Based Harmonization) as a method for harmonizing variables across cohort studies to facilitate multicohort studies. METHODS: SONAR used semantic learning from variable descriptions and distribution learning from study participant data. Our method learned an embedding vector for each variable and used pairwise cosine similarity to score the similarity between variables. This approach was built off 3 National Institutes of Health cohorts, including the Cardiovascular Health Study, the Multi-Ethnic Study of Atherosclerosis, and the Women's Health Initiative. We also used gold standard labels to further refine the embeddings in a supervised manner. RESULTS: The method was evaluated using manually curated gold standard labels from the 3 National Institutes of Health cohorts. We evaluated both the intracohort and intercohort variable harmonization performance. The supervised SONAR method outperformed existing benchmark methods for almost all intracohort and intercohort comparisons using area under the curve and top-k accuracy metrics. Notably, SONAR was able to significantly improve harmonization of concepts that were difficult for existing semantic methods to harmonize. CONCLUSIONS: SONAR achieves accurate variable harmonization within and between cohort studies by harnessing the complementary strengths of semantic learning and variable distribution learning.
Keywords: Algorithms; Cohort Studies; Female; Humans; Machine Learning; Semantics

Selected social and lifestyle correlates of brain health markers: the Cross-Cohort Collaboration Consortium. - Grasset, Leslie; Bis, Joshua C; Frenzel, Stefan; Kojis, Daniel; Simino, Jeannette; Yaqub, Amber; Beiser, Alexa; Berr, Claudine; Bressler, Jan; Bülow, Robin; DeCarli, Charles S; Fohner, Alison E; et al. (Alzheimers Dement, 2025)
INTRODUCTION: To investigate the associations of education level, marital status, and physical activity with dementia risk and brain MRI markers. METHODS: Data from six community-based samples from the Cross-Cohort Collaboration Consortium were analyzed. Self-reported education level, marital status, and physical activity at age 60 to 75 years were harmonized. Subsamples of participants with brain MRI markers at time of exposure were selected. Associations with dementia risk and cross-sectional MRI markers were meta-analyzed. RESULTS: Higher education level was associated with lower dementia risk (hazard ratio [HR] = 0.65, 95% confidence interval [CI] = 0.59; 0.72 vs low level) but not significantly with brain MRI markers. Compared with being unmarried, being married was only associated with higher total brain and hippocampal volumes. Being physically active was associated with lower dementia risk (HR = 0.73, 95% CI = 0.52; 1.04), as well as larger total brain volume and smaller white matter hyperintensity volume. DISCUSSION: This study provides further evidence regarding the contribution of education level and physical activity to dementia resilience. HIGHLIGHTS: Education level, marital status, and physical activity are thought to contribute to resilience against ADRD. We used random-effects meta-analysis to summarize results from six community-based samples from the CCC. In this cross-cohort meta-analysis, higher education level and being physically active were associated with lower risk of dementia. In cross-sectional analyses, being married was associated with larger TBV and HV, while being physically active was associated with larger TBV and lower WMHV.
Keywords: Aged; Brain; Cohort Studies; Cross-Sectional Studies; Dementia; Educational Status; Exercise; Female; Humans; Life Style; Magnetic Resonance Imaging; Male; Marital Status; Middle Aged; Risk Factors

Sequencing in over 50,000 cases identifies coding and structural variation underlying atrial fibrillation risk. - Choi, Seung Hoan; Jurgens, Sean J; Xiao, Ling; Hill, Matthew C; Haggerty, Christopher M; Sveinbjörnsson, Garðar; Morrill, Valerie N; Marston, Nicholas A; Weng, Lu-Chen; Pirruccello, James P; Arnar, David O; Gudbjartsson, Daniel Fannar; et al. (Nat Genet, 2025)
Atrial fibrillation (AF) is a prevalent and morbid abnormality of the heart rhythm with a strong genetic component. Here, we meta-analyzed genome and exome sequencing data from 36 studies that included 52,416 AF cases and 277,762 controls. In burden tests of rare coding variation, we identified novel associations between AF and the genes MYBPC3, LMNA, PKP2, FAM189A2 and KDM5B. We further identified associations between AF and rare structural variants owing to deletions in CTNNA3 and duplications of GATA4. We broadly replicated our findings in independent samples from MyCode, deCODE and UK Biobank. Finally, we found that CRISPR knockout of KDM5B in stem-cell-derived atrial cardiomyocytes led to a shortening of the action potential duration and widespread transcriptomic dysregulation of genes relevant to atrial homeostasis and conduction. Our results highlight the contribution of rare coding and structural variants to AF, including genetic links between AF and cardiomyopathies, and expand our understanding of the rare variant architecture for this common arrhythmia.
Keywords: Atrial Fibrillation; Case-Control Studies; Exome Sequencing; Genetic Predisposition to Disease; Genetic Variation; Genome-Wide Association Study; Humans; Myocytes, Cardiac; Risk Factors

A statistical framework for multi-trait rare variant analysis in large-scale whole-genome sequencing studies. - Li, Xihao; Chen, Han; Selvaraj, Margaret Sunitha; Van Buren, Eric; Zhou, Hufeng; Wang, Yuxuan; Sun, Ryan; McCaw, Zachary R; Yu, Zhi; Jiang, Min-Zhi; DiCorpo, Daniel; Gaynor, Sheila M; et al. (Nat Comput Sci, 2025)
Large-scale whole-genome sequencing (WGS) studies have improved our understanding of the contributions of coding and noncoding rare variants to complex human traits. Leveraging association effect sizes across multiple traits in WGS rare variant association analysis can improve statistical power over single-trait analysis, and also detect pleiotropic genes and regions. Existing multi-trait methods have limited ability to perform rare variant analysis of large-scale WGS data. We propose MultiSTAAR, a statistical framework and computationally scalable analytical pipeline for functionally informed multi-trait rare variant analysis in large-scale WGS studies. MultiSTAAR accounts for relatedness, population structure and correlation among phenotypes by jointly analyzing multiple traits, and further empowers rare variant association analysis by incorporating multiple functional annotations. We applied MultiSTAAR to jointly analyze three lipid traits in 61,838 multi-ethnic samples from the Trans-Omics for Precision Medicine (TOPMed) Program. We discovered and replicated new associations with lipid traits missed by single-trait analysis.
Keywords: Genetic Variation; Genome, Human; Genome-Wide Association Study; Humans; Lipids; Phenotype; Polymorphism, Single Nucleotide; Quantitative Trait Loci; Whole Genome Sequencing

Ultra-processed foods, plant and animal sources, and all-cause, cardiovascular, and cancer mortality in older adults in the United States: results from the Cardiovascular Health Study. - Feinberg, Alyssa; Rebholz, Casey M; Lemaitre, Rozenn N; Fretts, Amanda M; Wiggins, Kerri; Sotoodehnia, Nona; Psaty, Bruce M; Kim, Hyunju (Am J Clin Nutr, 2025)
BACKGROUND: Ultra-processed food (UPF) consumption is associated with adverse health outcomes. Plant- and animal-sourced UPFs have a unique nutritional composition to improve palatability, which may impact health, but evidence is limited. OBJECTIVES: The objective of this study was to investigate the association between UPF intake, plant- and animal-sourced UPFs, and mortality outcomes in older adults. METHODS: We conducted prospective analyses of 2582 participants (median age: 77 y) in the Cardiovascular Health Study who completed a food frequency questionnaire (FFQ) in 1995-1996. We used responses from the FFQ to identify UPF and classify UPF based on their source (plant or animal). Cox proportional hazard regression models were used to study the association between UPF, plant- and animal-sourced UPF, and mortality outcomes (all-cause, cardiovascular disease [CVD] related, non-CVD related, and cancer). RESULTS: Over a median follow-up of 10 y, there were 2242 deaths. After adjusting for sociodemographic characteristics and health behaviors, per standard deviation (SD) higher intake of UPF was associated with 8%-10% higher risk of all-cause mortality (hazard ratio [HR]: 1.08; 95% confidence interval [CI]: 1.02, 1.14), non-CVD related mortality (HR: 1.10; 95% CI: 1.03, 1.18), and cancer mortality (HR: 1.13; 95% CI: 1.08, 1.46). Similarly, per SD, higher intake of plant- and animal-sourced UPFs was associated with a 4%-17% higher risk of all-cause mortality, non-CVD related mortality, and cancer mortality. However, in a model additionally adjusting for clinical factors, the associations between plant-sourced UPF and mortality attenuated, except for cancer mortality. No significant associations were observed for CVD-related mortality. CONCLUSION: Higher consumption of UPF and plant- and animal-sourced UPFs was associated with higher risk of all-cause, non-CVD-related, and cancer mortality. Our findings emphasize the need to consider the impact of food processing, even in plant-sourced foods, to prevent a shorter lifespan in older adults. Findings on plant-sourced UPF and mortality require replication.

Whole genome sequence association analysis of brain structural volume measures in the NHLBI TOPMed Program highlights novel loci in diverse participants. - Shade, Lincoln Mp; Sharifitabar, Mohsen; Beiser, Alexa; Satizabal, Claudia L; Mosley, Thomas H; Curran, Joanne E; Bressler, Jan; Heckbert, Susan R; Hughes, Timothy M; Austin, Thomas R; Nasrallah, Ilya M; Launer, Lenore J; et al. (medRxiv, 2025)
Brain structural volumes are highly heritable and are linked to multiple neuropsychological outcomes, including Alzheimer's disease (AD). Genome-wide association studies have successfully identified genetic variants associated with intracranial volume (ICV), total brain volume (TBV), hippocampal volume (HV), and lateral ventricular volume (LVV). However, these studies mostly focused on common genetic variants with minor allele frequencies (MAF) > 1%, and individuals included in most of these studies were of predominantly European ancestry. Here, we performed whole-genome sequence (WGS) association studies of MRI brain volumes in 7,674 individuals of diverse race and ethnicity from the Trans-Omics for Precision Medicine (TOPMed) program. We identified novel genetic loci on chromosomes 13 and 16 near and associated with HV and TBV, respectively (lead variants rs115674829, -value = 1.7×10 in pooled analysis and rs150440001, -value = 6.6×10 in black participants). Both lead variant minor A alleles are rarer in white participants (MAF = 0.14% and 0.03%) and in Hispanic participants (MAF = 1.5% and 0.17%) but more common in black participants (MAF = 13% and 1.5%). Rare variant aggregated analyses identified a gene encoding a kinase involved in neuroinflammation and promising target for AD treatment, suggestively associated with LVV (-value=5×10). This study provides new insights into the genetic correlates of brain structural volumes and illustrates the importance of leveraging WGS data and cohorts of diverse race and ethnicity to better characterize the genetic architecture of complex polygenic traits.

Whole genome sequencing analysis of body mass index identifies novel African ancestry-specific risk allele. - Zhang, Xinruo; Brody, Jennifer A; Graff, Mariaelisa; Highland, Heather M; Chami, Nathalie; Xu, Hanfei; Wang, Zhe; Ferrier, Kendra R; Chittoor, Geetha; Josyula, Navya Shilpa; Meyer, Mariah; Gupta, Shreyash; et al. (Nat Commun, 2025)
Obesity is a major public health crisis associated with high mortality rates. Previous genome-wide association studies (GWAS) investigating body mass index (BMI) have largely relied on imputed data from European individuals. This study leveraged whole-genome sequencing (WGS) data from 88,873 participants from the Trans-Omics for Precision Medicine (TOPMed) Program, of which 51% were of non-European population groups. We discovered 18 BMI-associated signals (P < 5 × 10), including two secondary signals. Notably, we identified and replicated a novel low-frequency single nucleotide polymorphism (SNP) in MTMR3 that was common in individuals of African descent. Using a diverse study population, we further identified two novel secondary signals in known BMI loci and pinpointed two likely causal variants in the POC5 and DMD loci. Our work demonstrates the benefits of combining WGS and diverse cohorts in expanding current catalog of variants and genes confer risk for obesity, bringing us one step closer to personalized medicine.
Keywords: Adult; African People; Alleles; Body Mass Index; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Male; Middle Aged; Obesity; Polymorphism, Single Nucleotide; Population Groups; Whole Genome Sequencing