Publications by authors named "Patricia A Peyser"

131 Publications

Epigenome-wide association study of mitochondrial genome copy number.

Hum Mol Genet 2021 Aug 20. Epub 2021 Aug 20.

Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.

We conducted cohort- and race-specific epigenome-wide association analyses of mtDNA copy number (mtDNA CN) measured in whole blood from participants of African and European origins in five cohorts (n = 6182, mean age 57-67 years, 65% women). In the meta-analysis of all the participants, we discovered 21 mtDNA CN-associated CpG sites (p < 1 x 10-7), with a 0.7 to 3.0 standard deviation increase (3 CpGs) or decrease (18 CpGs) in mtDNA CN corresponding to a 1% increase in DNA methylation. Several significant CpGs have been reported to be associated with at least two risk factors (e.g. chronological age or smoking) for cardiovascular disease (CVD). Five genes (PRDM16, NR1H3, XRCC3, POLK, and PDSS2), which harbor nine significant CpGs, are known to be involved in mitochondrial biosynthesis and functions. For example, NR1H3 encodes a transcription factor that is differentially expressed during an adipose tissue transition. The methylation level of cg09548275 in NR1H3 was negatively associated with mtDNA CN (effect size = -1.71, p = 4 x 10-8) and positively associated with the NR1H3 expression level (effect size = 0.43, p = 0.0003), which indicates that the methylation level in NR1H3 may underlie the relationship between mtDNA CN, the NR1H3 transcription factor, and energy expenditure. In summary, the study results suggest that mtDNA CN variation in whole blood is associated with DNA methylation levels in genes that are involved in a wide range of mitochondrial activities. These findings will help reveal molecular mechanisms between mtDNA CN and CVD.
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http://dx.doi.org/10.1093/hmg/ddab240DOI Listing
August 2021

Population sequencing data reveal a compendium of mutational processes in the human germ line.

Science 2021 08 12;373(6558):1030-1035. Epub 2021 Aug 12.

Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.

Biological mechanisms underlying human germline mutations remain largely unknown. We statistically decompose variation in the rate and spectra of mutations along the genome using volume-regularized nonnegative matrix factorization. The analysis of a sequencing dataset (TOPMed) reveals nine processes that explain the variation in mutation properties between loci. We provide a biological interpretation for seven of these processes. We associate one process with bulky DNA lesions that are resolved asymmetrically with respect to transcription and replication. Two processes track direction of replication fork and replication timing, respectively. We identify a mutagenic effect of active demethylation primarily acting in regulatory regions and a mutagenic effect of long interspersed nuclear elements. We localize a mutagenic process specific to oocytes from population sequencing data. This process appears transcriptionally asymmetric.
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http://dx.doi.org/10.1126/science.aba7408DOI Listing
August 2021

Multiethnic Genome-Wide Association Study of Subclinical Atherosclerosis in Individuals With Type 2 Diabetes.

Circ Genom Precis Med 2021 Aug 9;14(4):e003258. Epub 2021 Jul 9.

Department of Epidemiology (N.F., G.H.), University of North Carolina, Chapel Hill.

Background: Coronary artery calcification (CAC) and carotid artery intima-media thickness (cIMT) are measures of subclinical atherosclerosis in asymptomatic individuals and strong risk factors for cardiovascular disease. Type 2 diabetes (T2D) is an independent cardiovascular disease risk factor that accelerates atherosclerosis.

Methods: We performed meta-analyses of genome-wide association studies in up to 2500 T2D individuals of European ancestry (EA) and 1590 T2D individuals of African ancestry with or without exclusion of prevalent cardiovascular disease, for CAC measured by cardiac computed tomography, and 3608 individuals of EA and 838 individuals of African ancestry with T2D for cIMT measured by ultrasonography within the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium.

Results: We replicated 2 loci (rs9369640 and rs9349379 near and rs10757278 near ) for CAC and one locus for cIMT (rs7412 and rs445925 near ) that were previously reported in the general EA populations. We identified one novel CAC locus (rs8000449 near at 13q13.3) at =2.0×10 in EA. No additional loci were identified with the meta-analyses of EA and African ancestry. The expression quantitative trait loci analysis with nearby expressed genes derived from arterial wall and metabolic tissues from the Genotype-Tissue Expression project pinpoints , encoding a matricellular protein involved in bone formation and bone matrix organization, as the potential candidate gene at this locus. In addition, we found significant associations (<3.1×10) for 3 previously reported coronary artery disease loci for these subclinical atherosclerotic phenotypes (rs2891168 near and rs11170820 near for CAC, and rs7412 near for cIMT).

Conclusions: Our results provide potential biological mechanisms that could link CAC and cIMT to increased cardiovascular disease risk in individuals with T2D.
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http://dx.doi.org/10.1161/CIRCGEN.120.003258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8435075PMC
August 2021

Accelerated DNA methylation age and medication use among African Americans.

Aging (Albany NY) 2021 06 3;13(11):14604-14629. Epub 2021 Jun 3.

Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA.

DNA methylation age acceleration, the discrepancy between epigenetic age and chronological age, is associated with mortality and chronic diseases, including diabetes, hypertension, and hyperlipidemia. In this study, we investigate whether medications commonly used to treat these diseases in 15 drug categories are associated with four epigenetic age acceleration measures: HorvathAge acceleration (HorvathAA), HannumAge acceleration (HannumAA), PhenoAge acceleration, and GrimAge acceleration (GrimAA) using cross-sectional (Phase 1, N=1,100) and longitudinal (Phases 1 and 2, N=266) data from African Americans in the Genetic Epidemiology Network of Arteriopathy (GENOA) study. In cross-sectional analyses, the use of calcium channel blockers was associated with 1.27 years lower HannumAA after adjusting for covariates including hypertension (p=0.001). Longitudinal analyses showed that, compared to those who never used antihypertensives, those who started to take antihypertensives after Phase 1 had a 0.97-year decrease in GrimAA (p=0.007). In addition, compared to those who never used NSAID analgesics, those who started to take them after Phase 1 had a 2.61-year increase in HorvathAA (p=0.0005). Our study demonstrates that three commonly used medications are associated with DNAm age acceleration in African Americans and sheds light on the potential epigenetic effects of pharmaceuticals on aging at the cellular level.
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http://dx.doi.org/10.18632/aging.203115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8221348PMC
June 2021

The trans-ancestral genomic architecture of glycemic traits.

Nat Genet 2021 06 31;53(6):840-860. Epub 2021 May 31.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.
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http://dx.doi.org/10.1038/s41588-021-00852-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610958PMC
June 2021

Genetic variants predictive of reproductive aging are associated with vasomotor symptoms in a multiracial/ethnic cohort.

Menopause 2021 04 26;28(8):883-892. Epub 2021 Apr 26.

Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI.

Objective: Vasomotor symptoms (VMS), hot flashes, and night sweats are cardinal symptoms of the menopausal transition. Little is known about genetic influences on VMS. This study evaluated whether previously identified genetic factors predictive of VMS, age at menarche, and age at menopause were associated with VMS in a multiracial/ethnic cohort.

Methods: For 702 White, 306 Black, 126 Chinese, and 129 Japanese women from the Study of Women's Health Across the Nation (SWAN) Genomic Substudy, we created polygenic risk scores (PRSs) from genome-wide association studies of VMS and ages at menarche and menopause. PRSs and single nucleotide polymorphisms (SNPs) from a previously identified VMS locus (tachykinin receptor 3 [TACR3]) were evaluated for associations with frequent VMS (VMS ≥6 days in the past 2 weeks at any visit) and with VMS trajectories (persistently low, early onset, final menstrual period onset, persistently high).

Results: The C-allele of rs74827081 in TACR3 was associated with reduced likelihood of frequent VMS in White women (odds ratio [OR] = 0.49 [95% CI, 0.29-0.83]). With higher menarche PRS (later menarche), Black women were less likely (OR = 0.55 [95% CI, 0.38-0.78]) to report frequent VMS. With higher PRS for age at menarche, Black women were also less likely to have a persistently high VMS trajectory (OR = 0.55 [95% CI, 0.34-0.91]), whereas White women (OR = 0.75 [95% CI, 0.58-0.98]) were less likely to have a final menstrual period onset trajectory (vs persistently low). Chinese women with higher menopause PRS were more likely to have frequent VMS (OR = 2.29 [95% CI, 1.39-3.78]). Associations were substantively similar after excluding rs74827081 C-allele carriers.

Conclusions: Genetic factors predictive of reproductive aging are also associated with VMS, suggesting that VMS have a polygenic architecture. Further study in this area may help to identify new targets for novel VMS therapies.
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http://dx.doi.org/10.1097/GME.0000000000001785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373653PMC
April 2021

Associations between polygenic risk score for age at menarche and menopause, reproductive timing, and serum hormone levels in multiple race/ethnic groups.

Menopause 2021 04 19;28(7):819-828. Epub 2021 Apr 19.

Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI.

Objective: We assessed associations of genetic loci that contribute to age at menarche and menopause with sentinel menopausal traits in multiple race/ethnic groups.

Methods: Genetic data from the Study of Women's Health Across the Nation include 738 White, 366 Black, 139 Chinese, and 145 Japanese women aged 42 to 52 at baseline. We constructed standardized polygenic risk scores (PRSs) using single nucleotide polymorphisms identified from large-scale genome-wide association studies meta-analyses of ages at menopause and menarche, evaluating associations with each trait within each race/ethnic group.

Results: Menopause PRS was significantly associated with age at menopause in White women after Bonferroni correction (P < 0.004) and nominally associated in Chinese and Japanese women (P < 0.05) (7.4-8.5 mo delay for one standard deviation [SD] increase in PRS). Menarche PRS was significantly associated with age at menarche in White (P < 0.004) and nominally associated in Black and Japanese women (P < 0.05) (2.6-4.8 mo delay for one SD increase). In White women, menarche and menopause PRSs were significantly associated (P < 0.004) with shorter and longer (5.9 and 9.6 mo for one SD increase) reproductive lifespans, respectively, and menopause PRS with a longer menopausal transition (7.1 mo for one SD increase). We observed a significant positive association (P < 0.004) between menopause PRS and E2 level 2 years before menopause and a nominal association (P < 0.05) 2 years after menopause in Japanese women.

Conclusions: In addition to menopausal timing, PRSs associated with onset and ending of reproductive life were associated with reproductive lifespan, length of the menopausal transition, and E2 levels in different race/ethnic groups.
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http://dx.doi.org/10.1097/GME.0000000000001775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8225555PMC
April 2021

A System for Phenotype Harmonization in the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine (TOPMed) Program.

Am J Epidemiol 2021 10;190(10):1977-1992

Genotype-phenotype association studies often combine phenotype data from multiple studies to increase statistical power. Harmonization of the data usually requires substantial effort due to heterogeneity in phenotype definitions, study design, data collection procedures, and data-set organization. Here we describe a centralized system for phenotype harmonization that includes input from phenotype domain and study experts, quality control, documentation, reproducible results, and data-sharing mechanisms. This system was developed for the National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine (TOPMed) program, which is generating genomic and other -omics data for more than 80 studies with extensive phenotype data. To date, 63 phenotypes have been harmonized across thousands of participants (recruited in 1948-2012) from up to 17 studies per phenotype. Here we discuss challenges in this undertaking and how they were addressed. The harmonized phenotype data and associated documentation have been submitted to National Institutes of Health data repositories for controlled access by the scientific community. We also provide materials to facilitate future harmonization efforts by the community, which include 1) the software code used to generate the 63 harmonized phenotypes, enabling others to reproduce, modify, or extend these harmonizations to additional studies, and 2) the results of labeling thousands of phenotype variables with controlled vocabulary terms.
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http://dx.doi.org/10.1093/aje/kwab115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8485147PMC
October 2021

Allele-specific variation at APOE increases nonalcoholic fatty liver disease and obesity but decreases risk of Alzheimer's disease and myocardial infarction.

Hum Mol Genet 2021 Jul;30(15):1443-1456

Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.

Nonalcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease and is highly correlated with metabolic disease. NAFLD results from environmental exposures acting on a susceptible polygenic background. This study performed the largest multiethnic investigation of exonic variation associated with NAFLD and correlated metabolic traits and diseases. An exome array meta-analysis was carried out among eight multiethnic population-based cohorts (n = 16 492) with computed tomography (CT) measured hepatic steatosis. A fixed effects meta-analysis identified five exome-wide significant loci (P < 5.30 × 10-7); including a novel signal near TOMM40/APOE. Joint analysis of TOMM40/APOE variants revealed the TOMM40 signal was attributed to APOE rs429358-T; APOE rs7412 was not associated with liver attenuation. Moreover, rs429358-T was associated with higher serum alanine aminotransferase, liver steatosis, cirrhosis, triglycerides and obesity; as well as, lower cholesterol and decreased risk of myocardial infarction and Alzheimer's disease (AD) in phenome-wide association analyses in the Michigan Genomics Initiative, United Kingdom Biobank and/or public datasets. These results implicate APOE in imaging-based identification of NAFLD. This association may or may not translate to nonalcoholic steatohepatitis; however, these results indicate a significant association with advanced liver disease and hepatic cirrhosis. These findings highlight allelic heterogeneity at the APOE locus and demonstrate an inverse link between NAFLD and AD at the exome level in the largest analysis to date.
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http://dx.doi.org/10.1093/hmg/ddab096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8283205PMC
July 2021

Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices.

Nat Commun 2021 04 12;12(1):2182. Epub 2021 Apr 12.

Division of Cardiology, George Washington University School of Medicine and Healthcare Sciences, Washington, DC, USA.

Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids.
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http://dx.doi.org/10.1038/s41467-021-22339-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042019PMC
April 2021

Epigenetic age acceleration is associated with cardiometabolic risk factors and clinical cardiovascular disease risk scores in African Americans.

Clin Epigenetics 2021 03 16;13(1):55. Epub 2021 Mar 16.

Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.

Background: Cardiovascular disease (CVD) is the leading cause of mortality among US adults. African Americans have higher burden of CVD morbidity and mortality compared to any other racial group. Identifying biomarkers for clinical risk prediction of CVD offers an opportunity for precision prevention and earlier intervention.

Results: Using linear mixed models, we investigated the cross-sectional association between four measures of epigenetic age acceleration (intrinsic (IEAA), extrinsic (EEAA), PhenoAge (PhenoAA), and GrimAge (GrimAA)) and ten cardiometabolic markers of hypertension, insulin resistance, and dyslipidemia in 1,100 primarily hypertensive African Americans from sibships in the Genetic Epidemiology Network of Arteriopathy (GENOA). We then assessed the association between epigenetic age acceleration and time to self-reported incident CVD using frailty hazard models and investigated CVD risk prediction improvement compared to models with clinical risk scores (Framingham risk score (FRS) and the atherosclerotic cardiovascular disease (ASCVD) risk equation). After adjusting for sex and chronological age, increased epigenetic age acceleration was associated with higher systolic blood pressure (IEAA), higher pulse pressure (EEAA and GrimAA), higher fasting glucose (PhenoAA and GrimAA), higher fasting insulin (EEAA), lower low density cholesterol (GrimAA), and higher triglycerides (GrimAA). A five-year increase in GrimAA was associated with CVD incidence with a hazard ratio of 1.54 (95% CI 1.22-2.01) and remained significant after adjusting for CVD risk factors. The addition of GrimAA to risk score models improved model fit using likelihood ratio tests (P = 0.013 for FRS and P = 0.008 for ASCVD), but did not improve C statistics (P > 0.05). Net reclassification index (NRI) showed small but significant improvement in reassignment of risk categories with the addition of GrimAA to FRS (NRI: 0.055, 95% CI 0.040-0.071) and the ASCVD equation (NRI: 0.029, 95% CI 0.006-0.064).

Conclusions: Epigenetic age acceleration measures are associated with traditional CVD risk factors in an African-American cohort with a high prevalence of hypertension. GrimAA was associated with CVD incidence and slightly improved prediction of CVD events over clinical risk scores.
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http://dx.doi.org/10.1186/s13148-021-01035-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962278PMC
March 2021

Discovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry.

Am J Hum Genet 2021 04 12;108(4):564-582. Epub 2021 Mar 12.

The Charles R. Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained ≤20 variants in the credible sets that jointly account for 99% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations.
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http://dx.doi.org/10.1016/j.ajhg.2021.02.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059339PMC
April 2021

Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program.

Nature 2021 02 10;590(7845):290-299. Epub 2021 Feb 10.

The Broad Institute of MIT and Harvard, Cambridge, MA, USA.

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes). In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.
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http://dx.doi.org/10.1038/s41586-021-03205-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875770PMC
February 2021

Genome-wide association study of serum liver enzymes implicates diverse metabolic and liver pathology.

Nat Commun 2021 02 5;12(1):816. Epub 2021 Feb 5.

Division of Gastroenterology and Hepatology, University of Michigan Health System, Ann Arbor, MI, USA.

Serum liver enzyme concentrations are the most frequently-used laboratory markers of liver disease, a major cause of mortality. We conduct a meta-analysis of genome-wide association studies of liver enzymes from UK BioBank and BioBank Japan. We identified 160 previously-unreported independent alanine aminotransferase, 190 aspartate aminotransferase, and 199 alkaline phosphatase genome-wide significant associations, with some affecting multiple different enzymes. Associated variants implicate genes that demonstrate diverse liver cell type expression and promote a range of metabolic and liver diseases. These findings provide insight into the pathophysiology of liver and other metabolic diseases that are associated with serum liver enzyme concentrations.
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http://dx.doi.org/10.1038/s41467-020-20870-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865025PMC
February 2021

Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability.

Nat Commun 2021 01 5;12(1):24. Epub 2021 Jan 5.

Department of Biostatistics and Data Science, Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA.

Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
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http://dx.doi.org/10.1038/s41467-020-19366-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785747PMC
January 2021

Loss-of-function genomic variants highlight potential therapeutic targets for cardiovascular disease.

Nat Commun 2020 12 18;11(1):6417. Epub 2020 Dec 18.

The Institute for Translational Genomics and Population Sciences, Department of Pediatrics and Los Angeles Biomedical Research Institute, Harbor-UCLA, Torrance, CA, USA.

Pharmaceutical drugs targeting dyslipidemia and cardiovascular disease (CVD) may increase the risk of fatty liver disease and other metabolic disorders. To identify potential novel CVD drug targets without these adverse effects, we perform genome-wide analyses of participants in the HUNT Study in Norway (n = 69,479) to search for protein-altering variants with beneficial impact on quantitative blood traits related to cardiovascular disease, but without detrimental impact on liver function. We identify 76 (11 previously unreported) presumed causal protein-altering variants associated with one or more CVD- or liver-related blood traits. Nine of the variants are predicted to result in loss-of-function of the protein. This includes ZNF529:p.K405X, which is associated with decreased low-density-lipoprotein (LDL) cholesterol (P = 1.3 × 10) without being associated with liver enzymes or non-fasting blood glucose. Silencing of ZNF529 in human hepatoma cells results in upregulation of LDL receptor and increased LDL uptake in the cells. This suggests that inhibition of ZNF529 or its gene product should be prioritized as a novel candidate drug target for treating dyslipidemia and associated CVD.
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http://dx.doi.org/10.1038/s41467-020-20086-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749177PMC
December 2020

A Noncoding Variant Near PPP1R3B Promotes Liver Glycogen Storage and MetS, but Protects Against Myocardial Infarction.

J Clin Endocrinol Metab 2021 01;106(2):372-387

Brigham and Women's Hospital, Havard University, Boston, MA, USA.

Context: Glycogen storage diseases are rare. Increased glycogen in the liver results in increased attenuation.

Objective: Investigate the association and function of a noncoding region associated with liver attenuation but not histologic nonalcoholic fatty liver disease.

Design: Genetics of Obesity-associated Liver Disease Consortium.

Setting: Population-based.

Main Outcome: Computed tomography measured liver attenuation.

Results: Carriers of rs4841132-A (frequency 2%-19%) do not show increased hepatic steatosis; they have increased liver attenuation indicative of increased glycogen deposition. rs4841132 falls in a noncoding RNA LOC157273 ~190 kb upstream of PPP1R3B. We demonstrate that rs4841132-A increases PPP1R3B through a cis genetic effect. Using CRISPR/Cas9 we engineered a 105-bp deletion including rs4841132-A in human hepatocarcinoma cells that increases PPP1R3B, decreases LOC157273, and increases glycogen perfectly mirroring the human disease. Overexpression of PPP1R3B or knockdown of LOC157273 increased glycogen but did not result in decreased LOC157273 or increased PPP1R3B, respectively, suggesting that the effects may not all occur via affecting RNA levels. Based on electronic health record (EHR) data, rs4841132-A associates with all components of the metabolic syndrome (MetS). However, rs4841132-A associated with decreased low-density lipoprotein (LDL) cholesterol and risk for myocardial infarction (MI). A metabolic signature for rs4841132-A includes increased glycine, lactate, triglycerides, and decreased acetoacetate and beta-hydroxybutyrate.

Conclusions: These results show that rs4841132-A promotes a hepatic glycogen storage disease by increasing PPP1R3B and decreasing LOC157273. rs4841132-A promotes glycogen accumulation and development of MetS but lowers LDL cholesterol and risk for MI. These results suggest that elevated hepatic glycogen is one cause of MetS that does not invariably promote MI.
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http://dx.doi.org/10.1210/clinem/dgaa855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823249PMC
January 2021

Inherited causes of clonal haematopoiesis in 97,691 whole genomes.

Nature 2020 10 14;586(7831):763-768. Epub 2020 Oct 14.

Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.

Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer and coronary heart disease-this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP). Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.
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http://dx.doi.org/10.1038/s41586-020-2819-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944936PMC
October 2020

Dynamic incorporation of multiple in silico functional annotations empowers rare variant association analysis of large whole-genome sequencing studies at scale.

Nat Genet 2020 09 24;52(9):969-983. Epub 2020 Aug 24.

Department of Data Sciences, Dana-Farber Cancer Institute and Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Large-scale whole-genome sequencing studies have enabled the analysis of rare variants (RVs) associated with complex phenotypes. Commonly used RV association tests have limited scope to leverage variant functions. We propose STAAR (variant-set test for association using annotation information), a scalable and powerful RV association test method that effectively incorporates both variant categories and multiple complementary annotations using a dynamic weighting scheme. For the latter, we introduce 'annotation principal components', multidimensional summaries of in silico variant annotations. STAAR accounts for population structure and relatedness and is scalable for analyzing very large cohort and biobank whole-genome sequencing studies of continuous and dichotomous traits. We applied STAAR to identify RVs associated with four lipid traits in 12,316 discovery and 17,822 replication samples from the Trans-Omics for Precision Medicine Program. We discovered and replicated new RV associations, including disruptive missense RVs of NPC1L1 and an intergenic region near APOC1P1 associated with low-density lipoprotein cholesterol.
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http://dx.doi.org/10.1038/s41588-020-0676-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483769PMC
September 2020

Smoking-by-genotype interaction in type 2 diabetes risk and fasting glucose.

PLoS One 2020 7;15(5):e0230815. Epub 2020 May 7.

Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, United States of America.

Smoking is a potentially causal behavioral risk factor for type 2 diabetes (T2D), but not all smokers develop T2D. It is unknown whether genetic factors partially explain this variation. We performed genome-environment-wide interaction studies to identify loci exhibiting potential interaction with baseline smoking status (ever vs. never) on incident T2D and fasting glucose (FG). Analyses were performed in participants of European (EA) and African ancestry (AA) separately. Discovery analyses were conducted using genotype data from the 50,000-single-nucleotide polymorphism (SNP) ITMAT-Broad-CARe (IBC) array in 5 cohorts from from the Candidate Gene Association Resource Consortium (n = 23,189). Replication was performed in up to 16 studies from the Cohorts for Heart Aging Research in Genomic Epidemiology Consortium (n = 74,584). In meta-analysis of discovery and replication estimates, 5 SNPs met at least one criterion for potential interaction with smoking on incident T2D at p<1x10-7 (adjusted for multiple hypothesis-testing with the IBC array). Two SNPs had significant joint effects in the overall model and significant main effects only in one smoking stratum: rs140637 (FBN1) in AA individuals had a significant main effect only among smokers, and rs1444261 (closest gene C2orf63) in EA individuals had a significant main effect only among nonsmokers. Three additional SNPs were identified as having potential interaction by exhibiting a significant main effects only in smokers: rs1801232 (CUBN) in AA individuals, rs12243326 (TCF7L2) in EA individuals, and rs4132670 (TCF7L2) in EA individuals. No SNP met significance for potential interaction with smoking on baseline FG. The identification of these loci provides evidence for genetic interactions with smoking exposure that may explain some of the heterogeneity in the association between smoking and T2D.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0230815PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205201PMC
August 2020

Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci.

Mol Psychiatry 2021 06 5;26(6):2111-2125. Epub 2020 May 5.

Health Disparities Research Section, Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA.

Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.
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http://dx.doi.org/10.1038/s41380-020-0719-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641978PMC
June 2021

Use of >100,000 NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium whole genome sequences improves imputation quality and detection of rare variant associations in admixed African and Hispanic/Latino populations.

PLoS Genet 2019 12 23;15(12):e1008500. Epub 2019 Dec 23.

Genomics Platform, Broad Institute, Cambridge, Massachusetts, United States of America.

Most genome-wide association and fine-mapping studies to date have been conducted in individuals of European descent, and genetic studies of populations of Hispanic/Latino and African ancestry are limited. In addition, these populations have more complex linkage disequilibrium structure. In order to better define the genetic architecture of these understudied populations, we leveraged >100,000 phased sequences available from deep-coverage whole genome sequencing through the multi-ethnic NHLBI Trans-Omics for Precision Medicine (TOPMed) program to impute genotypes into admixed African and Hispanic/Latino samples with genome-wide genotyping array data. We demonstrated that using TOPMed sequencing data as the imputation reference panel improves genotype imputation quality in these populations, which subsequently enhanced gene-mapping power for complex traits. For rare variants with minor allele frequency (MAF) < 0.5%, we observed a 2.3- to 6.1-fold increase in the number of well-imputed variants, with 11-34% improvement in average imputation quality, compared to the state-of-the-art 1000 Genomes Project Phase 3 and Haplotype Reference Consortium reference panels. Impressively, even for extremely rare variants with minor allele count <10 (including singletons) in the imputation target samples, average information content rescued was >86%. Subsequent association analyses of TOPMed reference panel-imputed genotype data with hematological traits (hemoglobin (HGB), hematocrit (HCT), and white blood cell count (WBC)) in ~21,600 African-ancestry and ~21,700 Hispanic/Latino individuals identified associations with two rare variants in the HBB gene (rs33930165 with higher WBC [p = 8.8x10-15] in African populations, rs11549407 with lower HGB [p = 1.5x10-12] and HCT [p = 8.8x10-10] in Hispanics/Latinos). By comparison, neither variant would have been genome-wide significant if either 1000 Genomes Project Phase 3 or Haplotype Reference Consortium reference panels had been used for imputation. Our findings highlight the utility of the TOPMed imputation reference panel for identification of novel rare variant associations not previously detected in similarly sized genome-wide studies of under-represented African and Hispanic/Latino populations.
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http://dx.doi.org/10.1371/journal.pgen.1008500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953885PMC
December 2019

Associations of autozygosity with a broad range of human phenotypes.

Nat Commun 2019 10 31;10(1):4957. Epub 2019 Oct 31.

Department of Neurology, Brain Centre Rudolf Magnus, University Medical Centre Utrecht, Utrecht University, Utrecht, 3584 CX, The Netherlands.

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F) for >1.4 million individuals, we show that F is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F are confirmed within full-sibling pairs, where the variation in F is independent of all environmental confounding.
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http://dx.doi.org/10.1038/s41467-019-12283-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823371PMC
October 2019

Insulin Resistance Exacerbates Genetic Predisposition to Nonalcoholic Fatty Liver Disease in Individuals Without Diabetes.

Hepatol Commun 2019 Jul 18;3(7):894-907. Epub 2019 Apr 18.

Division of Statistical Genomics, Department of Genetics Washington University School of Medicine St. Louis MO.

The accumulation of excess fat in the liver (hepatic steatosis) in the absence of heavy alcohol consumption causes nonalcoholic fatty liver disease (NAFLD), which has become a global epidemic. Identifying metabolic risk factors that interact with the genetic risk of NAFLD is important for reducing disease burden. We tested whether serum glucose, insulin, insulin resistance, triglyceride (TG), low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, body mass index (BMI), and waist-to-hip ratio adjusted for BMI interact with genetic variants in or near the patatin-like phospholipase domain containing 3 () gene, the glucokinase regulatory protein () gene, the neurocan/transmembrane 6 superfamily member 2 () gene and the lysophospholipase-like 1 () gene to exacerbate hepatic steatosis, estimated by liver attenuation. We performed association analyses in 10 population-based cohorts separately and then meta-analyzed results in up to 14,751 individuals (11,870 of European ancestry and 2,881 of African ancestry). We found that rs738409 significantly interacted with insulin, insulin resistance, BMI, glucose, and TG to increase hepatic steatosis in nondiabetic individuals carrying the G allele. Additionally, rs780094 significantly interacted with insulin, insulin resistance, and TG. Conditional analyses using the two largest European ancestry cohorts in the study showed that insulin levels accounted for most of the interaction of rs738409 with BMI, glucose, and TG in nondiabetic individuals. Insulin, -rs738409, and their interaction accounted for at least 8% of the variance in hepatic steatosis in these two cohorts. Insulin resistance, either directly or through the resultant elevated insulin levels, more than other metabolic traits, appears to amplify the -rs738409-G genetic risk for hepatic steatosis. Improving insulin resistance in nondiabetic individuals carrying rs738409-G may preferentially decrease hepatic steatosis.
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http://dx.doi.org/10.1002/hep4.1353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6601321PMC
July 2019

A multi-ancestry genome-wide study incorporating gene-smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure.

Hum Mol Genet 2019 08;28(15):2615-2633

Icelandic Heart Association, Kopavogur, Iceland.

Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene-smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene-smoking interaction analysis and 38 were newly identified (P < 5 × 10-8, false discovery rate < 0.05). We also identified nine new signals near known loci. Of the 136 loci, 8 showed significant interaction with smoking status. They include CSMD1 previously reported for insulin resistance and BP in the spontaneously hypertensive rats. Many of the 38 new loci show biologic plausibility for a role in BP regulation. SLC26A7 encodes a chloride/bicarbonate exchanger expressed in the renal outer medullary collecting duct. AVPR1A is widely expressed, including in vascular smooth muscle cells, kidney, myocardium and brain. FHAD1 is a long non-coding RNA overexpressed in heart failure. TMEM51 was associated with contractile function in cardiomyocytes. CASP9 plays a central role in cardiomyocyte apoptosis. Identified only in African ancestry were 30 novel loci. Our findings highlight the value of multi-ancestry investigations, particularly in studies of interaction with lifestyle factors, where genomic and lifestyle differences may contribute to novel findings.
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http://dx.doi.org/10.1093/hmg/ddz070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6644157PMC
August 2019

Mendelian randomization evaluation of causal effects of fibrinogen on incident coronary heart disease.

PLoS One 2019 10;14(5):e0216222. Epub 2019 May 10.

Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.

Background: Fibrinogen is an essential hemostatic factor and cardiovascular disease risk factor. Early attempts at evaluating the causal effect of fibrinogen on coronary heart disease (CHD) and myocardial infraction (MI) using Mendelian randomization (MR) used single variant approaches, and did not take advantage of recent genome-wide association studies (GWAS) or multi-variant, pleiotropy robust MR methodologies.

Methods And Findings: We evaluated evidence for a causal effect of fibrinogen on both CHD and MI using MR. We used both an allele score approach and pleiotropy robust MR models. The allele score was composed of 38 fibrinogen-associated variants from recent GWAS. Initial analyses using the allele score used a meta-analysis of 11 European-ancestry prospective cohorts, free of CHD and MI at baseline, to examine incidence CHD and MI. We also applied 2 sample MR methods with data from a prevalent CHD and MI GWAS. Results are given in terms of the hazard ratio (HR) or odds ratio (OR), depending on the study design, and associated 95% confidence interval (CI). In single variant analyses no causal effect of fibrinogen on CHD or MI was observed. In multi-variant analyses using incidence CHD cases and the allele score approach, the estimated causal effect (HR) of a 1 g/L higher fibrinogen concentration was 1.62 (CI = 1.12, 2.36) when using incident cases and the allele score approach. In 2 sample MR analyses that accounted for pleiotropy, the causal estimate (OR) was reduced to 1.18 (CI = 0.98, 1.42) and 1.09 (CI = 0.89, 1.33) in the 2 most precise (smallest CI) models, out of 4 models evaluated. In the 2 sample MR analyses for MI, there was only very weak evidence of a causal effect in only 1 out of 4 models.

Conclusions: A small causal effect of fibrinogen on CHD is observed using multi-variant MR approaches which account for pleiotropy, but not single variant MR approaches. Taken together, results indicate that even with large sample sizes and multi-variant approaches MR analyses still cannot exclude the null when estimating the causal effect of fibrinogen on CHD, but that any potential causal effect is likely to be much smaller than observed in epidemiological studies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0216222PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6510421PMC
January 2020

A Peripheral Blood DNA Methylation Signature of Hepatic Fat Reveals a Potential Causal Pathway for Nonalcoholic Fatty Liver Disease.

Diabetes 2019 05 1;68(5):1073-1083. Epub 2019 Apr 1.

Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN.

Nonalcoholic fatty liver disease (NAFLD) is a risk factor for type 2 diabetes (T2D). We aimed to identify the peripheral blood DNA methylation signature of hepatic fat. We conducted epigenome-wide association studies of hepatic fat in 3,400 European ancestry (EA) participants and in 401 Hispanic ancestry and 724 African ancestry participants from four population-based cohort studies. Hepatic fat was measured using computed tomography or ultrasound imaging and DNA methylation was assessed at >400,000 cytosine-guanine dinucleotides (CpGs) in whole blood or CD14+ monocytes using a commercial array. We identified 22 CpGs associated with hepatic fat in EA participants at a false discovery rate <0.05 (corresponding = 6.9 × 10) with replication at Bonferroni-corrected < 8.6 × 10 Mendelian randomization analyses supported the association of hypomethylation of cg08309687 () with NAFLD ( = 2.5 × 10). Hypomethylation of the same CpG was also associated with risk for new-onset T2D ( = 0.005). Our study demonstrates that a peripheral blood-derived DNA methylation signature is robustly associated with hepatic fat accumulation. The hepatic fat-associated CpGs may represent attractive biomarkers for T2D. Future studies are warranted to explore mechanisms and to examine DNA methylation signatures of NAFLD across racial/ethnic groups.
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http://dx.doi.org/10.2337/DB18-1193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6477898PMC
May 2019
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