Publications by authors named "Gina M Peloso"

102 Publications

Sugar-sweetened Beverage Consumption May Modify Associations between Genetic Variants in the CHREBP Locus and HDL-C and TG Concentrations.

Circ Genom Precis Med 2021 Jul 16. Epub 2021 Jul 16.

Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.

- Carbohydrate responsive element binding protein (ChREBP) is a transcription factor that responds to sugar consumption. Sugar-sweetened beverage (SSB) consumption and genetic variants in the locus have separately been linked to high-density lipoprotein cholesterol (HDL-C) and triglyceride (TG) concentrations. We hypothesized SSB consumption would modify the association between genetic variants in the locus and dyslipidemia. - Data from 11 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium (N=63,599) and the UK Biobank (UKB) (N=59,220) were used to quantify associations of SSB consumption, genetic variants, and their interaction on HDL-C and TG concentrations using linear regression models. A total of 1,606 single-nucleotide polymorphisms (SNPs) within or near were considered. SSB consumption was estimated from validated questionnaires and participants were grouped by their estimated intake. - In a meta-analysis, rs71556729 was significantly associated with higher HDL-C concentrations only among the highest SSB consumers [β (95% CI) = 2.12 (1.16, 3.07) mg/dl; <0.0002], but not significantly among the lowest SSB consumers (=0.81; <0.0001). Similar results were observed for two additional variants (rs35709627 and rs71556736). For TG, rs55673514 was positively associated with TG concentrations only among the highest SSB consumers [β (95% CI): 0.06 (0.02, 0.09) per allele count for log(mg/dl), =0.001], but not the lowest SSB consumers (=0.84; =0.0005). - Our results identified genetic variants in the locus that may protect against SSB-associated reductions in HDL-C and other variants that may exacerbate SSB-associated increases in TG concentrations.
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http://dx.doi.org/10.1161/CIRCGEN.120.003288DOI Listing
July 2021

A System for Phenotype Harmonization in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program.

Am J Epidemiol 2021 Apr 16. Epub 2021 Apr 16.

Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington.

Genotype-phenotype association studies often combine phenotype data from multiple studies to increase 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 program, which is generating genomic and other omics data for >80 studies with extensive phenotype data. To date, 63 phenotypes have been harmonized across thousands of participants from up to 17 studies per phenotype (participants recruited 1948-2012). 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 code used to generate the 63 harmonized phenotypes, enabling others to reproduce, modify or extend these harmonizations to additional studies; and (2) results of labeling thousands of phenotype variables with controlled vocabulary terms.
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http://dx.doi.org/10.1093/aje/kwab115DOI Listing
April 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

Alternative splicing of alters the risk for severe COVID-19.

medRxiv 2021 Mar 25. Epub 2021 Mar 25.

A locus containing has been identified as a risk locus for severe COVID-19 among Europeans ancestry individuals, with a protective haplotype of ∼75 kilobases derived from Neanderthals. Here, we show that among several potentially causal variants at this locus, a splice variant of occurs in people of African ancestry independently of the Neanderthal haplotype and confers protection against COVID-19 of a magnitude similar to that seen in individuals without African ancestry.
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http://dx.doi.org/10.1101/2021.03.20.21254005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010745PMC
March 2021

Robust, flexible, and scalable tests for Hardy-Weinberg equilibrium across diverse ancestries.

Genetics 2021 May;218(1)

Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.

Traditional Hardy-Weinberg equilibrium (HWE) tests (the χ2 test and the exact test) have long been used as a metric for evaluating genotype quality, as technical artifacts leading to incorrect genotype calls often can be identified as deviations from HWE. However, in data sets composed of individuals from diverse ancestries, HWE can be violated even without genotyping error, complicating the use of HWE testing to assess genotype data quality. In this manuscript, we present the Robust Unified Test for HWE (RUTH) to test for HWE while accounting for population structure and genotype uncertainty, and to evaluate the impact of population heterogeneity and genotype uncertainty on the standard HWE tests and alternative methods using simulated and real sequence data sets. Our results demonstrate that ignoring population structure or genotype uncertainty in HWE tests can inflate false-positive rates by many orders of magnitude. Our evaluations demonstrate different tradeoffs between false positives and statistical power across the methods, with RUTH consistently among the best across all evaluations. RUTH is implemented as a practical and scalable software tool to rapidly perform HWE tests across millions of markers and hundreds of thousands of individuals while supporting standard VCF/BCF formats. RUTH is publicly available at https://www.github.com/statgen/ruth.
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http://dx.doi.org/10.1093/genetics/iyab044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128395PMC
May 2021

Lipoprotein(a) and Coronary Artery Disease Risk Without a Family History of Heart Disease.

J Am Heart Assoc 2021 Feb 26;10(5):e017470. Epub 2021 Feb 26.

Cardiovascular Research Center and Center for Genomic Medicine Massachusetts General Hospital Boston MA.

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http://dx.doi.org/10.1161/JAHA.120.017470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174293PMC
February 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

Heterozygous Gene Deficiency and Risk of Coronary Artery Disease.

Circ Genom Precis Med 2020 10 30;13(5):417-423. Epub 2020 Aug 30.

Center for Genomic Medicine (C.A.E., P.N., N.G., S.G., A.V.K., S.K.), Massachusetts General Hospital, Boston.

Background: Familial sitosterolemia is a rare Mendelian disorder characterized by hyperabsorption and decreased biliary excretion of dietary sterols. Affected individuals typically have complete genetic deficiency-homozygous loss-of-function (LoF) variants-in the or genes and have substantially elevated plasma sitosterol and LDL (low-density lipoprotein) cholesterol (LDL-C) levels. The impact of partial genetic deficiency of or -as occurs in heterozygous carriers of LoF variants-on LDL-C and risk of coronary artery disease (CAD) has remained uncertain.

Methods: We first recruited 9 sitosterolemia families, identified causative LoF variants in or , and evaluated the associations of these or LoF variants with plasma phytosterols and lipid levels. We next assessed for LoF variants in or in CAD cases (n=29 321) versus controls (n=357 326). We tested the association of rare LoF variants in or with blood lipids and risk for CAD. Rare LoF variants were defined as protein-truncating variants with minor allele frequency <0.1% in or .

Results: In sitosterolemia families, 7 pedigrees harbored causative LoF variants in and 2 pedigrees in . Homozygous LoF variants in either or led to marked elevations in sitosterol and LDL-C. Of those sitosterolemia families, heterozygous carriers of LoF variants exhibited increased sitosterol and LDL-C levels compared with noncarriers. Within large-scale CAD case-control cohorts, prevalence of rare LoF variants in and in was ≈0.1% each. heterozygous LoF variant carriers had significantly elevated LDL-C levels (25 mg/dL [95% CI, 14-35]; =1.1×10) and were at 2-fold increased risk of CAD (odds ratio, 2.06 [95% CI, 1.27-3.35]; =0.004). By contrast, heterozygous LoF carrier status was not associated with increased LDL-C or risk of CAD.

Conclusions: Although familial sitosterolemia is traditionally considered as a recessive disorder, we observed that heterozygous carriers of an LoF variant in had significantly increased sitosterol and LDL-C levels and a 2-fold increase in risk of CAD.
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http://dx.doi.org/10.1161/CIRCGEN.119.002871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983048PMC
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

Genetic Variation in Cardiometabolic Traits and Medication Targets and the Risk of Hypertensive Disorders of Pregnancy.

Circulation 2020 Aug 17;142(7):711-713. Epub 2020 Aug 17.

Cardiology Division (M.C.H., K.A., M.J.W., A.A.S., N.S.S., P.N.), Massachusetts General Hospital, Harvard Medical School, Boston.

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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.047936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7436942PMC
August 2020

Cardiovascular health, genetic risk, and risk of dementia in the Framingham Heart Study.

Neurology 2020 09 20;95(10):e1341-e1350. Epub 2020 Jul 20.

From the Departments of Biostatistics (G.M.P., A.S.B., V.X., A.L.D.) and Epidemiology (R.S.V.), Boston University School of Public Health; Boston University and NHLBI's Framingham Heart Study (A.S.B., C.L.S., V.X., R.S.V., A.L.D., S.S.), Framingham; Department of Neurology (A.S.B., C.L.S., A.L.D., S.S.), Boston University School of Medicine, MA; Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases (C.L.S., S.S.), University of Texas Health Sciences Center, San Antonio; Sections of Preventive Medicine & Epidemiology and Cardiology (V.X., R.S.V.), Department of Medicine, Boston University, MA; Melbourne Dementia Research Centre (M.P.P.), The Florey Institute for Neuroscience and Mental Health; Faculty of Medicine, Dentistry, and Health Sciences (M.P.P.), University of Melbourne, Parkville; Centre for Human Psychopharmacology (M.P.P.), Swinburne University of Technology, Hawthorn, Australia; and Harvard T.H. Chan School of Public Health (M.P.P.), Boston, MA.

Objective: To determine the joint role of ideal cardiovascular health (CVH) and genetic risk on risk of dementia.

Methods: We categorized CVH on the basis of the American Heart Association Ideal CVH Index and genetic risk through a genetic risk score (GRS) of common genetic variants and the ε4 genotype in 1,211 Framingham Heart Study (FHS) offspring cohort participants. We used multivariable Cox proportional hazards regression models to examine the association between CVH, genetic risk, and incident all-cause dementia with up to 10 years of follow-up (mean 8.4 years, 96 incident dementia cases), adjusting for age, sex, and education.

Results: We observed that a high GRS (>80th percentile) was associated with a 2.6-fold risk of dementia (95% confidence interval [CI] of hazard ratio [HR] 1.23-5.29; = 0.012) compared with having a low GRS (<20th percentile); carrying at least 1 ε4 allele was associated with a 2.3-fold risk of dementia compared with not carrying an ε4 allele (95% CI of HR 1.49-3.53; = 0.0002), and having a favorable CVH showed a 0.45-fold lower risk of dementia (95% CI of HR 0.20-1.01; = 0.0527) compared to having an unfavorable CVH when all 3 components were included in the model. We did not observe an interaction between CVH and GRS ( = 0.99) or ε4 ( = 0.16).

Conclusions: We observed that both genetic risk and CVH contribute additively to dementia risk.
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http://dx.doi.org/10.1212/WNL.0000000000010306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538213PMC
September 2020

Evaluation of population stratification adjustment using genome-wide or exonic variants.

Genet Epidemiol 2020 10 30;44(7):702-716. Epub 2020 Jun 30.

Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts.

Population stratification may cause an inflated type-I error and spurious association when assessing the association between genetic variations with an outcome. Many genetic association studies are now using exonic variants, which captures only 1% of the genome, however, population stratification adjustments have not been evaluated in the context of exonic variants. We compare the performance of two established approaches: principal components analysis (PCA) and mixed-effects models and assess the utility of genome-wide (GW) and exonic variants, by simulation and using a data set from the Framingham Heart Study. Our results illustrate that although the PCs and genetic relationship matrices computed by GW and exonic markers are different, the type-I error rate of association tests for common variants with additive effect appear to be properly controlled in the presence of population stratification. In addition, by considering single nucleotide variants (SNVs) that have different levels of confounding by population stratification, we also compare the power across multiple association approaches to account for population stratification such as PC-based corrections and mixed-effects models. We find that while these two methods achieve a similar power for SNVs that have a low or medium level of confounding by population stratification, mixed-effects model can reach a higher power for SNVs highly confounded by population stratification.
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http://dx.doi.org/10.1002/gepi.22332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722041PMC
October 2020

EDEM3 Modulates Plasma Triglyceride Level through Its Regulation of LRP1 Expression.

iScience 2020 Apr 11;23(4):100973. Epub 2020 Mar 11.

Center for Genomic Medicine, Massachusetts General Hospital, Simches 5.500, 185 Cambridge St., Boston, MA 02114, USA. Electronic address:

Human genetics studies have uncovered genetic variants that can be used to guide biological research and prioritize molecular targets for therapeutic intervention for complex diseases. We have identified a missense variant (P746S) in EDEM3 associated with lower blood triglyceride (TG) levels in >300,000 individuals. Functional analyses in cell and mouse models show that EDEM3 deficiency strongly increased the uptake of very-low-density lipoprotein and thereby reduced the plasma TG level, as a result of up-regulated expression of LRP1 receptor. We demonstrate that EDEM3 deletion up-regulated the pathways for RNA and endoplasmic reticulum protein processing and transport, and consequently increased the cell surface mannose-containing glycoproteins, including LRP1. Metabolomics analyses reveal a cellular TG accumulation under EDEM3 deficiency, a profile consistent with individuals carrying EDEM3 P746S. Our study identifies EDEM3 as a regulator of blood TG, and targeted inhibition of EDEM3 may provide a complementary approach for lowering elevated blood TG concentrations.
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http://dx.doi.org/10.1016/j.isci.2020.100973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093811PMC
April 2020

Beverage Consumption and Longitudinal Changes in Lipoprotein Concentrations and Incident Dyslipidemia in US Adults: The Framingham Heart Study.

J Am Heart Assoc 2020 03 26;9(5):e014083. Epub 2020 Feb 26.

Nutritional Epidemiology Program Jean Mayer USDA Human Nutrition Research Center on Aging Tufts University Boston MA USA.

Background Limited data are available on the prospective relationship between beverage consumption and plasma lipid and lipoprotein concentrations. Two major sources of sugar in the US diet are sugar-sweetened beverages (SSBs) and 100% fruit juices. Low-calorie sweetened beverages are common replacements. Methods and Results Fasting plasma lipoprotein concentrations were measured in the FOS (Framingham Offspring Study) (1991-2014; N=3146) and Generation Three (2002-2001; N=3584) cohorts. Beverage intakes were estimated from food frequency questionnaires and grouped into 5 intake categories. Mixed-effect linear regression models were used to examine 4-year changes in lipoprotein measures, and Cox proportional hazard models were used to estimate hazard ratios for incident dyslipidemia, adjusting for potential confounding factors. We found that regular (>1 serving per day) versus low (<1 serving per month) SSB consumption was associated with a greater mean decrease in high-density lipoprotein cholesterol (β±standard error -1.6±0.4 mg/dL; <0.0001) and increase in triglyceride (β±standard error: 4.4±2.2 mg/dL; =0.003) concentrations. Long-term regular SSB consumers also had a higher incidence of high triglyceride (hazard ratio, 1.52; 95% CI, 1.03-2.25) compared with low consumers. Although recent regular low-calorie sweetened beverage consumers had a higher incidence of high non-high-density lipoprotein cholesterol (hazard ratio, 1.40; 95% CI, 1.17-1.69) and low-density lipoprotein cholesterol (hazard ratio, 1.27; 95% CI, 1.05-1.53) concentrations compared with low consumers, cumulative average intakes of low-calorie sweetened beverages were not associated with changes in non-high-density lipoprotein cholesterol, low-density lipoprotein cholesterol concentrations, or incident dyslipidemias. Conclusions SSB intake was associated with adverse changes in high-density lipoprotein cholesterol and triglyceride concentrations, along with a higher risk of incident dyslipidemia, suggesting that increased SSB consumption may contribute to the development of dyslipidemia.
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http://dx.doi.org/10.1161/JAHA.119.014083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335580PMC
March 2020

Searching for parent-of-origin effects on cardiometabolic traits in imprinted genomic regions.

Eur J Hum Genet 2020 05 2;28(5):646-655. Epub 2020 Jan 2.

Braun School of Public Health, The Hebrew University of Jerusalem, 99112102, Jerusalem, Israel.

Cardiometabolic traits pose a major global public health burden. Large-scale genome-wide association studies (GWAS) have identified multiple loci accounting for up to 30% of the genetic variance in complex traits such as cardiometabolic traits. However, the contribution of parent-of-origin effects (POEs) to complex traits has been largely ignored in GWAS. Family-based studies enable the assessment of POEs in genetic association analyses. We investigated POEs on a range of complex traits in 3 family-based studies. The discovery phase was carried out in large pedigrees from the Kibbutzim Family Study (n = 901 individuals) and in 872 parent-offspring trios from the Jerusalem Perinatal Study. Focusing on imprinted genomic regions, we examined parent-specific associations with 12 complex traits (i.e., body-size, blood pressure, lipids), mostly cardiometabolic risk traits. Forty five of the 11,967 SNPs initially found to have POE were evaluated for replication (p value < 1 × 10) in Framingham Heart Study families (max n = 8000 individuals). Three common variants yielded evidence of POE in the meta-analysis. Two variants, located on chr6 in the HLA region, showed a paternal effect on height (rs1042136: β = -0.023, p value = 1.5 × 10 and rs1431403: β = -0.011, p value = 5.4 × 10). The corresponding maternally-derived effects were statistically nonsignificant. The variant rs9332053, located on chr13 in RCBTB2 gene, demonstrated a maternal effect on hip circumference (β = -4.24, p value = 9.6 × 10; β = 1.29, p value = 0.23). These findings provide evidence for the utility of incorporating POEs into association studies of cardiometabolic traits, especially anthropometric traits. The study highlights the benefits of using family-based data for deciphering the genetic architecture of complex traits.
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http://dx.doi.org/10.1038/s41431-019-0568-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7170899PMC
May 2020

Long-Term Cardiovascular Risk in Women With Hypertension During Pregnancy.

J Am Coll Cardiol 2019 12 11;74(22):2743-2754. Epub 2019 Nov 11.

Cardiology Division and Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts; Cardiovascular Research Center and Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts. Electronic address:

Background: History of a hypertensive disorder of pregnancy (HDP) among women may be useful to refine atherosclerotic cardiovascular disease risk assessments. However, future risk of diverse cardiovascular conditions in asymptomatic middle-aged women with prior HDP remains unknown.

Objectives: The purpose of this study was to examine the long-term incidence of diverse cardiovascular conditions among middle-aged women with and without prior HDP.

Methods: Women in the prospective, observational UK Biobank age 40 to 69 years who reported ≥1 live birth were included. Noninvasive arterial stiffness measurement was performed in a subset of women. Cox models were fitted to associate HDP with incident cardiovascular diseases. Causal mediation analyses estimated the contribution of conventional risk factors to observed associations.

Results: Of 220,024 women included, 2,808 (1.3%) had prior HDP. The mean age at baseline was 57.4 ± 7.8 years, and women were followed for median 7 years (interquartile range: 6.3 to 7.7 years). Women with HDP had elevated arterial stiffness indexes and greater prevalence of chronic hypertension compared with women without HDP. Overall, 7.0 versus 5.3 age-adjusted incident cardiovascular conditions occurred per 1,000 women-years for women with versus without prior HDP, respectively (p = 0.001). In analysis of time-to-first incident cardiovascular diagnosis, prior HDP was associated with a hazard ratio (HR) of 1.3 (95% CI: 1.04 to 1.60; p = 0.02). HDP was associated with greater incidence of CAD (HR: 1.8; 95% CI: 1.3 to 2.6; p < 0.001), heart failure (HR: 1.7; 95% CI: 1.04 to 2.60; p = 0.03), aortic stenosis (HR: 2.9; 95% CI: 1.5 to 5.4; p < 0.001), and mitral regurgitation (HR: 5.0; 95% CI: 1.5 to 17.1; p = 0.01). In causal mediation analyses, chronic hypertension explained 64% of HDP's association with CAD and 49% of HDP's association with heart failure.

Conclusions: Hypertensive disorders of pregnancy are associated with accelerated cardiovascular aging and more diverse cardiovascular conditions than previously appreciated, including valvular heart disease. Cardiovascular risk after HDP is largely but incompletely mediated by development of chronic hypertension.
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http://dx.doi.org/10.1016/j.jacc.2019.09.052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981240PMC
December 2019

Rare Protein-Truncating Variants in APOB, Lower Low-Density Lipoprotein Cholesterol, and Protection Against Coronary Heart Disease.

Circ Genom Precis Med 2019 05;12(5):e002376

Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (A.V.K., M.C., S.K.).

Background Familial hypobetalipoproteinemia is a genetic disorder caused by rare protein-truncating variants (PTV) in the gene encoding APOB (apolipoprotein B), the major protein component of LDL (low-density lipoprotein) and triglyceride-rich lipoprotein particles. Whether heterozygous APOB deficiency is associated with decreased risk for coronary heart disease (CHD) is uncertain. We combined family-based and large scale gene-sequencing to characterize the association of rare PTVs in APOB with circulating LDL-C (LDL cholesterol), triglycerides, and risk for CHD. Methods We sequenced the APOB gene in 29 Japanese hypobetalipoproteinemia families, as well as 57 973 individuals derived from 12 CHD case-control studies-18 442 with early-onset CHD and 39 531 controls. We defined PTVs as variants that lead to a premature stop, disrupt canonical splice-sites, or lead to insertions/deletions that shift reading frame. We tested the association of rare APOB PTV carrier status with blood lipid levels and CHD. Results Among 29 familial hypobetalipoproteinemia families, 8 families harbored APOB PTVs. Carrying 1 APOB PTV was associated with 55 mg/dL lower LDL-C ( P=3×10) and 53% lower triglyceride level ( P=2×10). Among 12 case-control studies, an APOB PTV was present in 0.038% of CHD cases as compared to 0.092% of controls. APOB PTV carrier status was associated with a 43 mg/dL lower LDL-C ( P=2×10), a 30% decrease in triglycerides ( P=5×10), and a 72% lower risk for CHD (odds ratio, 0.28; 95% CI, 0.12-0.64; P=0.002). Conclusions Rare PTV mutations in APOB which are associated with lower LDL-C and reduced triglycerides also confer protection against CHD.
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http://dx.doi.org/10.1161/CIRCGEN.118.002376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7044908PMC
May 2019

Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution.

Nat Genet 2019 03 18;51(3):452-469. Epub 2019 Feb 18.

Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.

Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.
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http://dx.doi.org/10.1038/s41588-018-0334-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6560635PMC
March 2019

Genetically elevated high-density lipoprotein cholesterol through the cholesteryl ester transfer protein gene does not associate with risk of Alzheimer's disease.

Alzheimers Dement (Amst) 2018 22;10:595-598. Epub 2018 Sep 22.

NHLBI's Framingham Heart Study, Framingham, MA, USA.

Introduction: There is conflicting evidence whether high-density lipoprotein cholesterol (HDL-C) is a risk factor for Alzheimer's disease (AD) and dementia. Genetic variation in the cholesteryl ester transfer protein () locus is associated with altered HDL-C. We aimed to assess AD risk by genetically predicted HDL-C.

Methods: Ten single nucleotide polymorphisms within the locus predicting HDL-C were applied to the International Genomics of Alzheimer's Project (IGAP) exome chip stage 1 results in up 16,097 late onset AD cases and 18,077 cognitively normal elderly controls. We performed instrumental variables analysis using inverse variance weighting, weighted median, and MR-Egger.

Results: Based on 10 single nucleotide polymorphisms distinctly predicting HDL-C in the locus, we found that HDL-C was not associated with risk of AD ( > .7).

Discussion: Our study does not support the role of HDL-C on risk of AD through HDL-C altered by . This study does not rule out other mechanisms by which HDL-C affects risk of AD.
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http://dx.doi.org/10.1016/j.dadm.2018.08.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6215982PMC
September 2018

Genetic Interaction with Plasma Lipids on Alzheimer's Disease in the Framingham Heart Study.

J Alzheimers Dis 2018 ;66(3):1275-1282

NHLBI's Framingham Heart Study, Framingham, MA, USA.

Epidemiological and genetic studies have pointed to the role of cholesterol in Alzheimer's disease (AD). We explored the interaction of a genetic risk score (GRS) of AD risk alleles with mid-life plasma lipid levels (LDL-C, HDL-C, and triglycerides) on risk for AD in the Framingham Heart Study (FHS). Mid-life (between the ages of 40-60 years old) lipid levels were obtained from individuals in the FHS Original and Offspring cohorts (157 cases and 2,882 controls) with genetic data and AD status available. Cox proportional hazards regression was performed to test the interaction between mid-life lipid levels and an AD GRS, as well as the individual contributing SNPs, on risk of incident AD adjusting for age, sex, and cohort. We found a significant interaction between a GRS of AD loci and log triglyceride levels on risk of clinical AD (p = 0.006), but no interaction of the GRS with HDL-C (p = 0.458) or LDL-C (p = 0.366). We then tested the interaction between the individual SNPs contributing to the GRS and log triglycerides. We found two SNPs that had interactions with triglycerides on AD risk that reached a p-value < 0.05 (rs11218343 and APOEɛ4). The association between some AD SNPs and risk of AD may be modified by triglyceride levels. Furthermore, sequential testing of a GRS with a set of traits on disease followed by testing individual SNPs for interaction provides a framework for narrowing the associations that need to be tested for interaction analyses. Replication is needed to confirm these findings.
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http://dx.doi.org/10.3233/JAD-180751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6460910PMC
November 2019

Evaluation of a phenotype imputation approach using GAW20 simulated data.

BMC Proc 2018 17;12(Suppl 9):56. Epub 2018 Sep 17.

Department of Biostatistics, Boston University School of Public Health, 801 Massachusetts Ave 3rd Floor, Boston, MA 02118 USA.

Statistical power, which is the probability of correctly rejecting a false null hypothesis, is a limitation of genome-wide association studies (GWAS). Sample size is a major component of statistical power that can be easily affected by missingness in phenotypic data and restrain the ability to detect associated single-nucleotide polymorphisms (SNPs) with small effect sizes. Although some phenotypes are hard to collect because of cost and loss to follow-up, correlated phenotypes that are easily collected can be leveraged for association analysis. In this paper, we evaluate a phenotype imputation method that incorporates family structure and correlation between multiple phenotypes using GAW20 simulated data. The distribution of missing values is derived using information contained in the missing sample's relatives and additional correlated phenotypes. We show that this imputation method can improve power in the association analysis compared with excluding observations with missing data, while achieving the correct Type I error rate. We also examine factors that may affect the imputation accuracy.
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http://dx.doi.org/10.1186/s12919-018-0134-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6157247PMC
September 2018

Network analysis of drug effect on triglyceride-associated DNA methylation.

BMC Proc 2018 17;12(Suppl 9):27. Epub 2018 Sep 17.

1Department of Biostatistics, Boston University, 801 Massachusetts Avenue 3rd Floor, Boston, MA 02118 USA.

Background: DNA methylation, an epigenetic modification, can be affected by environmental factors and thus regulate gene expression levels that can lead to alterations of certain phenotypes. Network analysis has been used successfully to discover gene sets that are expressed differently across multiple disease states and suggest possible pathways of disease progression. We applied this framework to compare DNA methylation levels before and after lipid-lowering medication and to identify modules that differ topologically between the two time points, revealing the association between lipid medication and these triglyceride-related methylation sites.

Methods: We performed quality control using beta-mixture quantile normalization on 463,995 cytosine-phosphate-guanine (CpG) sites and deleted problematic sites, resulting in 423,004 probes. We identified 14,850 probes that were nominally associated with triglycerides prior to treatment and performed weighted gene correlation network analysis (WGCNA) to construct pre- and posttreatment methylation networks of these probes. We then applied both WGCNA module preservation and generalized Hamming distance (GHD) to identify modules with topological differences between the pre- and posttreatment. For modules with structural changes between 2 time points, we performed pathway-enrichment analysis to gain further insight into the biological function of the genes from these modules.

Results: Six triglyceride-associated modules were identified using pretreatment methylation probes. The same 3 modules were not preserved in posttreatment data using both the module-preservation and the GHD methods. Top-enriched pathways for the 3 differentially methylated modules are sphingolipid signaling pathway, proteoglycans in cancer, and metabolic pathways ( values < 0.005). One module in particular included an enrichment of lipid-related pathways among the top results.

Conclusions: The same 3 modules, which were differentially methylated between pre- and posttreatment, were identified using both WGCNA module-preservation and GHD methods. Pathway analysis revealed that triglyceride-associated modules contain groups of genes that are involved in lipid signaling and metabolism. These 3 modules may provide insight into the effect of fenofibrate on changes in triglyceride levels and these methylation sites.
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http://dx.doi.org/10.1186/s12919-018-0130-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6157190PMC
September 2018

Genetics of blood lipids among ~300,000 multi-ethnic participants of the Million Veteran Program.

Nat Genet 2018 11 1;50(11):1514-1523. Epub 2018 Oct 1.

Initiative for Noncommunicable Diseases, Health Systems and Population Studies Division, International Centre for Diarrheal Disease Research, Dhaka, Bangladesh.

The Million Veteran Program (MVP) was established in 2011 as a national research initiative to determine how genetic variation influences the health of US military veterans. Here we genotyped 312,571 MVP participants using a custom biobank array and linked the genetic data to laboratory and clinical phenotypes extracted from electronic health records covering a median of 10.0 years of follow-up. Among 297,626 veterans with at least one blood lipid measurement, including 57,332 black and 24,743 Hispanic participants, we tested up to around 32 million variants for association with lipid levels and identified 118 novel genome-wide significant loci after meta-analysis with data from the Global Lipids Genetics Consortium (total n > 600,000). Through a focus on mutations predicted to result in a loss of gene function and a phenome-wide association study, we propose novel indications for pharmaceutical inhibitors targeting PCSK9 (abdominal aortic aneurysm), ANGPTL4 (type 2 diabetes) and PDE3B (triglycerides and coronary disease).
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http://dx.doi.org/10.1038/s41588-018-0222-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6521726PMC
November 2018

Publisher Correction: Deep coverage whole genome sequences and plasma lipoprotein(a) in individuals of European and African ancestries.

Nat Commun 2018 08 23;9(1):3493. Epub 2018 Aug 23.

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.

The original version of this article contained an error in the name of the author Ramachandran S. Vasan, which was incorrectly given as Vasan S. Ramachandran. This has now been corrected in both the PDF and HTML versions of the article.
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http://dx.doi.org/10.1038/s41467-018-05975-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6107495PMC
August 2018

Deep-coverage whole genome sequences and blood lipids among 16,324 individuals.

Nat Commun 2018 08 23;9(1):3391. Epub 2018 Aug 23.

School of Medicine, University of Maryland, Baltimore, MD, 21201, USA.

Large-scale deep-coverage whole-genome sequencing (WGS) is now feasible and offers potential advantages for locus discovery. We perform WGS in 16,324 participants from four ancestries at mean depth >29X and analyze genotypes with four quantitative traits-plasma total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, and triglycerides. Common variant association yields known loci except for few variants previously poorly imputed. Rare coding variant association yields known Mendelian dyslipidemia genes but rare non-coding variant association detects no signals. A high 2M-SNP LDL-C polygenic score (top 5th percentile) confers similar effect size to a monogenic mutation (~30 mg/dl higher for each); however, among those with severe hypercholesterolemia, 23% have a high polygenic score and only 2% carry a monogenic mutation. At these sample sizes and for these phenotypes, the incremental value of WGS for discovery is limited but WGS permits simultaneous assessment of monogenic and polygenic models to severe hypercholesterolemia.
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http://dx.doi.org/10.1038/s41467-018-05747-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6107638PMC
August 2018

Deep coverage whole genome sequences and plasma lipoprotein(a) in individuals of European and African ancestries.

Nat Commun 2018 07 4;9(1):2606. Epub 2018 Jul 4.

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.

Lipoprotein(a), Lp(a), is a modified low-density lipoprotein particle that contains apolipoprotein(a), encoded by LPA, and is a highly heritable, causal risk factor for cardiovascular diseases that varies in concentrations across ancestries. Here, we use deep-coverage whole genome sequencing in 8392 individuals of European and African ancestry to discover and interpret both single-nucleotide variants and copy number (CN) variation associated with Lp(a). We observe that genetic determinants between Europeans and Africans have several unique determinants. The common variant rs12740374 associated with Lp(a) cholesterol is an eQTL for SORT1 and independent of LDL cholesterol. Observed associations of aggregates of rare non-coding variants are largely explained by LPA structural variation, namely the LPA kringle IV 2 (KIV2)-CN. Finally, we find that LPA risk genotypes confer greater relative risk for incident atherosclerotic cardiovascular diseases compared to directly measured Lp(a), and are significantly associated with measures of subclinical atherosclerosis in African Americans.
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http://dx.doi.org/10.1038/s41467-018-04668-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6031652PMC
July 2018

Observational and Genetic Associations of Resting Heart Rate With Aortic Valve Calcium.

Am J Cardiol 2018 05 13;121(10):1246-1252. Epub 2018 Feb 13.

Division of Intramural Research, National Heart Lung and Blood Institute (NHLBI) and NHLBI Framingham Heart Study, Framingham Massachusetts; Cardiology Section, Boston Veterans Administration Healthcare System, Harvard Medical School, Boston, Massachusetts. Electronic address:

It is unknown if lifelong exposure to increased hemodynamic stress from an elevated resting heart rate (HR) may contribute to aortic valve calcium (AVC). We performed multivariate regression analyses using data from 1,266 Framingham Heart Study (FHS) Offspring cohort participants and 6,764 Multi-Ethnic Study of Atherosclerosis (MESA) participants. We constructed a genetic risk score (GRS) for HR using summary-level data in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) AVC Consortium to investigate if there was evidence in favor of a causal relation. AVC was present in 39% of FHS Offspring cohort participants and in 13% of MESA cohort participants. In multivariate adjusted models, participants in the highest resting HR quartiles had significantly greater prevalence of AVC, with a prevalence ratio of 1.19 (95% confidence interval [CI] 0.99 to 1.44) for the FHS Offspring cohort and 1.32 (95% CI 1.12 to 1.63) for the MESA cohort, compared with those in the lowest quartile. There was a similar increase in the prevalence of AVC per standard deviation increase in resting HR in both FHS Offspring (prevalence ratio 1.08, 95% CI 1.01 to 1.15) and MESA (1.10, 95% CI 1.03 to 1.17). In contrast with these observational findings, a HR associated GRS was not significantly associated with AVC. Although our observational analysis indicates that a higher resting HR is associated with AVC, our genetic results do not support a causal relation. Unmeasured environmental and/or lifestyle factors associated with both increased resting HR and AVC that are not fully explained by covariates in our observational models may account for the association between resting HR and AVC.
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http://dx.doi.org/10.1016/j.amjcard.2018.01.048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6788291PMC
May 2018

Publisher Correction: Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.

Nat Genet 2018 05;50(5):766-767

Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany.

In the version of this article originally published, one of the two authors with the name Wei Zhao was omitted from the author list and the affiliations for both authors were assigned to the single Wei Zhao in the author list. In addition, the ORCID for Wei Zhao (Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA) was incorrectly assigned to author Wei Zhou. The errors have been corrected in the HTML and PDF versions of the article.
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http://dx.doi.org/10.1038/s41588-018-0082-3DOI Listing
May 2018
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