Institute for Translational Genomics and Population science

Los Angeles, CA, United States

Institute for Translational Genomics and Population science

Los Angeles, CA, United States
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Nelson S.C.,University of Washington | Stilp A.M.,University of Washington | Papanicolaou G.J.,U.S. National Institutes of Health | Taylor K.D.,Institute for Translational Genomics and Population science | And 3 more authors.
Human Molecular Genetics | Year: 2015

Imputation is commonly used in genome-wide association studies to expand the set of genetic variants available for analysis. Larger and more diverse reference panels, such as the final Phase 3 of the 1000 Genomes Project, hold promise for improving imputation accuracy in genetically diverse populations such as Hispanics/Latinos in the USA. Here, we sought to empirically evaluate imputation accuracy when imputing to a 1000 Genomes Phase 3 versus a Phase 1 reference, using participants from the Hispanic Community Health Study/Study of Latinos. Our assessments included calculating the correlation between imputed and observed allelic dosage in a subset of samples genotyped on a supplemental array. We observed that the Phase 3 reference yielded higher accuracy at rare variants, but that the two reference panels were comparable at common variants. At a sample level, the Phase 3 reference improved imputation accuracy in Hispanic/Latino samples from the Caribbean more than for Mainland samples, which we attribute primarily to the additional reference panel samples available in Phase 3. We conclude that a 1000 Genomes Project Phase 3 reference panel can yield improved imputation accuracy compared with Phase 1, particularly for rare variants and for samples of certain genetic ancestry compositions. Our findings can inform imputation design for other genome-wide association studies of participants with diverse ancestries, especially as larger and more diverse reference panels continue to become available. © The Author 2016. Published by Oxford University Press. All rights reserved.


Shendre A.,University of Alabama at Birmingham | Wiener H.,University of Alabama at Birmingham | Irvin M.R.,University of Alabama at Birmingham | Overton E.T.,University of Alabama | And 4 more authors.
Circulation: Cardiovascular Genetics | Year: 2017

Background - Local ancestry may contribute to the disproportionate burden of subclinical and clinical cardiovascular disease among admixed African Americans compared with other populations, suggesting a rationale for admixture mapping. Methods and Results - We estimated local European ancestry (LEA) using Local Ancestry inference in adMixed Populations using Linkage Disequilibrium method (LAMP-LD) and evaluated the association with common carotid artery intima-media thickness (cCIMT) using multivariable linear regression analysis among 1554 African Americans from MESA (Multi-Ethnic Study of Atherosclerosis). We conducted secondary analysis to examine the significant cCIMT-LEA associations with clinical cardiovascular disease events. We observed genome-wide significance in relation to cCIMT association with the SERGEF gene (secretion-regulating guanine nucleotide exchange factor; β=0.0137; P=2.98×10 - 4), also associated with higher odds of stroke (odds ratio=1.71; P=0.02). Several regions, in particular CADPS gene (Ca 2+ -dependent secretion activator 1) region identified in MESA, were also replicated in the ARIC cohort (Atherosclerosis Risk in Communities). We observed other cCIMT-LEA regions associated with other clinical events, most notably the regions harboring CKMT2 gene (creatine kinase, mitochondrial 2) and RASGRF2 gene (Ras protein-specific guanine nucleotide-releasing factor 2) with all clinical events except stroke, the LRRC3B gene (leucine-rich repeat containing 3B) with myocardial infarction, the PRMT3 gene (protein arginine methyltransferase 3) with stroke, and the LHFPL2 gene (lipoma high mobility group protein I-C fusion partner-like 2) with hard and all coronary heart disease. Conclusions - We identified several novel LEA regions, in addition to previously identified genetic variations, associated with cCIMT and cardiovascular disease events among African Americans. © 2017 American Heart Association, Inc.


Lee C.C.,University of Toronto | Watkins S.M.,Lipomics Technologies | Lorenzo C.,University of Texas Health Science Center at San Antonio | Il'Yasova D.,Georgia State University | And 4 more authors.
Diabetes Care | Year: 2016

OBJECTIVE Recent studies using untargeted metabolomics approaches have suggested that plasma branched-chain amino acids (BCAAs) are associated with incident diabetes. However, little is known about the role of plasma BCAAs in metabolic abnormalities underlying diabetes and whether these relationships are consistent across ethnic populations at high risk for diabetes. We investigated the associations of BCAAs with insulin sensitivity (SI), acute insulin response (AIR), and metabolic clearance of insulin (MCRI) in a multiethnic cohort. RESEARCH DESIGN AND METHODS In 685 participants without diabetes of the Insulin Resistance Atherosclerosis Study (IRAS) (290 Caucasians, 165 African Americans, and 230 Hispanics),wemeasured plasma BCAAs (sum of valine, leucine, and isoleucine) by mass spectrometry and SI, AIR, and MCRI by frequently sampled intravenous glucose tolerance tests. RESULTS Elevated plasma BCAAs were inversely associated with SI andMCRI and positively associated with fasting insulin in regression models adjusted for potential confounders (β = 20.0012 [95% CI20.0018,20.00059], P < 0.001 for SI; β =20.0013 [95% CI 20.0018, 20.00082], P < 0.001 for MCRI; and β = 0.0015 [95% CI 0.0008, 0.0023], P < 0.001 for fasting insulin). The association of BCAA with SI was significantly modified by ethnicity, with the association only being significant in Caucasians and Hispanics. Elevated plasma BCAAs were associated with incident diabetes in Caucasians and Hispanics (multivariable-adjusted odds ratio per 1-SD increase in plasma BCAAs: 1.67 [95% CI 1.21, 2.29], P = 0.002) but not in African Americans. Plasma BCAAs were not associated with SI-adjusted AIR. CONCLUSIONS Plasma BCAAs are associated with incident diabetes and underlying metabolic abnormalities, although the associations were generally stronger in Caucasians and Hispanics. © 2016 by the American Diabetes Association.


PubMed | Lipomics Technologies, Retired, University of Texas Health Science Center at San Antonio, University of Toronto and 2 more.
Type: Journal Article | Journal: Diabetes care | Year: 2016

Recent studies using untargeted metabolomics approaches have suggested that plasma branched-chain amino acids (BCAAs) are associated with incident diabetes. However, little is known about the role of plasma BCAAs in metabolic abnormalities underlying diabetes and whether these relationships are consistent across ethnic populations at high risk for diabetes. We investigated the associations of BCAAs with insulin sensitivity (SI), acute insulin response (AIR), and metabolic clearance of insulin (MCRI) in a multiethnic cohort.In 685 participants without diabetes of the Insulin Resistance Atherosclerosis Study (IRAS) (290 Caucasians, 165 African Americans, and 230 Hispanics), we measured plasma BCAAs (sum of valine, leucine, and isoleucine) by mass spectrometry and SI, AIR, and MCRI by frequently sampled intravenous glucose tolerance tests.Elevated plasma BCAAs were inversely associated with SI and MCRI and positively associated with fasting insulin in regression models adjusted for potential confounders ( = -0.0012 [95% CI -0.0018, -0.00059], P < 0.001 for SI; = -0.0013 [95% CI -0.0018, -0.00082], P < 0.001 for MCRI; and = 0.0015 [95% CI 0.0008, 0.0023], P < 0.001 for fasting insulin). The association of BCAA with SI was significantly modified by ethnicity, with the association only being significant in Caucasians and Hispanics. Elevated plasma BCAAs were associated with incident diabetes in Caucasians and Hispanics (multivariable-adjusted odds ratio per 1-SD increase in plasma BCAAs: 1.67 [95% CI 1.21, 2.29], P = 0.002) but not in African Americans. Plasma BCAAs were not associated with SI-adjusted AIR.Plasma BCAAs are associated with incident diabetes and underlying metabolic abnormalities, although the associations were generally stronger in Caucasians and Hispanics.


PubMed | University of Minnesota, Morehouse School of Medicine, University of Turku, Center for Human Genetics and 38 more.
Type: Journal Article | Journal: American journal of human genetics | Year: 2016

Platelet production, maintenance, and clearance are tightly controlled processes indicative of platelets important roles in hemostasis and thrombosis. Platelets are common targets for primary and secondary prevention of several conditions. They are monitored clinically by complete blood counts, specifically with measurements of platelet count (PLT) and mean platelet volume (MPV). Identifying genetic effects on PLT and MPV can provide mechanistic insights into platelet biology and their role in disease. Therefore, we formed the Blood Cell Consortium (BCX) to perform a large-scale meta-analysis of Exomechip association results for PLT and MPV in 157,293 and 57,617 individuals, respectively. Using the low-frequency/rare coding variant-enriched Exomechip genotyping array, we sought to identify genetic variants associated with PLT and MPV. In addition to confirming 47 known PLT and 20 known MPV associations, we identified 32 PLT and 18 MPV associations not previously observed in the literature across the allele frequency spectrum, including rare large effect (FCER1A), low-frequency (IQGAP2, MAP1A, LY75), and common (ZMIZ2, SMG6, PEAR1, ARFGAP3/PACSIN2) variants. Several variants associated with PLT/MPV (PEAR1, MRVI1, PTGES3) were also associated with platelet reactivity. In concurrent BCX analyses, there was overlap of platelet-associated variants with red (MAP1A, TMPRSS6, ZMIZ2) and white (PEAR1, ZMIZ2, LY75) blood cell traits, suggesting common regulatory pathways with shared genetic architecture among these hematopoietic lineages. Our large-scale Exomechip analyses identified previously undocumented associations with platelet traits and further indicate that several complex quantitative hematological, lipid, and cardiovascular traits share genetic factors.


PubMed | Tobago Health Studies Office, Brown University, University of Verona, Childrens Hospital Oakland Research Institute and 35 more.
Type: Journal Article | Journal: American journal of human genetics | Year: 2016

Knowledge of the genetic basis of the type 2 diabetes (T2D)-related quantitative traits fasting glucose (FG) and insulin (FI) in African ancestry (AA) individuals has been limited. In non-diabetic subjects of AA (n = 20,209) and European ancestry (EA; n = 57,292), we performed trans-ethnic (AA+EA) fine-mapping of 54 established EA FG or FI loci with detailed functional annotation, assessed their relevance in AA individuals, and sought previously undescribed loci through trans-ethnic (AA+EA) meta-analysis. We narrowed credible sets of variants driving association signals for 22/54 EA-associated loci; 18/22 credible sets overlapped with active islet-specific enhancers or transcription factor (TF) binding sites, and 21/22 contained at least one TF motif. Of the 54 EA-associated loci, 23 were shared between EA and AA. Replication with an additional 10,096 AA individuals identified two previously undescribed FI loci, chrX FAM133A (rs213676) and chr5 PELO (rs6450057). Trans-ethnic analyses with regulatory annotation illuminate the genetic architecture of glycemic traits and suggest gene regulation as a target to advance precision medicine for T2D. Our approach to utilize state-of-the-art functional annotation and implement trans-ethnic association analysis for discovery and fine-mapping offers a framework for further follow-up and characterization of GWAS signals of complex trait loci.


PubMed | University of Washington, Northwestern University, San Diego State University, University of Illinois at Chicago and 6 more.
Type: | Journal: American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics | Year: 2016

Although generalized anxiety disorder (GAD) is heritable and aggregates in families, no genomic loci associated with GAD have been reported. We aimed to discover potential loci by conducting a genome-wide analysis of GAD symptoms in a large, population-based sample of Hispanic/Latino adults. Data came from 12,282 participants (aged 18-74) in the Hispanic Community Health Study/Study of Latinos. Using a shortened Spielberger Trait Anxiety measure, we analyzed the following: (i) a GAD symptoms score restricted to the three items tapping diagnostic features of GAD as defined by DSM-V; and (ii) a total trait anxiety score based on summing responses to all ten items. We first calculated the heritability due to common variants (h

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