Accessibility issues or difficulties with this website?
Call 919-962-2073 or email hchsadministration@unc.edu.

A Genome-wide Association Study Discovers 46 Loci of the Human Metabolome in the Hispanic Community Health Study/Study of Latinos.

TitleA Genome-wide Association Study Discovers 46 Loci of the Human Metabolome in the Hispanic Community Health Study/Study of Latinos.
Publication TypePublication
Year2020
AuthorsFeofanova EV, Chen H, Dai Y, Jia P, Grove ML, Morrison AC, Qi Q, Daviglus M, Cai J, North KE, Laurie CC, Kaplan RC, Boerwinkle E, Yu B
JournalAm J Hum Genet
Volume107
Issue5
Pagination849-863
Date Published2020 11 05
ISSN1537-6605
KeywordsAdult, Chromans, Cohort Studies, Coronary Disease, Cytochrome P450 Family 4, Diabetes Mellitus, Type 2, Female, Gene Expression, Genetic Predisposition to Disease, Genome, Human, genome-wide association study, Hispanic Americans, Humans, Male, Membrane Transport Proteins, Metabolome, Middle Aged, Phenotype, Polymorphism, Single Nucleotide, Propionates, Public Health, Quantitative Trait Loci, Quantitative Trait, Heritable, Vitamin E
Abstract

Variation in levels of the human metabolome reflect changes in homeostasis, providing a window into health and disease. The genetic impact on circulating metabolites in Hispanics, a population with high cardiometabolic disease burden, is largely unknown. We conducted genome-wide association analyses on 640 circulating metabolites in 3,926 Hispanic Community Health Study/Study of Latinos participants. The estimated heritability for 640 metabolites ranged between 0%-54% with a median at 2.5%. We discovered 46 variant-metabolite pairs (p value < 1.2 × 10, minor allele frequency ≥ 1%, proportion of variance explained [PEV] mean = 3.4%, PEV = 1%-22%) with generalized effects in two population-based studies and confirmed 301 known locus-metabolite associations. Half of the identified variants with generalized effect were located in genes, including five nonsynonymous variants. We identified co-localization with the expression quantitative trait loci at 105 discovered and 151 known loci-metabolites sets. rs5855544, upstream of SLC51A, was associated with higher levels of three steroid sulfates and co-localized with expression levels of SLC51A in several tissues. Mendelian randomization (MR) analysis identified several metabolites associated with coronary heart disease (CHD) and type 2 diabetes. For example, two variants located in or near CYP4F2 (rs2108622 and rs79400241, respectively), involved in vitamin E metabolism, were associated with the levels of octadecanedioate and vitamin E metabolites (gamma-CEHC and gamma-CEHC glucuronide); MR analysis showed that genetically high levels of these metabolites were associated with lower odds of CHD. Our findings document the genetic architecture of circulating metabolites in an underrepresented Hispanic/Latino community, shedding light on disease etiology.

DOI10.1016/j.ajhg.2020.09.003
Alternate JournalAm J Hum Genet
PubMed ID33031748
PubMed Central IDPMC7675000
Grant ListHHSN268201300005C / HL / NHLBI NIH HHS / United States
HHSN268201300001C / HL / NHLBI NIH HHS / United States
R01 DK119268 / DK / NIDDK NIH HHS / United States
N01HC65235 / HL / NHLBI NIH HHS / United States
U01 HG004402 / HG / NHGRI NIH HHS / United States
N01HC65234 / HL / NHLBI NIH HHS / United States
HHSN268201700001I / HL / NHLBI NIH HHS / United States
R01 HL087641 / HL / NHLBI NIH HHS / United States
HHSN268201700003I / HL / NHLBI NIH HHS / United States
P30 ES010126 / ES / NIEHS NIH HHS / United States
HHSN268201300004C / HL / NHLBI NIH HHS / United States
UL1 RR025005 / RR / NCRR NIH HHS / United States
R01 DK120870 / DK / NIDDK NIH HHS / United States
R01 HG009974 / HG / NHGRI NIH HHS / United States
R01 HL059367 / HL / NHLBI NIH HHS / United States
R01 HL086694 / HL / NHLBI NIH HHS / United States
N01HC65236 / HL / NHLBI NIH HHS / United States
N01HC65233 / HL / NHLBI NIH HHS / United States
HHSN268201700002C / HL / NHLBI NIH HHS / United States
N01HC65237 / HL / NHLBI NIH HHS / United States
HHSN268201700004I / HL / NHLBI NIH HHS / United States
P30 DK020541 / DK / NIDDK NIH HHS / United States
R01 HL140976 / HL / NHLBI NIH HHS / United States
HHSN268201300003C / HG / NHGRI NIH HHS / United States
R01 HL142003 / HL / NHLBI NIH HHS / United States
HHSN268201700005C / HL / NHLBI NIH HHS / United States
HHSN268201700001C / HL / NHLBI NIH HHS / United States
HHSN268201700003C / HL / NHLBI NIH HHS / United States
R01 HL141824 / HL / NHLBI NIH HHS / United States
HHSN268201700004C / HL / NHLBI NIH HHS / United States
HHSN268201700002I / HL / NHLBI NIH HHS / United States
HHSN268201700005I / HL / NHLBI NIH HHS / United States
R01 HL060712 / HL / NHLBI NIH HHS / United States
MS#: 
0639
Manuscript Lead/Corresponding Author Affiliation: 
Ancillary Study Investigators - Not at HCHS/SOL site
ECI: 
Yes
Manuscript Affiliation: 
Field Center: Bronx (Einstein College of Medicine)
Manuscript Status: 
Published