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

Elena V. Feofanova, Han Chen, Yulin Dai, Peilin Jia, Megan L. Grove, Alanna C. Morrison, Qibin Qi, Martha Daviglus, Jianwen Cai, Kari E. North, Cathy C. Laurie, Robert C. Kaplan, Eric Boerwinkle, Bing Yu

Research output: Contribution to journalArticlepeer-review

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 × 10−10, minor allele frequency ≥ 1%, proportion of variance explained [PEV] mean = 3.4%, PEVrange = 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.

Original languageEnglish (US)
Pages (from-to)849-863
Number of pages15
JournalAmerican Journal of Human Genetics
Volume107
Issue number5
DOIs
StatePublished - Nov 5 2020

Keywords

  • Hispanic/Latino community
  • genome-wide association study
  • metabolomics

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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