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

Am J Hum Genet. 2020 Nov 5;107(5):849-863. doi: 10.1016/j.ajhg.2020.09.003. Epub 2020 Oct 7.

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.

Keywords: Hispanic/Latino community; genome-wide association study; metabolomics.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Chromans / metabolism
  • Cohort Studies
  • Coronary Disease / diagnosis
  • Coronary Disease / ethnology
  • Coronary Disease / genetics*
  • Coronary Disease / metabolism
  • Cytochrome P450 Family 4 / genetics
  • Cytochrome P450 Family 4 / metabolism
  • Diabetes Mellitus, Type 2 / diagnosis
  • Diabetes Mellitus, Type 2 / ethnology
  • Diabetes Mellitus, Type 2 / genetics*
  • Diabetes Mellitus, Type 2 / metabolism
  • Female
  • Gene Expression
  • Genetic Predisposition to Disease*
  • Genome, Human*
  • Genome-Wide Association Study
  • Hispanic or Latino
  • Humans
  • Male
  • Membrane Transport Proteins / genetics
  • Membrane Transport Proteins / metabolism
  • Metabolome / genetics*
  • Middle Aged
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Propionates / metabolism
  • Public Health
  • Quantitative Trait Loci*
  • Quantitative Trait, Heritable
  • Vitamin E / metabolism

Substances

  • Chromans
  • Membrane Transport Proteins
  • Propionates
  • organic solute transporter alpha, human
  • Vitamin E
  • 2,7,8-trimethyl-2-(beta-carboxyethyl)-6-hydroxychroman
  • Cytochrome P450 Family 4
  • CYP4F2 protein, human

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