Sequence-Based Analysis of Lipid-Related Metabolites in a Multiethnic Study

Genetics: A Periodical Record of Investigations Bearing on Heredity and Variation

Xiaoming Liu^1¹  Elena V. Feofanova^1²  Bing Yu^1³  Donna Muzny^2⁴  Ginger A. Metcalf^2⁵ 

[1] Human Genetics Center, University of Texas Health Science Center at Houston, Texas 77030;Human Genetics Center, University of Texas Health Science Center at Houston, Texas 77030^1;Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030^2;Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030^4;Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina 27101^3

关键词: lipids;    metabolome;    rare variants;    whole genome sequencing;   

DOI  :  10.1534/genetics.118.300751

学科分类：医学（综合）

来源: Genetics Society of America

【 摘 要 】

Small molecule lipid-related metabolites are important components of fatty acid and steroid metabolism—two important contributors to human health. This study investigated the extent to which rare and common genetic variants spanning the human genome influence the lipid-related metabolome. Sequence data from 1552 European-Americans (EA) and 1872 African-Americans (AA) were analyzed to examine the impact of common and rare variants on the levels of 102 circulating lipid-related metabolites measured by a combination of chromatography and mass spectroscopy. We conducted single variant tests [minor allele frequency (MAF) > 5%, statistical significance P -value ≤ 2.45 × 10⁻¹⁰] and tests aggregating rare variants (MAF ≤ 5%) across multiple genomic motifs, such as coding regions and regulatory domains, and sliding windows. Multiethnic meta-analyses detected 53 lipid-related metabolites-locus pairs, which were inspected for evidence of consistent signal between the two ethnic groups. Thirty-eight lipid-related metabolite-genomic region associations were consistent across ethnicities, among which seven were novel. The regions contain genes that are related to metabolite transport ( SLC10A1 ) and metabolism ( SCD , FDX1 , UGT2B15 , and FADS2 ). Six of the seven novel findings lie in expression quantitative trait loci affecting the expression levels of 14 surrounding genes in multiple tissues. Imputed expression levels of 10 of the affected genes were associated with four corresponding lipid-related traits in at least one tissue. Our findings offer valuable insight into circulating lipid-related metabolite regulation in a multiethnic population.

【 授权许可】

CC BY