Exome Sequencing Identifies Genetic Variants Associated with Circulating Lipid Levels in Mexican Americans: The Insulin Resistance Atherosclerosis Family Study (IRASFS)

Chuan Gao, Keri L. Tabb, Latchezar M. Dimitrov, Kent D. Taylor, Nan Wang, Xiuqing Guo, Jirong Long, Jerome I. Rotter, Richard M. Watanabe, Joanne E. Curran, John Blangero, Carl D. Langefeld, Donald W. Bowden, Nicholette D. Palmer

    Research output: Contribution to journalArticlepeer-review

    3 Scopus citations

    Abstract

    Genome-wide association studies have identified numerous variants associated with lipid levels; yet, the majority are located in non-coding regions with unclear mechanisms. In the Insulin Resistance Atherosclerosis Family Study (IRASFS), heritability estimates suggest a strong genetic basis: low-density lipoprotein (LDL, h2 = 0.50), high-density lipoprotein (HDL, h2 = 0.57), total cholesterol (TC, h2 = 0.53), and triglyceride (TG, h2 = 0.42) levels. Exome sequencing of 1,205 Mexican Americans (90 pedigrees) from the IRASFS identified 548,889 variants and association and linkage analyses with lipid levels were performed. One genome-wide significant signal was detected in APOA5 with TG (rs651821, PTG = 3.67 × 10-10, LODTG = 2.36, MAF = 14.2%). In addition, two correlated SNPs (r2 = 1.0) rs189547099 (PTG = 6.31 × 10-08, LODTG = 3.13, MAF = 0.50%) and chr4:157997598 (PTG = 6.31 × 10-08, LODTG = 3.13, MAF = 0.50%) reached exome-wide significance (P < 9.11 × 10-08). rs189547099 is an intronic SNP in FNIP2 and SNP chr4:157997598 is intronic in GLRB. Linkage analysis revealed 46 SNPs with a LOD > 3 with the strongest signal at rs1141070 (LODLDL = 4.30, PLDL = 0.33, MAF = 21.6%) in DFFB. A total of 53 nominally associated variants (P < 5.00 × 10-05, MAF ≥ 1.0%) were selected for replication in six Mexican-American cohorts (N = 3,280). The strongest signal observed was a synonymous variant (rs1160983, PLDL = 4.44 × 10-17, MAF = 2.7%) in TOMM40. Beyond primary findings, previously reported lipid loci were fine-mapped using exome sequencing in IRASFS. These results support that exome sequencing complements and extends insights into the genetics of lipid levels.

    Original languageEnglish (US)
    Article number5603
    JournalScientific reports
    Volume8
    Issue number1
    DOIs
    StatePublished - Dec 1 2018

    ASJC Scopus subject areas

    • General

    Fingerprint Dive into the research topics of 'Exome Sequencing Identifies Genetic Variants Associated with Circulating Lipid Levels in Mexican Americans: The Insulin Resistance Atherosclerosis Family Study (IRASFS)'. Together they form a unique fingerprint.

    Cite this