TY - JOUR
T1 - Exome Sequencing Identifies Genetic Variants Associated with Circulating Lipid Levels in Mexican Americans
T2 - The Insulin Resistance Atherosclerosis Family Study (IRASFS)
AU - Gao, Chuan
AU - Tabb, Keri L.
AU - Dimitrov, Latchezar M.
AU - Taylor, Kent D.
AU - Wang, Nan
AU - Guo, Xiuqing
AU - Long, Jirong
AU - Rotter, Jerome I.
AU - Watanabe, Richard M.
AU - Curran, Joanne E.
AU - Blangero, John
AU - Langefeld, Carl D.
AU - Bowden, Donald W.
AU - Palmer, Nicholette D.
N1 - Funding Information:
This research was jointly supported by HG007112 from the national Human Genome Research Institute (NHGRI) and DK097524 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Computational resources were provided, in part, by the Wake Forest School of Medicine Center for Public Health Genomics. The authors would like to acknowledge the members of the GUARDIAN Consortium with research supported by DK085175 from NIDDK and from the following grants: IRAS Classic (HL047887, HL047889, HL047890, and HL47902), IRAS Family Study (HL060944 and HL061019), BetaGene (DK061628), MACAD (HL088457), HTN-IR (HL069794), and NIDDM (HL055798). The authors thank the other investigators, the staff, and the participants of the studies for their valuable contributions. The provision of genotyping data was supported in part by UL1TR000124 (CTSI), DK063491 (DRC), DK081350, HG007112 and DK087914.
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41598-018-23727-2
DO - 10.1038/s41598-018-23727-2
M3 - Article
AN - SCOPUS:85044962177
VL - 8
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
IS - 1
M1 - 5603
ER -