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 journalArticle

2 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Exome
Insulin Resistance
Atherosclerosis
Lipids
Genome-Wide Association Study
HDL Lipoproteins
Pedigree
LDL Lipoproteins
Single Nucleotide Polymorphism
Triglycerides
Cholesterol
Genome

ASJC Scopus subject areas

  • General

Cite this

Exome Sequencing Identifies Genetic Variants Associated with Circulating Lipid Levels in Mexican Americans : The Insulin Resistance Atherosclerosis Family Study (IRASFS). / Gao, Chuan; Tabb, Keri L.; Dimitrov, Latchezar M.; Taylor, Kent D.; Wang, Nan; Guo, Xiuqing; Long, Jirong; Rotter, Jerome I.; Watanabe, Richard M.; Curran, Joanne E.; Blangero, John; Langefeld, Carl D.; Bowden, Donald W.; Palmer, Nicholette D.

In: Scientific Reports, Vol. 8, No. 1, 5603, 01.12.2018.

Research output: Contribution to journalArticle

Gao, C, Tabb, KL, Dimitrov, LM, Taylor, KD, Wang, N, Guo, X, Long, J, Rotter, JI, Watanabe, RM, Curran, JE, Blangero, J, Langefeld, CD, Bowden, DW & Palmer, ND 2018, 'Exome Sequencing Identifies Genetic Variants Associated with Circulating Lipid Levels in Mexican Americans: The Insulin Resistance Atherosclerosis Family Study (IRASFS)', Scientific Reports, vol. 8, no. 1, 5603. https://doi.org/10.1038/s41598-018-23727-2
Gao, Chuan ; Tabb, Keri L. ; Dimitrov, Latchezar M. ; Taylor, Kent D. ; Wang, Nan ; Guo, Xiuqing ; Long, Jirong ; Rotter, Jerome I. ; Watanabe, Richard M. ; Curran, Joanne E. ; Blangero, John ; Langefeld, Carl D. ; Bowden, Donald W. ; Palmer, Nicholette D. / Exome Sequencing Identifies Genetic Variants Associated with Circulating Lipid Levels in Mexican Americans : The Insulin Resistance Atherosclerosis Family Study (IRASFS). In: Scientific Reports. 2018 ; Vol. 8, No. 1.
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title = "Exome Sequencing Identifies Genetic Variants Associated with Circulating Lipid Levels in Mexican Americans: The Insulin Resistance Atherosclerosis Family Study (IRASFS)",
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.",
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T2 - The Insulin Resistance Atherosclerosis Family Study (IRASFS)

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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.

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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.

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