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

Authors

Chuan Gao
Keri L. Tabb
Latchezar Dimitrov
Kent D. Taylor
Nan Wang
Xiuqing Guo
Jirong Long
Jerome I. Rotter
Richard M. Watanabe
Joanne E. Curran, The University of Texas Rio Grande Valley
John Blangero, The University of Texas Rio Grande Valley

Document Type

Article

Publication Date

4-4-2018

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.

Comments

Copyright © The Author(s) 2018

Recommended Citation

Gao, C., Tabb, K. L., Dimitrov, L. M., Taylor, K. D., Wang, N., Guo, X., Long, J., Rotter, J. I., Watanabe, R. M., Curran, J. E., Blangero, J., Langefeld, C. D., Bowden, D. W., & Palmer, N. D. (2018). Exome Sequencing Identifies Genetic Variants Associated with Circulating Lipid Levels in Mexican Americans: The Insulin Resistance Atherosclerosis Family Study (IRASFS). Scientific reports, 8(1), 5603. https://doi.org/10.1038/s41598-018-23727-2

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Publication Title

Sci Rep.

DOI

10.1038/s41598-018-23727-2

Academic Level

faculty

Mentor/PI Department

Office of Human Genetics