Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol

Authors

Leslie A. Lange, The University of North Carolina at Chapel Hill
Youna Hu, University of Michigan, Ann Arbor
He Zhang, University of Michigan, Ann Arbor
Chenyi Xue, University of Michigan, Ann Arbor
Ellen M. Schmidt, University of Michigan, Ann Arbor
Zheng Zheng Tang, The University of North Carolina at Chapel Hill
Chris Bizon, Renaissance Computing Institute
Ethan M. Lange, The University of North Carolina at Chapel Hill
Joshua D. Smith, University of Washington, Seattle
Emily H. Turner, University of Washington, Seattle
Goo Jun, University of Michigan, Ann Arbor
Hyun Min Kang, University of Michigan, Ann Arbor
Gina Peloso, Massachusetts General Hospital
Paul Auer, Fred Hutchinson Cancer Research Center
Kuo Ping Li, University of Michigan, Ann Arbor
Jason Flannick, Broad Institute
Ji Zhang, University of Michigan, Ann Arbor
Christian Fuchsberger, University of Michigan, Ann Arbor
Kyle Gaulton, The Wellcome Centre for Human Genetics
Cecilia Lindgren, The Wellcome Centre for Human Genetics
Adam Locke, University of Michigan, Ann Arbor
Alisa Manning, Broad Institute
Xueling Sim, University of Michigan, Ann Arbor
Manuel A. Rivas, The Wellcome Centre for Human Genetics
Oddgeir L. Holmen, Norges teknisk-naturvitenskapelige universitet
Omri Gottesman, Icahn School of Medicine at Mount Sinai
Yingchang Lu, Icahn School of Medicine at Mount Sinai
Douglas Ruderfer, Icahn School of Medicine at Mount Sinai
Eli A. Stahl, Icahn School of Medicine at Mount Sinai
Qing Duan, The University of North Carolina at Chapel Hill
Yun Li, The University of North Carolina at Chapel Hill
Peter Durda, University of Vermont

Document Type

Journal Article

Publication Date

2-6-2014

Journal

American Journal of Human Genetics

Volume

94

Issue

2

DOI

10.1016/j.ajhg.2014.01.010

Abstract

Elevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98th or <2nd percentile). Follow-up analyses included sequencing of 1,302 additional individuals and genotype-based analysis of 52,221 individuals. We observed significant evidence of association between LDL-C and the burden of rare or low-frequency variants in PNPLA5, encoding a phospholipase-domain-containing protein, and both known and previously unidentified variants in PCSK9, LDLR and APOB, three known lipid-related genes. The effect sizes for the burden of rare variants for each associated gene were substantially higher than those observed for individual SNPs identified from GWASs. We replicated the PNPLA5 signal in an independent large-scale sequencing study of 2,084 individuals. In conclusion, this large whole-exome-sequencing study for LDL-C identified a gene not known to be implicated in LDL-C and provides unique insight into the design and analysis of similar experiments. © 2014 The American Society of Human Genetics.

APA Citation

Lange, L., Hu, Y., Zhang, H., Xue, C., Schmidt, E., Tang, Z., Bizon, C., Lange, E., Smith, J., Turner, E., Jun, G., Kang, H., Peloso, G., Auer, P., Li, K., Flannick, J., Zhang, J., Fuchsberger, C., Gaulton, K., Lindgren, C., Locke, A., Manning, A., Sim, X., Rivas, M., Holmen, O., Gottesman, O., Lu, Y., Ruderfer, D., Stahl, E., Duan, Q., Li, Y., & Durda, P. (2014). Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol. American Journal of Human Genetics, 94 (2). http://dx.doi.org/10.1016/j.ajhg.2014.01.010