Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol
- Lange, Leslie A
- Hu, Youna
- Zhang, He
- Xue, Chenyi
- Schmidt, Ellen M
- Tang, Zheng-Zheng
- Bizon, Chris
- Lange, Ethan M
- Smith, Joshua D
- Turner, Emily H
- Jun, Goo
- Kang, Hyun Min
- Peloso, Gina
- Auer, Paul
- Li, Kuo-Ping
- Flannick, Jason
- Zhang, Ji
- Fuchsberger, Christian
- Gaulton, Kyle
- Lindgren, Cecilia
- Locke, Adam
- Manning, Alisa
- Sim, Xueling
- Rivas, Manuel A
- Holmen, Oddgeir L
- Gottesman, Omri
- Lu, Yingchang
- Ruderfer, Douglas
- Stahl, Eli A
- Duan, Qing
- Li, Yun
- Durda, Peter
- Jiao, Shuo
- Isaacs, Aaron
- Hofman, Albert
- Bis, Joshua C
- Correa, Adolfo
- Griswold, Michael E
- Jakobsdottir, Johanna
- Smith, Albert V
- Schreiner, Pamela J
- Feitosa, Mary F
- Zhang, Qunyuan
- Huffman, Jennifer E
- Crosby, Jacy
- Wassel, Christina L
- Do, Ron
- Franceschini, Nora
- Martin, Lisa W
- Robinson, Jennifer G
DOIAbstract
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 (>98(th) or <2(nd) 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,...
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