| Literature DB >> 24507775 |
Leslie A Lange1, Youna Hu2, He Zhang3, Chenyi Xue4, Ellen M Schmidt4, Zheng-Zheng Tang5, Chris Bizon6, Ethan M Lange7, Joshua D Smith8, Emily H Turner8, Goo Jun2, Hyun Min Kang2, Gina Peloso9, Paul Auer10, Kuo-Ping Li2, Jason Flannick11, Ji Zhang3, Christian Fuchsberger2, Kyle Gaulton12, Cecilia Lindgren12, Adam Locke2, Alisa Manning13, Xueling Sim2, Manuel A Rivas12, Oddgeir L Holmen14, Omri Gottesman15, Yingchang Lu16, Douglas Ruderfer17, Eli A Stahl17, Qing Duan1, Yun Li18, Peter Durda19, Shuo Jiao20, Aaron Isaacs21, Albert Hofman22, Joshua C Bis23, Adolfo Correa24, Michael E Griswold24, Johanna Jakobsdottir25, Albert V Smith26, Pamela J Schreiner27, Mary F Feitosa28, Qunyuan Zhang28, Jennifer E Huffman29, Jacy Crosby30, Christina L Wassel31, Ron Do9, Nora Franceschini32, Lisa W Martin33, Jennifer G Robinson34, Themistocles L Assimes35, David R Crosslin36, Elisabeth A Rosenthal37, Michael Tsai27, Mark J Rieder8, Deborah N Farlow38, Aaron R Folsom27, Thomas Lumley39, Ervin R Fox24, Christopher S Carlson20, Ulrike Peters20, Rebecca D Jackson40, Cornelia M van Duijn21, André G Uitterlinden41, Daniel Levy42, Jerome I Rotter43, Herman A Taylor44, Vilmundur Gudnason26, David S Siscovick45, Myriam Fornage46, Ingrid B Borecki28, Caroline Hayward29, Igor Rudan47, Y Eugene Chen3, Erwin P Bottinger15, Ruth J F Loos16, Pål Sætrom48, Kristian Hveem14, Michael Boehnke2, Leif Groop49, Mark McCarthy50, Thomas Meitinger51, Christie M Ballantyne52, Stacey B Gabriel53, Christopher J O'Donnell54, Wendy S Post55, Kari E North32, Alexander P Reiner56, Eric Boerwinkle30, Bruce M Psaty57, David Altshuler58, Sekar Kathiresan59, Dan-Yu Lin5, Gail P Jarvik60, L Adrienne Cupples61, Charles Kooperberg20, James G Wilson62, Deborah A Nickerson8, Goncalo R Abecasis2, Stephen S Rich63, Russell P Tracy64, Cristen J Willer65.
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 (>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, 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.Entities:
Mesh：
Substances：
Year: 2014 PMID： 24507775 PMCID： PMC3928660 DOI： 10.1016/j.ajhg.2014.01.010
Source DB: PubMed Journal: Am J Hum Genet ISSN： 0002-9297 Impact factor: 11.025