Whole genome sequence analysis of blood lipid levels in >66,000 individuals
Margaret Sunitha Selvaraj, Xihao Li, Zilin Li, Akhil Pampana, David Zhang, Joseph Park, Stella Aslibekyan, Joshua C. Bis, Jennifer A. Brody, Brian E. Cade, Lee‐Ming Chuang, Ren‐Hua Chung, Joanne E. Curran, Lisa de las Fuentes, Paul S. de Vries, Ravindranath Duggirala, Barry I. Freedman, Mariaelisa Graff, Xiuqing Guo, Nancy L. Heard‐Costa, Bertha Hidalgo, Chii‐Min Hwu, Marguerite R. Irvin, Tanika N. Kelly, Brian G. Kral, Leslie A. Lange, Xiaohui Li, Martin Lisa, Steven A. Lubitz, Ani Manichaikul, Michael Preuß, May E. Montasser, Alanna C. Morrison, Take Naseri, Jeffrey R. O’Connell, Nicholette D. Palmer, Patricia A. Peyser, Muagututi‘a Sefuiva Reupena, Jennifer A. Smith, Xiao Sun, Kent D. Taylor, Russell P. Tracy, Michael Y. Tsai, Zhe Wang, Yuxuan Wang, Wei Bao, John T. Wilkins, Lisa R. Yanek, Wei Zhao, Donna K. Arnett, John Blangero, Eric Boerwinkle, Donald W. Bowden, Yii‐Der Ida Chen, Adolfo Correa, L. Adrienne Cupples, Susan K. Dutcher, Patrick T. Ellinor, Myriam Fornage, Stacey Gabriel, Søren Germer, Richard A. Gibbs, Jiang He, Robert C. Kaplan, Sharon L. R. Kardia, Ryan Kim, Charles Kooperberg, Ruth J. F. Loos, Karine A. Viaud‐Martinez, Rasika A. Mathias, Stephen T. McGarvey, Braxton D. Mitchell, Deborah A. Nickerson, Kari E. North, Bruce M. Psaty, Susan Redline, Alex P. Reiner, Ramachandran S. Vasan, Stephen S. Rich, Cristen J. Willer, Jerome I. Rotter, Daniel J. Rader, Xihong Lin, Namiko Abe, Gonçalo R. Abecasis, François Aguet, Christine M. Albert, Laura Almasy, Álvaro Alonso, Seth A. Ament, Peter Anderson, Pramod Anugu, Deborah Applebaum‐Bowden, Kristin Ardlie, Dan E. Arking, Allison E. Ashley‐Koch, Tim Assimes, Paul L. Auer, Dimitrios Avramopoulos, Najib Ayas
Abstract
Blood lipids are heritable modifiable causal factors for coronary artery disease. Despite well-described monogenic and polygenic bases of dyslipidemia, limitations remain in discovery of lipid-associated alleles using whole genome sequencing (WGS), partly due to limited sample sizes, ancestral diversity, and interpretation of clinical significance. Among 66,329 ancestrally diverse (56% non-European) participants, we associate 428M variants from deep-coverage WGS with lipid levels; ~400M variants were not assessed in prior lipids genetic analyses. We find multiple lipid-related genes strongly associated with blood lipids through analysis of common and rare coding variants. We discover several associated rare non-coding variants, largely at Mendelian lipid genes. Notably, we observe rare LDLR intronic variants associated with markedly increased LDL-C, similar to rare LDLR exonic variants. In conclusion, we conducted a systematic whole genome scan for blood lipids expanding the alleles linked to lipids for multiple ancestries and characterize a clinically-relevant rare non-coding variant model for lipids.