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Whole genome sequence analysis of blood lipid levels in >66,000 individuals

By Margaret Sunitha Selvaraj, Xihao Li, Zilin Li, Akhil Pampana, David Y. 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 Heard-Costa, Bertha Hidalgo, Chii-Min Hwu, Marguerite R Irvin, Tanika N Kelly, Brian G Kral, Leslie Lange, Xiaohui Li, Martin Lisa, Steven Lubitz, Ani W. Manichaikul, Preuss Michael, May E Montasser, Alanna C. Morrison, Take Naseri, Jeffrey R O'Connell, Nicholette D Palmer, Patricia A. Peyser, Muagututia S Reupena, Jennifer A Smith, Xiao Sun, Kent D. Taylor, Russell P Tracy, Michael Y Tsai, Zhe Wang, Yuxuan Wang, Bao Wei, 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, Soren Germer, Richard Gibbs, Jiang He, Robert C. Kaplan, Sharon LR Kardia, Ryan Kim, Charles Kooperberg, Ruth JF Loos, Karine Martinez, Rasika A. Mathias, Stephen T. McGarvey, Braxton D Mitchell, Deborah Nickerson, Kari E North, Bruce M Psaty, Susan Redline, Alexander P Reiner, Ramachandran S. Vasan, Stephen S. Rich, Cristen J Willer, Jerome I. Rotter, Daniel Rader, Xihong Lin, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Gina M. Peloso, Pradeep Natarajan

Posted 12 Oct 2021
bioRxiv DOI: 10.1101/2021.10.11.463514

Plasma lipids are heritable modifiable causal factors for coronary artery disease, the leading cause of death globally. Despite the well-described monogenic and polygenic bases of dyslipidemia, limitations remain in discovery of lipid-associated alleles using whole genome sequencing, partly due to limited sample sizes, ancestral diversity, and interpretation of potential clinical significance. Increasingly larger whole genome sequence datasets with plasma lipids coupled with methodologic advances enable us to more fully catalog the allelic spectrum for lipids. Here, among 66,329 ancestrally diverse (56% non-European ancestry) participants, we associate 428M variants from deep-coverage whole genome sequences with plasma lipids. Approximately 400M of these variants were not studied in prior lipids genetic analyses. We find multiple lipid-related genes strongly associated with plasma lipids through analysis of common and rare coding variants. We additionally discover several significantly associated rare non-coding variants largely at Mendelian lipid genes. Notably, we detect 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 plasma lipids expanding the alleles linked to lipids for multiple ancestries and characterize a clinically-relevant rare non-coding variant model for lipids.

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