1. Whole genome sequence analysis of blood lipid levels in >66,000 individuals.
- Author
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Selvaraj MS, Li X, Li Z, Pampana A, Zhang DY, Park J, Aslibekyan S, Bis JC, Brody JA, Cade BE, Chuang LM, Chung RH, Curran JE, de las Fuentes L, de Vries PS, Duggirala R, Freedman BI, Graff M, Guo X, Heard-Costa N, Hidalgo B, Hwu CM, Irvin MR, Kelly TN, Kral BG, Lange L, Li X, Lisa M, Lubitz SA, Manichaikul AW, Michael P, Montasser ME, Morrison AC, Naseri T, O'Connell JR, Palmer ND, Peyser PA, Reupena MS, Smith JA, Sun X, Taylor KD, Tracy RP, Tsai MY, Wang Z, Wang Y, Bao W, Wilkins JT, Yanek LR, Zhao W, Arnett DK, Blangero J, Boerwinkle E, Bowden DW, Chen YI, Correa A, Cupples LA, Dutcher SK, Ellinor PT, Fornage M, Gabriel S, Germer S, Gibbs R, He J, Kaplan RC, Kardia SLR, Kim R, Kooperberg C, Loos RJF, Viaud-Martinez KA, Mathias RA, McGarvey ST, Mitchell BD, Nickerson D, North KE, Psaty BM, Redline S, Reiner AP, Vasan RS, Rich SS, Willer C, Rotter JI, Rader DJ, Lin X, Peloso GM, and Natarajan P
- Subjects
- Alleles, Cholesterol, LDL, Humans, Whole Genome Sequencing, Genome-Wide Association Study, Lipids
- 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., (© 2022. The Author(s).)
- Published
- 2022
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