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


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.





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Publication Info

Selvaraj, Margaret Sunitha, Xihao Li, Zilin Li, Akhil Pampana, David Y Zhang, Joseph Park, Stella Aslibekyan, Joshua C Bis, et al. (2022). Whole genome sequence analysis of blood lipid levels in >66,000 individuals. Nature communications, 13(1). p. 5995. 10.1038/s41467-022-33510-7 Retrieved from https://hdl.handle.net/10161/30074.

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