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

Abstract
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.
Competing Interest Statement
P.N. reports investigator-initiated grant support from Amgen, Apple, AstraZeneca, and Boston Scientific, personal fees from Apple, AstraZeneca, Blackstone Life Sciences, Foresite Labs, Genentech, and Novartis, and spousal employment at Vertex, all unrelated to the present work. BP serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. MEM receives funding from Regeneron Pharmaceutical Inc. unrelated to this work. SA has employment and equity in 23andMe, Inc. The spouse of CJW works at Regeneron.
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