Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10−72), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10−4), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10−5). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids.
|State||Published - Dec 1 2021|
Bibliographical noteFunding Information:
P.N. reports grants from Amgen, Apple, Boston Scientific, and Novartis, and consulting income from Apple, Blackstone Life Sciences, Genentech, and Novartis. S.L. reports grants from Bristol Myers Squibb / Pfizer, Bayer AG, and Boehringer Ingelheim, and consulting income from Bristol Myers Squibb / Pfizer and Bayer AG. P.E. is supported by a grant from Bayer AG to the Broad Institute focused on the genetics and therapeutics of cardiovascular diseases. P.E. reports consulting income from Bayer AG, Quest Diagnostics, and Novartis. All others declare no competing interests for the present work.
This work was supported by grants from the National Heart, Lung, and Blood Institute (NHLBI): R01HL142711 (to P.N. and G.M.P.), K08HL140203 (to P.N.), R03HL141439 and K01HL125751 (to G.M.P.). P.N. is also supported by a Hassenfeld Scholar Award from the Massachusetts General Hospital, Fondation Leducq (TNE-18CVD04), and additional grants from the National Heart, Lung, and Blood Institute (R01HL148565 and R01HL148050). P.S.de.V. is supported by American Heart Association grant number 18CDA34110116. B.E.C. and J.L. are supported by R35HL135818, HL113338, and HL46380. B.E.C. is also supported by K01HL135405. S.L. is supported by NIH grant 1R01HL139731 and American Heart Association 18SFRN34250007. Whole-genome sequencing (WGS) for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung, and Blood Institute (NHLBI). Centralized read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1; contract HHSN268201800002I). Phenotype harmonization, data management, sample-identity QC, and general study coordination were provided by the TOPMed Data Coordinating Center (3R01HL-120393-02S1; contract HHSN268201800001I). We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed. Please refer to Supplementary Notes 1–4 for study-specific acknowledgements. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services.
© 2021, The Author(s).
ASJC Scopus subject areas
- Chemistry (all)
- Biochemistry, Genetics and Molecular Biology (all)
- Physics and Astronomy (all)