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

TitleWhole genome sequence analysis of blood lipid levels in >66,000 individuals.
Publication TypeJournal Article
Year of Publication2022
AuthorsSelvaraj, MSunitha, Li, X, Li, Z, Pampana, A, Zhang, DY, Park, J, Aslibekyan, S, Bis, JC, Brody, JA, Cade, BE, Chuang, L-M, Chung, R-H, Curran, JE, Fuentes, Lde Las, de Vries, PS, Duggirala, R, Freedman, BI, Graff, M, Guo, X, Heard-Costa, N, Hidalgo, B, Hwu, C-M, 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, Y-DIda, Correa, A, L Cupples, A, Dutcher, SK, Ellinor, PT, Fornage, M, Gabriel, S, Germer, S, Gibbs, RA, 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, Natarajan, P
Corporate AuthorsNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
JournalNat Commun
Volume13
Issue1
Pagination5995
Date Published2022 Oct 11
ISSN2041-1723
KeywordsAlleles, Cholesterol, LDL, Genome-Wide Association Study, Humans, Lipids, Whole Genome Sequencing
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.

DOI10.1038/s41467-022-33510-7
Alternate JournalNat Commun
PubMed ID36220816
PubMed Central IDPMC9553944
Grant ListK01 AG059898 / AG / NIA NIH HHS / United States
R01 HL148565 / HL / NHLBI NIH HHS / United States
R35 HL135818 / HL / NHLBI NIH HHS / United States
R35 CA197449 / CA / NCI NIH HHS / United States
R01 HL142711 / HL / NHLBI NIH HHS / United States
K08 HL141601 / HL / NHLBI NIH HHS / United States
P01 HL045522 / HL / NHLBI NIH HHS / United States
R01 HL121007 / HL / NHLBI NIH HHS / United States
U19 CA203654 / CA / NCI NIH HHS / United States
R01 HL127564 / HL / NHLBI NIH HHS / United States
R03 HL154284 / HL / NHLBI NIH HHS / United States
R01 HL151283 / HL / NHLBI NIH HHS / United States
R01 HL157635 / HL / NHLBI NIH HHS / United States
R01 HL135242 / HL / NHLBI NIH HHS / United States
R01 HL139731 / HL / NHLBI NIH HHS / United States
U01 HL072507 / HL / NHLBI NIH HHS / United States
R01 HL090682 / HL / NHLBI NIH HHS / United States
R01 HL153805 / HL / NHLBI NIH HHS / United States
R01 MH078111 / MH / NIMH NIH HHS / United States
R01 HL113338 / HL / NHLBI NIH HHS / United States
R01 HL093093 / HL / NHLBI NIH HHS / United States
R01 HL148050 / HL / NHLBI NIH HHS / United States
R01 HL163560 / HL / NHLBI NIH HHS / United States
R01 HL113323 / HL / NHLBI NIH HHS / United States
R01 MH078143 / MH / NIMH NIH HHS / United States
R01 HL087263 / HL / NHLBI NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
R01 HL151152 / HL / NHLBI NIH HHS / United States
U01 DK085524 / DK / NIDDK NIH HHS / United States
I01 CX001737 / CX / CSRD VA / United States
P30 DK020541 / DK / NIDDK NIH HHS / United States
K01 HL135405 / HL / NHLBI NIH HHS / United States
R01 HL140570 / HL / NHLBI NIH HHS / United States
U01 HL072515 / HL / NHLBI NIH HHS / United States
R01 MH083824 / MH / NIMH NIH HHS / United States
T32 CA154274 / CA / NCI NIH HHS / United States
U01 HG009088 / HG / NHGRI NIH HHS / United States
I01 BX005831 / BX / BLRD VA / United States

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