Rare variant contribution to the heritability of coronary artery disease.

TitleRare variant contribution to the heritability of coronary artery disease.
Publication TypeJournal Article
Year of Publication2024
AuthorsRocheleau, G, Clarke, SL, Auguste, G, Hasbani, NR, Morrison, AC, Heath, AS, Bielak, LF, Iyer, KR, Young, EP, Stitziel, NO, Jun, G, Laurie, C, Broome, JG, Khan, AT, Arnett, DK, Becker, LC, Bis, JC, Boerwinkle, E, Bowden, DW, Carson, AP, Ellinor, PT, Fornage, M, Franceschini, N, Freedman, BI, Heard-Costa, NL, Hou, L, Chen, Y-DIda, Kenny, EE, Kooperberg, C, Kral, BG, Loos, RJF, Lutz, SM, Manson, JAE, Martin, LW, Mitchell, BD, Nassir, R, Palmer, ND, Post, WS, Preuss, MH, Psaty, BM, Raffield, LM, Regan, EA, Rich, SS, Smith, JA, Taylor, KD, Yanek, LR, Young, KA, Hilliard, AT, Tcheandjieu, C, Peyser, PA, Vasan, RS, Rotter, JI, Miller, CL, Assimes, TL, de Vries, PS, Do, R
Corporate AuthorsNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
JournalNat Commun
Volume15
Issue1
Pagination8741
Date Published2024 Oct 09
ISSN2041-1723
KeywordsCase-Control Studies, Coronary Artery Disease, Female, Gene Frequency, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Male, Middle Aged, Polymorphism, Single Nucleotide, White People, Whole Genome Sequencing
Abstract

Whole genome sequences (WGS) enable discovery of rare variants which may contribute to missing heritability of coronary artery disease (CAD). To measure their contribution, we apply the GREML-LDMS-I approach to WGS of 4949 cases and 17,494 controls of European ancestry from the NHLBI TOPMed program. We estimate CAD heritability at 34.3% assuming a prevalence of 8.2%. Ultra-rare (minor allele frequency ≤ 0.1%) variants with low linkage disequilibrium (LD) score contribute ~50% of the heritability. We also investigate CAD heritability enrichment using a diverse set of functional annotations: i) constraint; ii) predicted protein-altering impact; iii) cis-regulatory elements from a cell-specific chromatin atlas of the human coronary; and iv) annotation principal components representing a wide range of functional processes. We observe marked enrichment of CAD heritability for most functional annotations. These results reveal the predominant role of ultra-rare variants in low LD on the heritability of CAD. Moreover, they highlight several functional processes including cell type-specific regulatory mechanisms as key drivers of CAD genetic risk.

DOI10.1038/s41467-024-52939-6
Alternate JournalNat Commun
PubMed ID39384761
PubMed Central IDPMC11464707
Grant ListR01 HL139731 / HL / NHLBI NIH HHS / United States
R01 HL120393 / HL / NHLBI NIH HHS / United States
R35 GM124836 / GM / NIGMS NIH HHS / United States
R01 HL092577 / HL / NHLBI NIH HHS / United States
U01 HL120393 / HL / NHLBI NIH HHS / United States
S10 OD026880 / OD / NIH HHS / United States
R35-GM124836 / / U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS) /
R01 HL146860 / HL / NHLBI NIH HHS / United States
HHSN268201500014C / HL / NHLBI NIH HHS / United States
S10 OD030463 / OD / NIH HHS / United States
R01 HL157635 / HL / NHLBI NIH HHS / United States
HHSN268201600033C / HL / NHLBI NIH HHS / United States
R01 HL055673 / HL / NHLBI NIH HHS / United States
HHSN268201100037C / HL / NHLBI NIH HHS / United States
R01 HL112064 / HL / NHLBI NIH HHS / United States
U54 HG003067 / HG / NHGRI NIH HHS / United States
R01 HL121007 / HL / NHLBI NIH HHS / United States
R01-HL139865, R01-HL155915 / / U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) /
R01 HL139865 / HL / NHLBI NIH HHS / United States
R01 HL089856 / HL / NHLBI NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
HHSN268201800001C / HL / NHLBI NIH HHS / United States
UM1 HG008853 / HG / NHGRI NIH HHS / United States
HHSN268201500015C / HL / NHLBI NIH HHS / United States
R01 HL164577 / HL / NHLBI NIH HHS / United States
UL1 TR004419 / TR / NCATS NIH HHS / United States
R01 HL148239 / HL / NHLBI NIH HHS / United States
R01 HL117626 / HL / NHLBI NIH HHS / United States
R01 HL155915 / HL / NHLBI NIH HHS / United States

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