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Rare variant contribution to the heritability of coronary artery disease.
Tuesday,2024-11-19 12:51 America/Los_Angeles — ecterry
| Title | Rare variant contribution to the heritability of coronary artery disease. |
| Publication Type | Journal Article |
| Year of Publication | 2024 |
| Authors | Rocheleau, 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-DI, 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/Institutional Authors | NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium |
| Journal | Nat Commun |
| Volume | 15 |
| Issue | 1 |
| Pagination | 8741 |
| Date Published | 2024 Oct 09 |
| ISSN | 2041-1723 |
| Keywords | Case-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 | <p>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.</p> |
| DOI | 10.1038/s41467-024-52939-6 |
| Alternate Journal | Nat Commun |
| PubMed ID | 39384761 |
| PubMed Central ID | PMC11464707 |
| Grant List | R01 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 |
ePub date:
24/10