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Whole Genome Analysis of Venous Thromboembolism: the Trans-Omics for Precision Medicine Program.
Wednesday,2023-04-05 17:23 America/Los_Angeles — ecterry
| Title | Whole Genome Analysis of Venous Thromboembolism: the Trans-Omics for Precision Medicine Program. |
| Publication Type | Journal Article |
| Year of Publication | 2023 |
| Authors | Seyerle, AA, Laurie, CA, Coombes, BJ, Jain, D, Conomos, MP, Brody, J, Chen, M-H, Gogarten, SM, Beutel, KM, Gupta, N, Heckbert, SR, Jackson, RD, Johnson, AD, Ko, D, Manson, JAE, McKnight, B, Metcalf, GA, Morrison, AC, Reiner, AP, Sofer, T, Tang, W, Wiggins, KL, Boerwinkle, E, de Andrade, M, Gabriel, SB, Gibbs, RA, Laurie, CC, Psaty, BM, Vasan, RS, Rice, K, Kooperberg, C, Pankow, JS, Smith, NL, Pankratz, N |
| Corporate/Institutional Authors | Trans-Omics for Precision Medicine Program |
| Journal | Circ Genom Precis Med |
| Pagination | e003532 |
| Date Published | 2023 Mar 24 |
| ISSN | 2574-8300 |
| Abstract | <p>Background Risk for venous thromboembolism has a strong genetic component. Whole genome sequencingfrom the Trans-Omics for Precision Medicine program allowed us to look for new associations, particularly rare variants missed by standard genome-wide association studies. Methods The 3793 cases and 7834 controls (11.6% of cases were Black, Hispanic/Latino, or Asian American) were analyzed using a single variant approach and an aggregate gene-based approach using our primary filter (included only loss-of-function and missense variants predicted to be deleterious) and our secondary filter (included all missense variants). Results Single variant analyses identified associations at 5 known loci. Aggregate gene-based analyses identified only (odds ratio, 6.2 for carriers of rare variants; =7.4×10) when using our primary filter. Employing our secondary variant filter led to a smaller effect size at (odds ratio, 3.8; =1.6×10), while excluding variants found only in rare isoforms led to a larger one (odds ratio, 7.5). Different filtering strategies improved the signal for 2 other known genes: became significant (minimum =1.8×10 with the secondary filter), while did not (minimum =4.4×10 with minor allele frequency <0.0005). Results were largely the same when restricting the analyses to include only unprovoked cases; however, one novel gene, , became significant (=4.4×10 using all missense variants with minor allele frequency <0.0005). Conclusions Here, we have demonstrated the importance of using multiple variant filtering strategies, as we detected additional genes when filtering variants based on their predicted deleteriousness, frequency, and presence on the most expressed isoforms. Our primary analyses did not identify new candidate loci; thus larger follow-up studies are needed to replicate the novel locus and to identify additional rare variation associated with venous thromboembolism.</p> |
| DOI | 10.1161/CIRCGEN.121.003532 |
| Alternate Journal | Circ Genom Precis Med |
| PubMed ID | 36960714 |
ePub date:
23/03