Whole Genome Analysis of Venous Thromboembolism: the Trans-Omics for Precision Medicine Program.

TitleWhole Genome Analysis of Venous Thromboembolism: the Trans-Omics for Precision Medicine Program.
Publication TypeJournal Article
Year of Publication2023
AuthorsSeyerle, 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 AuthorsTrans-Omics for Precision Medicine Program
JournalCirc Genom Precis Med
Date Published2023 Apr
KeywordsGene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Precision Medicine, Venous Thromboembolism

BACKGROUND: Risk for venous thromboembolism has a strong genetic component. Whole genome sequencing from the TOPMed program (Trans-Omics for Precision Medicine) 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 individuals of African, Hispanic/Latino, or Asian ancestry) 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

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.

Alternate JournalCirc Genom Precis Med
PubMed ID36960714
PubMed Central IDPMC10151032
Grant ListR01 HL154385 / HL / NHLBI NIH HHS / United States