PB0387 - Rare Variant Aggregate Association Testing VTE Meta-Analysis: the INVENT Consortium

Sunday, June 23, 2024

13:45 – 14:45 ICT

Room: Exhibition Hall

Presenting Author(s)

NS

Nicholas L. Smith, PhD

Professor
University of Washington
Seattle, Washington, United States

Co-Author(s)

SL

Susana Lozano-Esparza

Graduate Student
University of Washington
Seattle, Washington, United States
MC

Matthew Conomos

Research Scientist
University of Washington
Seattle, Washington, United States
JB

Jennifer Brody

Research Scientist
University of Washington
Seattle, Washington, United States
SA

Sebastian Armasu

Research Scientist
Mayo Clinic
Rochester, Minnesota, United States
TH

Therese Haugdahl Nøst

Professor
Norwegian University of Science and Technology
Trondheim, Nord-Trondelag, Norway
AM

Angel Martínez Pérez

Research Scientist
Sant Pau Research Institute
Barcelona, Catalonia, Spain
MC

Ming-Huei Chen

Research Scientist
National Heart, Lung, and Blood Institute
Framingham, Massachusetts, United States
JH

John-Bjarne Hansen

Professor
Thrombosis Research Center (TREC), Department of Clinical Medicine, UiT - the Arctic University of Norway
Tromsø, Troms, Norway
Astrid van Hylckama Vlieg

Associate professor
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
Leiden, Zuid-Holland, Netherlands
MS

Maria Sabater Lleal

Research Scientist
Sant Pau Research Institute
Barcelona, Catalonia, Spain
Christopher Kabrhel, MD MPH

Director, Center for Vascular Emergencies
Massachusetts General Hospital
Boston, Massachusetts, United States
David-Alexandre Trégouët

Senior Investigator
Bordeaux Population Health research Center, Inserm U1219, Bordeaux University
Bordeaux, Aquitaine, France
DC

Daniel Chasman

Professor
Harvard Medical School
Boston, Massachusetts, United States
NP

Nathan Pankratz

Professor
University of Minnesota
Minneapolis, Minnesota, United States

Background: Identifying rare genetic variants (minor allele frequency [MAF] < 0.5%) associated with venous thromboembolism (VTE) may provide deeper insights into its inherited causes.

Aims: We explored aggregating rare variants identified through whole-genome sequencing (WGS) and dense imputation to identify genes harboring rare genetic variants that are associated with VTE.

Methods: We meta-analyzed summary gene-based aggregate rare variants to associate with VTE in 20 studies that included 40,443 VTE cases and up to 4 controls for each. Participants were primarily of European ancestry. Gene boundaries were defined by Gencode v38 transcript size, plus 50kb +/- from the transcription start site. Each study used logistic mixed models to adjust for covariates age, sex, study, genetic ancestry principal components, and other study-specific variables; covariance proportional to an empirical kinship matrix or genetic relationship matrix was included as a random effect. Rare variants within each gene were filtered using 3 annotation-based strategies. Score statistics were meta-analyzed for each variant, and Burden, SKAT, and SMMAT tests were performed using 3 MAF-based weighting strategies to evaluate aggregate association.

Results: Seven genetic regions containing 13 genes met statistical significance. This included PROC, PROS1, FGB, F10, and RFWD3, all of which were uniquely identified within each region. The RFWD2 gene is novel, not previously demonstrating associations with VTE. A statistical signal on chromosome 9 near ABO with known variants was identified, and conditional analyses are underway to better understand rare-variant contributions to this signal. Similarly, a locus on chromosome 11 near F2 was identified and conditional analyses are underway to better understand the contribution of the F2 variants to the signal in this region.

Conclusion(s): We identified novel, rare genetic variation in genes newly or previously associated with VTE. Additional conditional analyses are planned to identify rare variants that may be underlying the association for previously identified VTE genes.