Please use this identifier to cite or link to this item: http://hdl.handle.net/2445/176335
Title: Efficient and flexible Integration of variant characteristics in rare variant association studies using integrated nested Laplace approximation
Author: Susak, Hana
Serra-Saurina, Laura
Demidov, German
Rabionet Janssen, Raquel
Domènech, Laura
Bosio, Mattia
Muyas, Francesc
Estivill, Xavier
Escaramís, Geòrgia
Ossowski, Stephan
Keywords: Genètica
Bioinformàtica
Malalties
Genetics
Bioinformatics
Diseases
Issue Date: 19-Feb-2021
Publisher: Public Library of Science (PLoS)
Abstract: Rare variants are thought to play an important role in the etiology of complex diseases and may explain a significant fraction of the missing heritability in genetic disease studies. Next-generation sequencing facilitates the association of rare variants in coding or regulatory regions with complex diseases in large cohorts at genome-wide scale. However, rare variant association studies (RVAS) still lack power when cohorts are small to medium-sized and if genetic variation explains a small fraction of phenotypic variance. Here we present a novel Bayesian rare variant Association Test using Integrated Nested Laplace Approximation (BATI). Unlike existing RVAS tests, BATI allows integration of individual or variant-specific features as covariates, while efficiently performing inference based on full model estimation. We demonstrate that BATI outperforms established RVAS methods on realistic, semi-synthetic whole-exome sequencing cohorts, especially when using meaningful biological context, such as functional annotation. We show that BATI achieves power above 70% in scenarios in which competing tests fail to identify risk genes, e.g. when risk variants in sum explain less than 0.5% of phenotypic variance. We have integrated BATI, together with five existing RVAS tests in the 'Rare Variant Genome Wide Association Study' (rvGWAS) framework for data analyzed by whole-exome or whole genome sequencing. rvGWAS supports rare variant association for genes or any other biological unit such as promoters, while allowing the analysis of essential functionalities like quality control or filtering. Applying rvGWAS to a Chronic Lymphocytic Leukemia study we identified eight candidate predisposition genes, including EHMT2 and COPS7A.
Note: Reproducció del document publicat a: https://doi.org/10.1371/journal.pcbi.1007784
It is part of: PLoS Computational Biology, 2021, vol. 17, num. 2, p. e1007784
URI: http://hdl.handle.net/2445/176335
Related resource: https://doi.org/10.1371/journal.pcbi.1007784
ISSN: 1553-734X
Appears in Collections:Articles publicats en revistes (Genètica, Microbiologia i Estadística)

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