Statistics to prioritize rare variants in family‐based sequencing studies with disease subtypes

Author:

Nieuwoudt Christina1,Farooq Fabiha Binte1,Brooks‐Wilson Angela23,Bureau Alexandre45ORCID,Graham Jinko1ORCID

Affiliation:

1. Department of Statistics and Actuarial Science Simon Fraser University Burnaby British Columbia Canada

2. Department of Biomedical Physiology and Kinesiology Simon Fraser University Burnaby British Columbia Canada

3. Canada's Michael Smith Genome Sciences Centre, BC Cancer Vancouver British Columbia Canada

4. Département de Médecine Sociale et Préventive Université Laval Québec City Québec Canada

5. Centre de recherche CERVO Québec City Québec Canada

Abstract

AbstractFamily‐based sequencing studies are increasingly used to find rare genetic variants of high risk for disease traits with familial clustering. In some studies, families with multiple disease subtypes are collected and the exomes of affected relatives are sequenced for shared rare variants (RVs). Since different families can harbor different causal variants and each family harbors many RVs, tests to detect causal variants can have low power in this study design. Our goal is rather to prioritize shared variants for further investigation by, for example, pathway analyses or functional studies. The transmission‐disequilibrium test prioritizes variants based on departures from Mendelian transmission in parent–child trios. Extending this idea to families, we propose methods to prioritize RVs shared in affected relatives with two disease subtypes, with one subtype more heritable than the other. Global approaches condition on a variant being observed in the study and assume a known probability of carrying a causal variant. In contrast, local approaches condition on a variant being observed in specific families to eliminate the carrier probability. Our simulation results indicate that global approaches are robust to misspecification of the carrier probability and prioritize more effectively than local approaches even when the carrier probability is misspecified.

Funder

Natural Sciences and Engineering Research Council of Canada

Canadian Institutes of Health Research

Publisher

Wiley

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