%0 Journal Article
%T Statistics to prioritize rare variants in family-based sequencing studies with disease subtypes.
%A Nieuwoudt C
%A Farooq FB
%A Brooks-Wilson A
%A Bureau A
%A Graham J
%J Genet Epidemiol
%V 0
%N 0
%D 2024 Jun 28
%M 38940260
%F 2.344
%R 10.1002/gepi.22579
%X Family-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.