Abstract：
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.
摘要：
基于家庭的测序研究越来越多地用于发现具有家族聚集性的疾病特征的高风险的罕见遗传变异。在一些研究中,收集具有多种疾病亚型的家庭，并对受影响亲属的外显子组进行测序，以确定共有的罕见变异（RV）。由于不同的家庭可以拥有不同的因果变体，每个家庭都拥有许多房车，在本研究设计中，检测因果变异的测试可能具有低功率。我们的目标是优先考虑共享变体，以便进一步调查，例如,途径分析或功能研究。传播不平衡测试根据父母三重奏中与孟德尔传播的偏离来优先考虑变体。把这个想法推广到家庭，我们提出了方法来优先考虑在患有两种疾病亚型的受影响亲属中共享的RV，一个亚型比另一个更可遗传。全局方法以研究中观察到的变体为条件，并假设携带因果变体的已知概率。相比之下,局部方法以在特定家庭中观察到的变体为条件，以消除携带者概率。我们的仿真结果表明，即使错误指定了载波概率，全局方法也对载波概率的错误指定具有鲁棒性，并且比局部方法更有效地进行优先级排序。
