Fernández, Maria V. Budde, John Del-Aguila, Jorge L. Ibañez, Laura Deming, Yuetiva Harari, Oscar Norton, Joanne C. Morris, John M. Goate, Alison group, NIA-LOAD family study NCRAD Cruchaga, Carlos Image1.PNG <p>Gene-based tests to study the combined effect of rare variants on a particular phenotype have been widely developed for case-control studies, but their evolution and adaptation for family-based studies, especially studies of complex incomplete families, has been slower. In this study, we have performed a practical examination of all the latest gene-based methods available for family-based study designs using both simulated and real datasets. We examined the performance of several collapsing, variance-component, and transmission disequilibrium tests across eight different software packages and 22 models utilizing a cohort of 285 families (N = 1,235) with late-onset Alzheimer disease (LOAD). After a thorough examination of each of these tests, we propose a methodological approach to identify, with high confidence, genes associated with the tested phenotype and we provide recommendations to select the best software and model for family-based gene-based analyses. Additionally, in our dataset, we identified PTK2B, a GWAS candidate gene for sporadic AD, along with six novel genes (CHRD, CLCN2, HDLBP, CPAMD8, NLRP9, and MAS1L) as candidate genes for familial LOAD.</p> gene-based;family-based;clustering;variance-component;transmission disequilibrium;rare variants;whole exome sequencing;Alzheimer's disease 2018-04-04
    https://frontiersin.figshare.com/articles/figure/Image1_PNG/6085361
10.3389/fnins.2018.00209.s001