AUTHOR=Fernández Maria V. , Budde John , Del-Aguila Jorge L. , Ibañez Laura , Deming Yuetiva , Harari Oscar , Norton Joanne , Morris John C. , Goate Alison M. ,  NIA-LOAD family study group ,  NCRAD , Cruchaga Carlos 

TITLE=Evaluation of Gene-Based Family-Based Methods to Detect Novel Genes Associated With Familial Late Onset Alzheimer Disease

JOURNAL=Frontiers in Neuroscience

VOLUME=12

YEAR=2018

URL=https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2018.00209

DOI=10.3389/fnins.2018.00209

ISSN=1662-453X

ABSTRACT=<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 (<italic>N</italic> = 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 <italic>PTK2B</italic>, a GWAS candidate gene for sporadic AD, along with six novel genes (<italic>CHRD, CLCN2, HDLBP, CPAMD8, NLRP9</italic>, and <italic>MAS1L</italic>) as candidate genes for familial LOAD.</p>