Evaluation of gene-based family-based methods to detect novel genes associated with familial late onset Alzheimer disease

Cruchaga, C.; Feranndez, M. V.; Budde, J.; Del-Aguila, J.; Ibanez, L.; Deming, Y.; Harari, O.; Norton, J.; Morris, J. C.; Goate, A.

doi:10.1101/242545

bioRxiv · 10.1101/242545

Evaluation of gene-based family-based methods to detect novel genes associated with familial late onset Alzheimer disease

Cruchaga, C.·Feranndez, M. V.·Budde, J.·Del-Aguila, J.·Ibanez, L.·Deming, Y.·Harari, O.·Norton, J.·Morris, J. C.·Goate, A.

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Abstract

Gene-based tests to study the combined effect of rare variants towards a particular phenotype have been widely developed for case-control studies, but their evolution and adaptation for family-based studies, especially for 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 have examined the performance of several collapsing, variance-component and transmission disequilibrium tests across eight different software and twenty-two 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 studied phenotype with high confidence 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, MAS1L) as candidates genes for familial LOAD.

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Cruchaga, C., Feranndez, M. V., Budde, J., Del-Aguila, J., Ibanez, L., Deming, Y., Harari, O., Norton, J., Morris, J. C., Goate, A.. 2018-01-08. Evaluation of gene-based family-based methods to detect novel genes associated with familial late onset Alzheimer disease. https://doi.org/10.1101/242545

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