• Jason A Chen, Qing Wang, Jeremy Davis-Turak, Yun Li, Anna M Karydas, Sandy C Hsu, Renee L Sears, Doxa Chatzopoulou, Alden Y Huang, Kevin J Wojta, Eric Klein, Jason Lee, Duane L Beekly, Adam Boxer, Kelley M Faber, Claudia M Haase, Josh Miller, Wayne W Poon, Ami Rosen, Howard Rosen, Anna Sapozhnikova, Jill Shapira, Arousiak Varpetian, Tatiana M Foroud, Robert W Levenson, Allan I Levey, Walter A Kukull, Mario F Mendez, John Ringman, Helena Chui, Carl Cotman, Charles DeCarli, Bruce L Miller, Daniel H Geschwind, and Giovanni Coppola.
• Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles.
• JAMA Neurol. 2015 Apr 1;72(4):414-22.

ImportancePrevious studies have indicated a heritable component of the etiology of neurodegenerative diseases such as Alzheimer disease (AD), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP). However, few have examined the contribution of low-frequency coding variants on a genome-wide level.ObjectiveTo identify low-frequency coding variants that affect susceptibility to AD, FTD, and PSP.Design, Setting, And ParticipantsWe used the Illumina HumanExome BeadChip array to genotype a large number of variants (most of which are low-frequency coding variants) in a cohort of patients with neurodegenerative disease (224 with AD, 168 with FTD, and 48 with PSP) and in 224 control individuals without dementia enrolled between 2005-2012 from multiple centers participating in the Genetic Investigation in Frontotemporal Dementia and Alzheimer's Disease (GIFT) Study. An additional multiancestral replication cohort of 240 patients with AD and 240 controls without dementia was used to validate suggestive findings. Variant-level association testing and gene-based testing were performed.Main Outcomes And MeasuresStatistical association of genetic variants with clinical diagnosis of AD, FTD, and PSP.ResultsGenetic variants typed by the exome array explained 44%, 53%, and 57% of the total phenotypic variance of AD, FTD, and PSP, respectively. An association with the known AD gene ABCA7 was replicated in several ancestries (discovery P=.0049, European P=.041, African American P=.043, and Asian P=.027), suggesting that exonic variants within this gene modify AD susceptibility. In addition, 2 suggestive candidate genes, DYSF (P=5.53×10(-5)) and PAXIP1 (P=2.26×10(-4)), were highlighted in patients with AD and differentially expressed in AD brain. Corroborating evidence from other exome array studies and gene expression data points toward potential involvement of these genes in the pathogenesis of AD.Conclusions And RelevanceLow-frequency coding variants with intermediate effect size may account for a significant fraction of the genetic susceptibility to AD and FTD. Furthermore, we found evidence that coding variants in the known susceptibility gene ABCA7, as well as candidate genes DYSF and PAXIP1, confer risk for AD.

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