Whole-exome sequencing in early-onset Alzheimer disease families identifies rare variants in multiple Alzheimer-related genes and processes. B. W. Kunkle1, M. A. Kohli1, B. N. Vardarajan2, C. Reitz2, A. C. Naj3, P. L. Whitehead1, W. R. Perry1, E. R. Martin1, G. W. Beecham1, J. R. Gilbert1, L. A. Farrer3, J. L. Haines4, G. D. Schellenberg5, R. P. Mayeux2, M. A. Pericak-Vance1, Alzheimer's Disease Genetics Consortium 1) John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA; 2) Taub Institute for Research on Alzheimer's Disease, Columbia University, New York, NY, USA; 3) Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; 4) School of Medicine, Boston University, Boston, MA, USA; 5) Center for Human Genetics Research, Vanderbilt University, Nashville, TN, USA.

   Mutations in APP, PSEN1 and PSEN2 lead to familial, early-onset Alzheimer disease (EOAD). These mutations account for only 60-70% of familial EOAD and ~11% of EOAD overall, leaving the majority of genetic risk for the most severe form of Alzheimer disease (AD) unexplained. We performed Whole-Exome Sequencing in Caribbean Hispanic and Caucasian EOAD families previously screened negative for APP, PSEN1, and PSEN2 to search for rare variants contributing to risk for EOAD. 60 individuals in 21 families were sequenced using the Agilent 50Mb kit on an Illumina HiSeq2000. Variant filtering for segregating, conserved and functional rare variants (MAF<0.1%) was performed on the families assuming both autosomal-dominant and X-linked dominant models. Filtered loci were examined for implication as AD candidate genes from GWAS or in biologically relevant KEGG Pathways. Variants were also followed up for association with AD in 13,748 individuals (7,652 affected) from the Alzheimers Disease Genetics Consortium (ADGC) genotyped on the exome chip, which included 195,039 variants with MAF<2%. Enrichment analysis of the variant list was conducted using DAVID. 984 variants in 886 genes passed our stringent filtering criteria, including 63 genes with rare segregating, conserved and functional variants in two or more families. A frameshift mutation in ABCA7 and a missense variant in ZCWPW1 are present in one of the 23 GWAS-confirmed AD candidate genes. Seven variants are in AD KEGG Pathway genes (BID, CYC1, ITPR1, ITPR2, LRP1, ATP2A1), including two variants in LRP1, a gene involved in AD through its roles in cholesterol transport and -amyloid modulation. Follow up in ADGC exome chip association results comparing EOAD vs. late-onset AD identified 13 of our filtered genes with suggestive associations (P<10-3), including ITM2C (P=1.2210-4), a gene known to inhibit the processing of APP by blocking access to alpha- and beta-secretase. Enrichment analysis of the list of rare conserved, functional variants showed significant, Benjamini FDR-adjusted enrichment for several AD-related processes including the ECM-receptor interaction and ABC transporters KEGG pathways; GO terms including homophilic cell adhesion and microtubule-based movement; and multiple INTERPRO cadherin classes. Exome sequencing of EOAD pedigrees identified multiple rare segregating variants with potential roles in AD pathogenesis, several of which were shared in two or more families.

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