Discovery of gene-gene interactions across multiple independent data sets of late onset Alzheimer disease from the Alzheimer Disease Genetics Consortium

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• 作者：Timothy J. Hohman^a ; William S. Bush^b ; Lan Jiang^c ; Kristin D. Brown-Gentry^c ; Eric S. Torstenson^c ; Scott M. Dudek^c ; Shubhabrata Mukherjee^d ; Adam Naj^e ; Brian W. Kunkle^f ; Marylyn D. Ritchie^g ; Eden R. Martin^f ; ^h ; Gerard D. Schellenbergⁱ ; Richard Mayeux^j ; Lindsay A. Farrer^k ; ^l ; ^m ; ⁿ ; ^o ; Margaret A. Pericak-Vance^f ; ^p ; Jonathan L. Haines^b ; Tricia A. Thornton-Wells^q ; ^{triciathorntonwells@gmail.com" class="auth_mail" title="E-mail the corresponding author} ; for the Alzheimer's Disease Genetics Consortium
• 关键词：Gene-gene interactions ; Epistasis ; Alzheimer disease ; Biofilter
• 刊名：Neurobiology of Aging
• 出版年：2016
• 出版时间：February 2016
• 年：2016
• 卷：38
• 期：Complete
• 页码：141-150
• 全文大小：794 K

文摘

Late-onset Alzheimer disease (AD) has a complex genetic etiology, involving locus heterogeneity, polygenic inheritance, and gene-gene interactions; however, the investigation of interactions in recent genome-wide association studies has been limited. We used a biological knowledge-driven approach to evaluate gene-gene interactions for consistency across 13 data sets from the Alzheimer Disease Genetics Consortium. Fifteen single nucleotide polymorphism (SNP)-SNP pairs within 3 gene-gene combinations were identified: SIRT1 × ABCB1, PSAP × PEBP4, and GRIN2B × ADRA1A. In addition, we extend a previously identified interaction from an endophenotype analysis between RYR3 × CACNA1C. Finally, post hoc gene expression analyses of the implicated SNPs further implicate SIRT1 and ABCB1, and implicate CDH23 which was most recently identified as an AD risk locus in an epigenetic analysis of AD. The observed interactions in this article highlight ways in which genotypic variation related to disease may depend on the genetic context in which it occurs. Further, our results highlight the utility of evaluating genetic interactions to explain additional variance in AD risk and identify novel molecular mechanisms of AD pathogenesis.