Hohman Timothy J, Bush William S, Jiang Lan, Brown-Gentry Kristin D, Torstenson Eric S, Dudek Scott M, Mukherjee Shubhabrata, Naj Adam, Kunkle Brian W, Ritchie Marylyn D, Martin Eden R, Schellenberg Gerard D, Mayeux Richard, Farrer Lindsay A, Pericak-Vance Margaret A, Haines Jonathan L, Thornton-Wells Tricia A
Vanderbilt Memory & Alzheimer's Center, Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA.
Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA.
Neurobiol Aging. 2016 Feb;38:141-150. doi: 10.1016/j.neurobiolaging.2015.10.031. Epub 2015 Nov 6.
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.
迟发性阿尔茨海默病（AD）具有复杂的遗传病因，涉及位点异质性、多基因遗传和基因-基因相互作用；然而，在最近的全基因组关联研究中，对相互作用的研究一直有限。我们采用了一种基于生物学知识的方法，来评估来自阿尔茨海默病遗传学联盟的13个数据集中基因-基因相互作用的一致性。在3种基因-基因组合中鉴定出15个单核苷酸多态性（SNP）-SNP对：SIRT1×ABCB1、PSAP×PEBP4和GRIN2B×ADRA1A。此外，我们扩展了先前在RYR3×CACNA1C之间的内表型分析中确定的一种相互作用。最后，对所涉及SNP的事后基因表达分析进一步表明了SIRT1和ABCB1的作用，并表明CDH23在AD的表观遗传分析中最近被确定为一个AD风险位点。本文中观察到的相互作用突出了与疾病相关的基因型变异可能如何取决于其发生的遗传背景。此外，我们的结果突出了评估遗传相互作用以解释AD风险中的额外变异并确定AD发病机制新分子机制的效用。
