Gusareva Elena S, Carrasquillo Minerva M, Bellenguez Céline, Cuyvers Elise, Colon Samuel, Graff-Radford Neill R, Petersen Ronald C, Dickson Dennis W, Mahachie John Jestinah M, Bessonov Kyrylo, Van Broeckhoven Christine, Harold Denise, Williams Julie, Amouyel Philippe, Sleegers Kristel, Ertekin-Taner Nilüfer, Lambert Jean-Charles, Van Steen Kristel
Systems and Modeling Unit, Montefiore Institute, University of Liege, Belgium; Bioinformatics and Modeling, GIGA-R, University of Liege, Belgium.
Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, USA.
Neurobiol Aging. 2014 Nov;35(11):2436-2443. doi: 10.1016/j.neurobiolaging.2014.05.014. Epub 2014 May 28.
We propose a minimal protocol for exhaustive genome-wide association interaction analysis that involves screening for epistasis over large-scale genomic data combining strengths of different methods and statistical tools. The different steps of this protocol are illustrated on a real-life data application for Alzheimer's disease (AD) (2259 patients and 6017 controls from France). Particularly, in the exhaustive genome-wide epistasis screening we identified AD-associated interacting SNPs-pair from chromosome 6q11.1 (rs6455128, the KHDRBS2 gene) and 13q12.11 (rs7989332, the CRYL1 gene) (p = 0.006, corrected for multiple testing). A replication analysis in the independent AD cohort from Germany (555 patients and 824 controls) confirmed the discovered epistasis signal (p = 0.036). This signal was also supported by a meta-analysis approach in 5 independent AD cohorts that was applied in the context of epistasis for the first time. Transcriptome analysis revealed negative correlation between expression levels of KHDRBS2 and CRYL1 in both the temporal cortex (β = -0.19, p = 0.0006) and cerebellum (β = -0.23, p < 0.0001) brain regions. This is the first time a replicable epistasis associated with AD was identified using a hypothesis free screening approach.
我们提出了一种用于全基因组关联相互作用分析的最小化方案，该方案涉及结合不同方法和统计工具的优势，对大规模基因组数据进行上位性筛选。该方案的不同步骤在阿尔茨海默病（AD）的实际数据应用中得到了说明（来自法国的2259名患者和6017名对照）。特别是，在全基因组上位性筛选中，我们从6号染色体q11.1（rs6455128，KHDRBS2基因）和13号染色体q12.11（rs7989332，CRY1基因）中鉴定出与AD相关的相互作用单核苷酸多态性对（p = 0.006，经多重检验校正）。在来自德国的独立AD队列（555名患者和824名对照）中的重复分析证实了发现的上位性信号（p = 0.036）。该信号也得到了首次在5个独立AD队列中应用的上位性荟萃分析方法的支持。转录组分析显示，在颞叶皮质（β = -0.19，p = 0.0006）和小脑（β = -0.23，p < 0.0001）脑区中，KHDRBS2和CRY1的表达水平呈负相关。这是首次使用无假设筛选方法鉴定出与AD相关的可重复上位性。
