Pathway Analysis of GWAS Provides New Insights into Genetic Susceptibility to 3 Inflammatory Diseases 英文参考文献.docVIP

PathwayAnalysisofGWASProvidesNewInsightsinto GeneticSusceptibilityto3InflammatoryDiseases HarikliaEleftherohorinou1,2.,VictoriaWright1.,CliveHoggart2,Anna-LiisaHartikainen3 ,Marjo-Riitta Jarvelin2,4,5,DavidBalding2,LachlanCoin2,MichaelLevin1* 1Division of Medicine, Department of Paediatrics, Imperial College London, London, United Kingdom, 2Division of Epidemiology, Department of Epidemiology and Public Health, Public Health and Primary Care, Imperial College London, London, United Kingdom, 3Department of Clinical Sciences/Obstetrics and Gynecology, University of Oulu, Oulu, Finland, 4Institute of Health Sciences and Biocenter Oulu, University of Oulu, Oulu, Finland, 5Department of Child and Adolescent Health, NationalInstituteofHealthandWelfare,UniversityofOulu,Oulu,Finland Abstract Although the introduction of genome-wide association studies (GWAS) have greatly increased the number of genes associatedwithcommondiseases,onlyasmallproportionofthepredictedgeneticcontributionhassofarbeenelucidated. Studying the cumulative variation of polymorphisms in multiple genes acting in functional pathways may provide a complementaryapproachtothemorecommonsingleSNPassociationapproachinunderstandinggeneticdeterminantsof commondisease.Wedevelopedanovelpathway-basedmethodtoassessthecombinedcontributionofmultiplegenetic variants acting within canonical biological pathways and applied it to data from 14,000 UK individuals with 7 common diseases.WetestedinflammatorypathwaysforassociationwithCrohn’sdisease(CD),rheumatoidarthritis(RA)andtype1 diabetes (T1D)with 4 non-inflammatory diseases as controls.Using a variable selection algorithm, weidentified variants responsible for the pathway association and evaluated their use for disease prediction using a 10 fold cross-validation frameworkinordertocalculateout-of-sampleareaundertheReceiverOperatingCurve(AUC).Thegeneralisabilityofthese predictive models was tested on an independent birth cohort from Northern Finland. Multiple canonical in