A Covering Method for Detecting Genetic Associations between Rare Variants and Common Phenotypes 英文参考文献.docVIP

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A Covering Method for Detecting Genetic Associations between Rare Variants and Common Phenotypes 英文参考文献.doc

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A Covering Method for Detecting Genetic Associations between Rare Variants and Common Phenotypes 英文参考文献

ACoveringMethodforDetectingGeneticAssociations betweenRareVariantsandCommonPhenotypes GauravBhatia1,2*,VikasBansal3,OlivierHarismendy3,NicholasJ.Schork3,EricJ.Topol4,KellyFrazer3,4, VineetBafna1,5 1DepartmentofComputerScienceandEngineering,UniversityofCaliforniaSanDiego,LaJolla,California,UnitedStatesofAmerica,2Harvard-MITDivisionofHealth Sciencesand Technology, Cambridge, Massachusetts,UnitedStates ofAmerica, 3ScrippsTranslationalScienceInstitute, LaJolla,California, United States ofAmerica, 4DepartmentofPediatrics,UniversityofCaliforniaSanDiego,LaJolla,California,UnitedStatesofAmerica,5InstituteforGenomicMedicine,UniversityofCaliforniaSan Diego,LaJolla,California,UnitedStatesofAmerica Abstract Genome wide association (GWA) studies, which test for association between common genetic markers and a disease phenotype,haveshownvaryingdegreesofsuccess.WhilemanyfactorscouldpotentiallyconfoundGWAstudies,wefocus onthepossibilitythatmultiple,rarevariants(RVs)mayactinconcerttoinfluencediseaseetiology.Here,wedescribean algorithm for RV analysis, RARECOVER. The algorithm combines a disparate collection of RVs with low effect and modest penetrance. Further, it does not require the rare variants be adjacent in location. Extensive simulations over a range of assumed penetrance and population attributable risk (PAR) values illustrate the power of our approach over other published methods, including the collapsing and weighted-collapsing strategies. To showcase the method, we apply RARECOVER to re-sequencing data from a cohort of 289 individuals at the extremes of Body Mass Index distribution (NC. Individual samples were re-sequenced at two genes, FAAH and MGLL, known to be involved in endocannabinoid metabolism (187Kbp for 148 obese and 150 controls). The RARECOVER analysis identifies exactly one significantlyassociatedregionineachgene,eachabout5Kbpintheupstreamregulatoryregions.Thedatasuggeststhat theRVshelpdisrupttheexpressionofthetwogenes,leadingtoloweredmetabolis