Brain and Blood Transcriptome-Wide Association Studies Identify Five Novel Genes Associated with Alzheimer’s Disease

Abstract

ABSTRACTINTRODUCTIONTranscriptome-wide Association Studies (TWAS) extend genome-wide association studies (GWAS) by integrating genetically-regulated gene expression models. We performed the most powerful AD-TWAS to date, using summary statistics fromcis-eQTL meta-analyses and the largest clinically-adjudicated Alzheimer’s Disease (AD) GWAS.METHODSWe implemented the OTTERS TWAS pipeline, leveragingcis-eQTL data from cortical brain tissue (MetaBrain; N=2,683) and blood (eQTLGen; N=31,684) to predict gene expression, then applied these models to AD-GWAS data (Cases=21,982; Controls=44,944).RESULTSWe identified and validated five novel gene associations in cortical brain tissue (PRKAG1,C3orf62,LYSMD4,ZNF439,SLC11A2) and six genes proximal to known AD-related GWAS loci (Blood:MYBPC3; Brain:MTCH2,CYB561,MADD,PSMA5,ANXA11). Further, using causal eQTL fine-mapping, we generated sparse models that retained the strength of the AD-TWAS association forMTCH2,MADD,ZNF439,CYB561, andMYBPC3.DISCUSSIONOur comprehensive AD-TWAS discovered new gene associations and provided insights into the functional relevance of previously associated variants.