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

ABSTRACT

INTRODUCTION: Transcriptome-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 from cis -eQTL meta-analyses and the largest clinically-adjudicated Alzheimer's Disease (AD) GWAS. METHODS: We implemented the OTTERS TWAS pipeline, leveraging cis -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). RESULTS: We 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 for MTCH2 , MADD , ZNF439 , CYB561 , and MYBPC3 . DISCUSSION: Our comprehensive AD-TWAS discovered new gene associations and provided insights into the functional relevance of previously associated variants.