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.