Brain and blood transcriptome-wide association studies identify five novel genes associated with Alzheimer's disease

BackgroundGenome-wide association studies (GWAS) have identified numerous genetic variants associated with Alzheimer's disease (AD), but their functional implications remain unclear. Transcriptome-wide association studies (TWAS) offer enhanced statistical power by analyzing genetic associations at the gene level rather than at the variant level, enabling assessment of how genetically-regulated gene expression influences AD risk. However, previous AD-TWAS have been limited by small expression quantitative trait loci (eQTL) reference datasets or reliance on AD-by-proxy phenotypes.ObjectiveTo perform the most powerful AD-TWAS to date using summary statistics from the largest available brain and blood <i>cis</i>-eQTL meta-analyses applied to the largest clinically-adjudicated AD GWAS.MethodsWe implemented the OTTERS TWAS pipeline to predict gene expression using the largest available <i>cis</i>-eQTL data from cortical brain tissue (MetaBrain; N = 2683) and blood (eQTLGen; N = 31,684), and 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 (<i>PRKAG1</i>, <i>C3orf62</i>, <i>LYSMD4</i>, <i>ZNF439</i>, <i>SLC11A2</i>) and six genes proximal to known AD-related GWAS loci (Blood: <i>MYBPC3</i>; Brain: <i>MTCH2</i>, <i>CYB561</i>, <i>MADD</i>, <i>PSMA5</i>, <i>ANXA11</i>). Further, using causal eQTL fine-mapping, we generated sparse models that retained the strength of the AD-TWAS association for <i>MTCH2</i>, <i>MADD</i>, <i>ZNF439</i>, <i>CYB561</i>, and <i>MYBPC3</i>.ConclusionsOur comprehensive AD-TWAS discovered new gene associations and provided insights into the functional relevance of previously associated variants, which enables us to further understand the genetic architecture underlying AD risk.