Multi-ancestry transcriptome-wide association studies of cognitive function, white matter hyperintensity, and Alzheimer’s disease

Abstract Genetic variants increase the risk of neurocognitive disorders in later life including Vascular Dementia (VaD) and Alzheimer’s disease (AD), but the precise relationships between genetic risk factors and underlying disease etiology are not well understood. Transcriptome-wide association studies (TWAS) can be leveraged to better characterize the genes and biological pathways underlying genetic influences on disease. To date, almost all existing TWAS have been conducted using expression studies from individuals of a single genetic ancestry, primarily European. Using the joint likelihood-based inference framework in Multi-ancEstry TRanscriptOme-wide analysis (METRO), we leveraged gene expression data from European (EA) and African ancestries (AA) to identify genes associated with general cognitive function, white matter hyperintensity (WMH), and AD. Regions were fine-mapped using Fine-mapping Of CaUsal gene Sets (FOCUS). We identified 266, 23, 69, and 2 genes associated with general cognitive function, WMH, AD (using EA GWAS summary statistics), and AD (using AA GWAS), respectively (Bonferroni-corrected alpha=P<2.9−10 -6 ), some of which were previously identified. Enrichment analysis showed that many of the identified genes were in pathways related to innate immunity, vascular dysfunction, and neuroinflammation. Further, downregulation of ICA1L was associated with higher WMH and with AD, indicating its potential contribution to overlapping AD and VaD neuropathology. To our knowledge, our study is the first TWAS of cognitive function and neurocognitive disorders that used expression mapping studies in multiple ancestries. This work may expand the benefits of TWAS studies beyond a single ancestry group and help to identify gene targets for pharmaceutical or preventative treatment for dementia. Author Summary Transcriptome-wide association studies (TWAS) can be used to understand the mechanisms of gene expression that underly disease etiology. However, to date, TWAS methods have mostly been used in a single ancestry group, especially European ancestry (EA), and few TWAS have focused on cognitive function or structural brain measures. We used a newly developed TWAS method called the Multi-ancEstry TRanscriptOme-wide analysis (METRO) to incorproate gene expression data from 801 EA and 1,032 African ancestry (AA) adults to identify genes associated with general cognitive function, structural brain changes called white matter hyperintensities (WMH) that predispose people to vascular dementia, and another form of dementia called Alzheimer’s disease (AD). We found that reduced gene expression of ICA1L was associated with more WMH and with AD, indicating its potential contribution to overlapping AD and vascular dementia neuropathologies. To our knowledge, our study is the first TWAS of cognitive function and neurocognitive disorders using multiple ancestries. This work may expand the benefits of TWAS studies beyond a single ancestry group and help to identify gene targets for pharmaceutical or preventative treatment for dementia.