Application of sparse group lasso in Transcriptome-Wide Association Studies to determine pathway-level genetic risk of brain aging

Music City Center 

Brain aging involves the gradual loss of structure and function of neurons and their connections, leading to cognitive decline and increased vulnerability to neurodegenerative diseases including Alzheimer's disease (AD). We have conducted a number of studies in UK Biobank (UKB) to identify the nongenetic risk factors (including smoking, blood pressure, allostatic load, diet and life essential 8) of white matter (WM) Brain Age Gap (BAG), a marker of brain aging predicted from multiple fractional anisotropy tract measurements obtained from diffusion tensor imaging data using machine learning algorithm. However, little is known about the genetic risk of brain aging. Genome-wide association studies (GWAS) only identify association and risk at SNP level, on the other hand, transcriptome-wide association studies (TWAS) methods integrate GWAS data and expression reference panels (e.g. expression QTL) to identify the associations at gene level potentially improving the interpretability. Existing TWAS methods, however, are dominantly univariate, the genes identified have little unifying biological themes thus limiting in its application to determine the genetic risk of complex polygenic trait like brain aging. We developed a novel pathway-guided TWAS method and embedded sparse group lasso within the framework to select genes and pathways most associated with brain aging using imaging and genetic data from UKB. We incorporated curated pathway databases including KEGG, Reactome and Biocarta and identified five major categories of pathways related to neural system, DNA repair, DNA metabolism, protein metabolism and immune defense most associated with WM BAG which cannot be found by existing TWAS methods. Our findings provide new insights into the genetics of brain aging and improve our understanding of the molecular mechanism of the aging brain and the transition to AD.

transcriptome-wide association studies (TWAS)

white matter brain aging

pathway

sparse group lasso