Genomic convergence of locus-based GWAS meta-analysis identifies AXIN1 as a novel Parkinson's gene.

Abstract

Parkinson's disease (PD) is a common, disabling neurodegenerative disorder with significant genetic underpinnings. Multiple genome-wide association studies (GWAS) have been conducted with identification of several PD loci. However, these only explain about 25% of PD genetic risk indicating that additional loci of modest effect remain to be discovered. Association clustering methods such as gene-based tests are more powerful than single-variant analysis for identifying modest genetic effects. Combined with the locus-based algorithm, OASIS, the most significant association signals can be homed in. Here, two dbGAP GWAS datasets (7415 subjects (2750 PD and 4845 controls) genotyped for 0.78 million SNPs) were analyzed using combined clustering algorithms to identify 88 PD candidate genes in 24 loci. These were further investigated for gene expression in substantia nigra (SN) of PD and control subjects on GEO datasets. Expression differences were also assessed in normal brains SN versus white matter on BRAINEAC datasets. This genetic and functional analysis identified AXIN1, a key regulator of Wnt/β-catenin signaling, as a novel PD gene. This finding links PD with inflammation. Other significantly associated genes were CSMD1, CLDN1, ZNF141, ZNF721, RHOT2, RICTOR, KANSL1, and ARHGAP27. Novel PD genes were identified using genomic convergence of gene-wide and locus-based tests and expression studies on archived datasets.