A Genome-wide Expression Association Analysis Identifies Genesand Pathways Associated with Amyotrophic Lateral Sclerosis

Abstract Amyotrophic lateral sclerosis (ALS) is a neurodegenerativedisease with strong genetic components. Toidentity novel risk variants for ALS, utilizing the latestgenome-wide association studies (GWAS) and eQTL studydata, we conducted a genome-wide expression associationanalysis by summary data-based Mendelian randomization(SMR) method. Summary data were derived from a largescaleGWAS of ALS, involving 12577 cases and 23475controls. The eQTL annotation dataset included 923,021cis-eQTL for 14,329 genes and 4732 trans-eQTL for 2612genes. Genome-wide single gene expression associationanalysis was conducted by SMR software. To identifyALS-associated biological pathways, the SMR analysisresults were further subjected to gene set enrichmentanalysis (GSEA). SMR single gene analysis identified onesignificant and four suggestive genes associated with ALS,including C9ORF72 (P value = 7.08 9 10-6), NT5C3L(P value = 1.33 9 10-5), GGNBP2 (P value = 1.81 910-5), ZNHIT3(P value = 2.94 9 10-5), and KIAA1600(P value = 9.97 9 10-5). GSEA identified 7 significantbiological pathways, such as PEROXISOME (empiricalP value = 0.006), GLYCOLYSIS_GLUCONEOGENESIS(empirical P value = 0.043), and ARACHIDONIC_ACID_METABOLISM (empirical P value = 0.040). Our studyprovides novel clues for the genetic mechanism studies ofALS.Keywords Amyotrophic lateral sclerosis GWAS Expression quantitative trait loci SM