Identifying Candidate Genes Associated with Sporadic Amyotrophic Lateral Sclerosis via Integrative Analysis of...

Amyotrophic lateral sclerosis, a fatal neurodegeneration disease affecting motor neurons in the brain and spinal cord, is difficult to diagnose and treat. The objective of this study is to identify novel candidate genes related to ALS. Transcriptome-wide association study of ALS was conducted by integrating the genome-wide association study summary data (including 1234 ALS patients and 2850 controls) and pre-computed gene expression weights of different tissues. The ALS-associated genes identified by TWAS were further compared with the differentially expressed genes detected by the mRNA expression profiles of the sporadic ALS. Functional enrichment and annotation analysis of identified genes were performed by an R package and the functional mapping and annotation software. TWAS identified 761 significant genes (P_TWAS < 0.05), 627 Gene ontology terms, and 8 Kyoto Encyclopedia of Genes and Genomes pathways for ALS, such as C9orf72, with three expression quantitative trait loci were found significantly: rs2453554 (P_{TWAS CBRS} = 4.68 × 10^-10, P_{TWAS CBRS} = 2.54 × 10^-9), rs10967976 (P_{TWAS CBRS} = 7.85 × 10^-10, P_{TWAS CBRS} = 8.91 × 10^-9, P_{TWAS CBRS} = 1.49 × 10^-7, P_{TWAS CBRS} = 5.59 × 10^-7), rs3849946 (P_{TWAS CBRS} = 7.69 × 10^-4, P_{TWAS YBL} = 4.02 × 10^-2), Mitochondrion (P_adj = 4.22 × 10^-16), and Cell cycle (P_adj = 2.04 × 10^-3). Moreover, 107 common genes, 4 KEGG pathways and 41 GO terms were detected by integrating mRNA expression profiles of sALS, such as CPVL (FC = 2.06, P_mRNA = 6.99 × 10^-6, P_{TWAS CBR} = 2.88 × 10^-2, P_{TWAS CBR} = 4.37 × 10^-2), Pyrimidine Metabolism (P_adj = 2.43 × 10^-2), and Cell Activation (P_adj = 5.54 × 10^-3). Multiple candidate genes and pathways were detected for ALS. Our findings may provide novel clues for understanding the genetic mechanism of ALS.