Polymorphism Of DISC1 Gene And Susceptibility Of SALS Was Found And Verified Based On Integrative Omics Analysis

Objective Amyotrophic lateral sclerosis(ALS)is a rare and devastating neurodegenerative disease that predominantly affects motor neurons leading to progressive paralysis,and ultimately dies.Approximately 5%~10% of ALS have a family history,is the familial amyotrophic lateral sclerosis(FALS),whereas the remaining 90% ~ 95% are sporadic amyotrophic sclerosis(sALS).Sporadic amyotrophic lateral sclerosis is a aging and complex disease characterized by both inheritance and the environment.Recently,genome-wide association study(GWAS)has revealed that many susceptible genes and a large number of risk SNP sites are associated with sporadic amyotrophic lateral sclerosis(sALS),but the molecular mechanism of disease still need further exploration.More importantly,the repeatability between existing GWAS screening was low;and almost all of the screening were concentrated in a few loci that were strictly consistent with the significance level of genome-wide(P<10-5),and a large number of genetic variants that played a minor effect were neglected.Accordingly,this study modifies the small effect sites associated with sALS by integrating multiple GWAS;the possible molecular mechanism of ALS was explored by pathway analysis;and furthermore,the specific functional genes of Chinese population were found and verified through the two-stage association analysis strategy.Methods We constructed an integrative dataset associated with sALS,based on two s ALS-related genome-wide association studies(GWAS)(the US and Irish studies)of different ethnic origin.The repeatability of GWAS among populations was evaluated by Gene set enrichment analysis(GSEA).Pathway analysis was used to reveal the functional pathways supported by the two studies,as well as the susceptibility genes associated with sALS in these pathways.To further verify the association between the NSD-function target genes and sALS,we preformed a two-stage case-control study(500 sALS patients and 500 controls).The sALS susceptibility locus of the candidate genes were found and tested step by step.Result Based on the integration analysis of two sALS-related genome-wideassociation studies(GWAS)(the US and Irish studies),in this study,371 susceptibility genes supported by both the two studies were found in 3,227sub-significant candidate genes set;whereas GSEA analysis,not only shows that there is significant repeatability of the two studies at the overall level(P<10-4),but also suggested that the ALS susceptibility genes identified by the two GWAS screens have similar functional backgrounds.Pathway analysis recealed that there were 34 common supported Gene Ontology(GO)biological processes pathway(P<10-2),of which 10 pathways were related to NSD function.At the same time,based on the pathway analysis of 79 ALS related susceptible or pathogenic genes had reported,also confirms the important role of NSD in the pathogenesis of ALS(P=0.0013).In these pathways,the nervous system developmental pathway(GO: 0007399)associated with the nervous system development(NSD-function)is further supported by the reported susceptibility and pathogenicity genes of sALS.In the whole genome case-control study based on Chinese population,there are four genes(DISC1,CNTN4,NRXN3,and ERBB4)were significant association with sALS(P<0.01),among the 17 common supported susceptibility genes associated with NSD-function.In the second stage,further confirmed through the Chinese population case-control study,shows that the polymorphic of rs3737597 in DISC1 gene involved in nervous system development pathway,was closely related to sALS.Conclusion The nervous system developmental pathway is a potential pathogenesis of sALS,among them,the polymorphism of rs3737597 in DISC1 might play some roles;the strategy combined a low significance criterion and a pathway-based analysis was feasible to elucidate the molecular mechanisms of some complex diseases.