The Study Of Susceptibility Loci For Sporadic Amyotrophic Lateral Sclerosis In Chinese Han Population

Objective Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease.According to the genetic characteristics, ALS can be classified as familial ALS andsporadic ALS. It’s well known that sporadic ALS is a complex disease attributes to theco-effect of both the environment and the genetics. Genome-wide association study(GWAS) is a technical, with high density and high coverage of single nucleuspolymorphism (SNP), has identified susceptibility genes for many complex disease.GWA studies for ALS have identified many risk SNP in Caucasian population, andoffered some susceptibility genes and pathogenesis for ALS. However, the GWAstudies and some validation studies for ALS have found that ALS may be a diseasewith ethic heterogeneity, and different populations have different susceptibility genes.Till now, there is none GWAS for ALS in Chinese population. It is unknown what thesusceptibility genes are for ALS in Chinese Han population and whether there aresome difference in susceptibility genes between Chinese Han and Caucasianpopulation. This research will use Illumina Beadchip and Sequenome MassArraySystem to genotype the SNPs and discuss the difference of susceptibility genes forALS between Chinese Han population and Caucasian population. Forthmore, we useGWAS to identify the special risk SNPs in Chinese Han population and useimputation analysis to locate the risk SNPsto susceptibility genes.Method We collect ALS cases from outpatient clinics of neurology departments ofmany hospitals in China and collect health controls from other outpatient departmentsand health examination centers. After rigid selection,1,239ALS cases and3,669health controls are included in the research.1)706cases and1,777controls areincluded in validating the SNP identified by GWAS in Caucasian population.5SNPs are genotyped by Sequenome MassArray System and each SNP is analyzed for thedifference of MAF between the cases and the controls in Chinese Han population. Wewill discuss whether the SNPs are the risk SNPs for ALS in Chinese Han population.2) In GWAS, we use llumina Human660-Quard BeadChip to genotype561,882SNPsin533cases and1,892controls of Chinese Han. After analysis, we select the topsuggestive SNPs into validation stage. The validation stage is conducted in anothercohort of Chinese Han. We use Sequenome MassArray System to genotype the topsuggestive SNPs and analyze the difference of MAF of each SNPs. We identify therisk SNPs from the results.3) In order to uncover susceptibility genes underlying eachof the association signals, we investigated the patterns of recombination and linkagedisequilibrium (LD) around the associated SNPs and impute SNPs around theidentified SNP for fine mapping.4) We validate the SNPs identified in Chinese Hanpopulation in multi-populations in west countries (US., United Kingdom, France,Ireland, Belgium, Sweden and Netherland) including3,500cases and10,035controls.We discuss the ethnic heterogeneity of ALS combining the two validation studies.Result Two of the5SNPs in validation study in Chinese Han are excluded fordeviated from the Hardy-Weigh equilibrium (P<0.05). The MAF of3SNPs aredemonstrated no significant difference between cases and controls in Chinese Han(rs2306677，p=0.7416；rs10260404，p=0.3557；rs2814707，p=0.5212). In discoverystage,90top suggestive SNPs show some association with ALS in Chinese Han. Inthe validation stage,4of the90suggestive SNPs showed consistent association in theindependent validation samples. Two of them showed significant association thatsurpassed the threshold for Bonferroni correction in the validation analysis(rs6703183, P=1.98×10-5; rs8141797, P=1.36×10-5), but the other2SNPs failed tosurvive Bonferroni correction (rs2055627, P=1.49×10-3; rs32897, P=4.18×10-2). Allthe4SNP showed more significant association in the joint analysis of the combinedGWAS and replication samples. The associations at2SNPs surpassed thegenome-wide significant threshold (P <5.0×10-8) in the combined samples, rs6703183 at1q32(Pcombined=2.92×10-8, OR=1.31) and rs8141797at22p11(Pcombined=2.35×10-9,OR=1.52). After imputation analysis, the2SNPs are located at the gene CAMK1Gand SUSD2respectively. We validate these2SNPs in Caucasian population; theresults present no associations between the SNPs and ALS both in multi-populationsand in each population.Conclusion1. There is no association between the SNP which are identified in Caucasianpopulation and ALS in Chinese Han.2. We identify2risk SNP for ALS in Chinese Han, rs6703183and rs8141797.3. The2SNP are located at the gene CAMK1G and SUSD2respectively, whichsuggest new susceptibility genes and pathogenesis mechanisms.4. There is no association between the SNP which are identified in Chinese Han andALS in Caucasian population.