孤独症全基因组阳性位点在中国汉族人群的验证

Replication study of autism GWAS hits in Chinese Han population

目的:探讨孤独症全基因组关联研究(GWAS)显示关联的阳性单核苷酸多态性位点(SNPs)在中国汉族人群中是否与孤独症存在关联。方法:符合美国精神障碍诊断与统计手册第4版(DSM-Ⅳ)诊断标准的孤独症儿童757例和成年正常对照1436例。选取既往GWAS中与孤独症全基因组水平显著关联的5个SNPs(NEGR1基因的rs1620977、CADPS基因的rs1452075、NUDT12基因附近的rs325506、COA8基因附近的rs10149470、KIZ基因附近的rs910805)和2个与既往报道阳性位点强连锁不平衡的SNPs(MMS22L基因附近的rs9375225和MROH5基因附近的rs746839),应用AgenaMassARRAY SNP分型方法对SNPs进行基因分型。采用Pearsonχ^(2)检验比较孤独症组和对照组各SNP等位基因和基因型的分布频率,分析其与孤独症的关联。结果:孤独症组NEGR1基因的rs1620977基因型和等位基因A的频率(病例vs.对照:17.2%vs.14.3%)和MROH5基因附近的rs746839的携带等位基因G的基因型频率(病例vs.对照:31.4%vs.26.0%)及G等位基因的频率(病例vs.对照:17.2%vs.14.3%)均高于正常对照组(P<0.05),且在男性中两组差异经Bonferroni校正后仍有统计学意义(P<0.007)。结论:中国汉族人群中NEGR1基因的rs1620977和MROH5基因附近的rs746839与孤独症关联,可能是孤独症的易感位点。

Objective:To investigate whether the positive single nucleotide polymorphisms(SNPs)in previous autism genome-wide association study(GW AS)are associated with autism in the Chinese Han population.Methods:According to the autism diagnosis of the Diagnostic and Statistical Manual of Mental Disorders,Fourth Edition(DSM-Ⅳ),757 Chinese Han children offected with autism and 1436 normal Chinese Han adults were recruited.Five genome-wide significant SNPs reported in previous autism GWAS(rs1620977 in NEGR1,rs1452075 in CADPS,rs325506 near NUDT12,rs10149470 near COA8 and rs910805 near KIZ)were selected.Besides,another two SNPs(rs9375225 near MMS22 L and rs746839 near MROH5)which were in strong linkage disequilibrium with autism GWAS hits were also included.Genotyping for 7 selected SNPs was performed by using Agena MassARRAY SNP genotyping assay.The frequency distribution of genotypes and alleles between the autistic patients and the controls was compared with the Pearson’sχ^(2) test to analyze the association between SNPs and autism.Results:The frequencies of the allele A of rs1620977 in NEGR1(cases vs.controls:17.2%vs.14.3%),the G carrying genotype(1.4%vs.26.0%)and the allele G(17.2%vs.14.3%)of rs746839 near MROH5 in autistic patients were higher than those in normal controls(P<0.05).These results remain statistically significant in the male population after Bonferroni correction(P<0.007).Conclusion:Rs1620977 in NEGR1 and rs746839 near MROH5 are associated with autism in the Chinese Han population.It suggests that these two SNPs might be susceptibility SNPs for autism in the Chinese Han population.