Studies On Susceptibility Gene Of Mental Retardation In The Iodine-deficient Areas Of China

Iodine deficiency is the commonest cause of preventable MentalRetardation (MR) worldwide. However not everyone in iodine-deficientareas is affected and familial aggregation is common. This suggests thatgenetic factors may also contribute. Thyroid hormone (TH) plays an important role in fetal and earlypostnatal brain development. The pro-hormone T4 (3,3′,5,5′-triiodo-thyronine) is converted in the brain to its active form, T3 , or itsinactive metabolite, reverse T3, mainly by the action of Deiodinase Type2 (DIO2) .To investigate the potential genetic contribution of DIO2 ,weperformed a case-control association study using three common SNPs in thegene (rs225014, rs225012 and rs225010) that were in strong linkagedisequilibrium with each other. The single marker analysis showedpositive association with rs225012 and rs225010. In particular withrs225012 TT genotype frequency was marked significantly higher in MR casesthan in controls (X2=9.18, P= 0.00246). When we compared the distributionsof common haplotypes, we also found significant differences betweenMental Retardation and controls in the haplotype combination of rs225012and rs225010 (X2= 15.04, df =2,global P value= 0.000549). This associationremained significant after FDR multiple testing correction (q-values=0.00011). We analyzed whether two SNPs were located near a splicing siteof mRNA through in silico analysis ,but found none. Another possibilityis that rs225012 and rs225010 and the haplotype combination with these 2碘缺乏地区精神发育迟滞易感基因的研究two SNPs may simply be in linkage disequilibrium with a functionalpolymorphism elsewhere in a gene nearby. The nearest functional candidate gene nearby is TITF1 (thyroidtranscript factor 1) and TSHR (thyroid hormone receptor or thyrotropinreceptor). TITF1 gene located in the upstream of DIO2 gene and TSHR waslocated in the downstream of DIO2 gene. We performed case-controlassociation study using two common SNPs in the TITF1 gene (Rs999460, andRs2076751) and five common SNPs in the TSHR gene. The result of singlelocus analysis and haplotype analysis all showed there is no significantassociation between control and mental retardation. We conclude that allelic variation in the DIO2 gene may affect theamount of T3 available and in an iodine-deficient environment partlydetermine overall risk of MR.