Association of the type 2 diabetes mellitus susceptibility gene, TCF7L2, with schizophrenia in an Arab-Israeli family sample

Abstract

Many reports in different populations have demonstrated linkage of the 10q24-q26 region to schizophrenia, thus encouraging further analysis of this locus for detection of specific schizophrenia genes. Our group previously reported linkage of the 10q24-q26 region to schizophrenia in a unique, homogeneous sample of Arab-Israeli families with multiple schizophrenia-affected individuals, under a dominant model of inheritance. To further explore this candidate region and identify specific susceptibility variants within it, we performed re-analysis of the 10q24-26 genotype data, taken from our previous genome-wide association study (GWAS) (Alkelai et al, 2011). We analyzed 2089 SNPs in an extended sample of 57 Arab Israeli families (189 genotyped individuals), under the dominant model of inheritance, which best fits this locus according to previously performed MOD score analysis. We found significant association with schizophrenia of the TCF7L2 gene intronic SNP, rs12573128, (p = 7.01×10⁻⁶) and of the nearby intergenic SNP, rs1033772, (p = 6.59×10⁻⁶) which is positioned between TCF7L2 and HABP2. TCF7L2 is one of the best confirmed susceptibility genes for type 2 diabetes (T2D) among different ethnic groups, has a role in pancreatic beta cell function and may contribute to the comorbidity of schizophrenia and T2D. These preliminary results independently support previous findings regarding a possible role of TCF7L2 in susceptibility to schizophrenia, and strengthen the importance of integrating linkage analysis models of inheritance while performing association analyses in regions of interest. Further validation studies in additional populations are required.

Figure 1. The 10q24-26 region.

(a) Graphical representation of the linkage region including the genes within it. The map of the linkage region was adapted from UCSC Genome Browser (http://genome.ucsc.edu/) (Mar. 2006 (NCBI36/hg18) assembly) (b) -log10(p-values) of all the SNPs analyzed in the 10q24-26 region, employing the dominant model and according to the position of the SNPs on the chromosome.

Figure 2. The TCF7L2 gene region.

(a) The map of the genomic region adapted from UCSC Genome Browser (http://genome.ucsc.edu/) (Mar. 2006 (NCBI36/hg18) assembly) (b) Haploview representation of the LD structure between two TCF7L2 significant SNPs (rs12573128 and rs1033772). (c) -log10(p-values) of all the SNPs analyzed between rs12573128 and rs1033772.