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.
Highlights
Chromosome 10q is remarkably rich in linkage findings for schizophrenia and bipolar disorder [1]
The 10q24–q26 region harbors a large number of protein coding genes (,130), many of them expressed in the CNS, specific schizophrenia susceptibility genes have not been identified in our sample
We focused on the 10q24–q26 linkage region and re-analyzed the available genotype data of 2089 SNPs positioned in this area (taken from our previous genome-wide association study (GWAS) (Alkelai et al, 2011) [11]) in order to study association with schizophrenia under the dominant model
Summary
Chromosome 10q is remarkably rich in linkage findings for schizophrenia and bipolar disorder [1]. Seven reports in different populations have demonstrated linkage of the 10q24–q26 region to schizophrenia [2,3,4,5,6,7,8]. The studies, demonstrating significant and suggestive schizophrenia linkage to 10q24-q26, greatly encourage a search for specific schizophrenia susceptibility genes in this region. Given the difference between studies in localization of linkage peaks and the fact that peaks in this region were not always the best detected ones in the cited studies, it is reasonable that the region may harbor multiple schizophrenia susceptibility genes with differential contributions to the phenotype in terms of variant frequency, effect size and mode of inheritance rather than a single schizophrenia susceptibility gene [9]. The 10q24–q26 region harbors a large number of protein coding genes (,130), many of them expressed in the CNS, specific schizophrenia susceptibility genes have not been identified in our sample
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