DOCK4 and CEACAM21 as novel schizophrenia candidate genes in the Jewish population.

It is well accepted that schizophrenia has a strong genetic component. Several genome-wide association studies (GWASs) of schizophrenia have been published in recent years ; most of them population based with a case-control design. Nevertheless, identifying the specific genetic variants which contribute to susceptibility to the disorder remains a challenging task. A family-based GWAS strategy may be helpful in the identification of schizophrenia susceptibility genes since it is protected against population stratifi- cation, enables better accounting for genotyping errors and is more sensitive for identification of rare variants which have a very low frequency in the general population. In this project we implemented a family-based GWAS of schizophrenia in a sample of 107 Jewish-Israeli families. We found one genome- wide significant association in the intron of the DOCK4 gene (rs2074127, p value=1.134r10 x 7 ) and six additional nominally significant association signals with p<1r10 x 5 . One of the top single nucleotide polymorphisms (p<1r10 x 5 ) which is located in the predicted intron of the CEACAM21 gene was significantly replicated in independent family-based sample of Arab-Israeli origin (rs4803480 : p value=0.002 ; combined p value=9.61r10x8), surviving correction for multiple testing. Both DOCK4 and CEACAM21 are biologically reasonable candidate genes for schizophrenia although generalizability of the association of DOCK4 with schizophrenia should be investigated in further studies. In addition, gene-wide significant associations were found within three schizophrenia candidate genes : PGBD1, RELN and PRODH, replicating previously reported associations. By application of a family-based strategy to GWAS, our study revealed new schizophrenia susceptibility loci in the Jewish-Israeli popu- lation. Received 8 March 2011 ; Reviewed 11 April 2011 ; Revised 19 April 2011 ; Accepted 13 May 201

Association of the Type 2 Diabetes Mellitus Susceptibility Gene, TCF7L2, with Schizophrenia in an Arab-Israeli Family Sample

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

Significant results for association with schizophrenia.

<p>P-values, allelic frequencies, and Hardy Weinberg equilibrium were obtained using PBAT. Genotyping rate, Mendelian errors, and OR were obtained using PLINK. Abbreviations: HW = Hardy Weinberg equilibrium; allele = minor allele; freq = allele frequency; Gen_rate = genotyping rate, Mend_err = Mendelian errors.</p

The <i>CADM2</i> gene is associated with processing speed performance – evidence among elderly with type 2 diabetes

<p><b>Objectives:</b> Recent large-scale meta-analysis of genome-wide association studies (GWAS) from multiple cohorts, demonstrated the association of the single nucleotide polymorphism (SNP) rs17518584, with processing speed (measured by the Digit Symbol Substitution Test (DSST) or the Letter Digit Substitution Test (LDST)), at GWAS significance level. This SNP is located within the cell adhesion molecule 2 (<i>CADM2</i>) gene. We aimed to validate this finding in our sample of 944 cognitively normal Jewish elderly individuals with type 2 diabetes (T2D), a population which is at risk for cognitive decline and dementia.</p> <p><b>Methods:</b> Using linear regression, we studied the association of rs17518584 with DSST performance, adjusting for demographic, T2D-related characteristics and cardiovascular factors. In secondary analyses, associations with performance in four cognitive domains (episodic memory, language/semantic categorisation, attention/working memory and executive function) and overall cognition were examined.</p> <p><b>Results:</b> Controlling for sex, age at cognitive assessment, years of education and ancestry, we found a significant association of rs17518584 with DSST performance (<i>P</i> = 0.013), consistent with the originally reported effect direction. Results remained significant even when the additional covariates (T2D-related and cardiovascular factors) were included in the analysis (<i>P</i> = 0.034). Moreover, this SNP was significantly associated with performance in the cognitive domains of language/semantic categorisation and executive function, as well as overall cognition.</p> <p><b>Conclusions:</b> Taken together, irrespective of T2D-related characteristics and cardiovascular factors, our findings provide independent support for the association of <i>CADM2</i> SNP rs17518584 with processing speed (and demonstrate association with additional cognitive phenotypes), among cognitively normal elderly individuals with T2D.</p

The 10q24-26 region.

<p>(a) Graphical representation of the linkage region including the genes within it. The map of the linkage region was adapted from UCSC Genome Browser (<a href="http://genome.ucsc.edu/" target="_blank">http://genome.ucsc.edu/</a>) (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.</p