Evidence for an interaction of schizophrenia susceptibility loci on chromosome 6q23.3 and 10q24.33–q26.13 in Arab Israeli families

Abstract

A genome scan for schizophrenia related loci in Arab Israeli families by Lerer et al. [Lerer et al. (2003); Mol Psychiatry 8:488-498] detected significant evidence for linkage at chromosome 6q23. Subsequent fine mapping [Levi et al. (2005); Eur J Hum Genet 13:763-771], association [Amann-Zalcenstein et al. (2006); Eur J Hum Genet 14:1111-1119] and replication studies [Ingason et al. (2007); Eur J Hum Genet 15:988-991] identified AHI1 as a putative susceptibility gene. The same genome scan revealed suggestive evidence for a schizophrenia susceptibility locus in the 10q23-26 region. Genes at these two loci may act independently in the pathogenesis of the disease in our homogeneous sample of Arab Israeli families or may interact with each other and with other factors in a common biological pathway. The purpose of our current study was to test the hypothesis of genetic interaction between these two loci and to identify the type of interaction between them. The initial stage of our study focused on the 10q23-q26 region which has not been explored further in our sample. The second stage of the study included a test for possible genetic interaction between the 6q23.3 locus and the refined 10q24.33-q26.13 locus. A final candidate region of 19.9 Mb between markers D10S222 (105.3 Mb) and D10S587 (125.2 Mb) was found on chromosome 10 by non-parametric and parametric linkage analyses. These linkage findings are consistent with previous reports in the same chromosomal region. Two-locus multipoint linkage analysis under three complex disease inheritance models (heterogeneity, multiplicative, and additive models) yielded a best maximum LOD score of 7.45 under the multiplicative model suggesting overlapping function of the 6q23.3 and 10q24.33-q26.13 loci.

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

“…While calculating the best-fitting penetrance for the 10q24–q26 locus by maximization of parametric LOD scores over genetic model parameters (MOD score analysis by varying penetrances and disease allele frequency), we showed that the 10q24–q26 locus had a dominant mode of inheritance in the studied Arab-Israeli sample. We refined the linkage region to D10S222 (105.3 Mb) - D10S587 (125.2 Mb) and also demonstrated genetic interaction of this locus with an additional locus, 6q23.3, which was significantly linked to schizophrenia [1]. Although 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.…”

“…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].…”

“…In a follow-up publication (Alkelai et al, 2009) [1] we further explored this region in exactly the same Arab sample, by genotyping additional markers and applying additional analytic approaches. While calculating the best-fitting penetrance for the 10q24–q26 locus by maximization of parametric LOD scores over genetic model parameters (MOD score analysis by varying penetrances and disease allele frequency), we showed that the 10q24–q26 locus had a dominant mode of inheritance in the studied Arab-Israeli sample.…”

Genetics of schizophrenia from a clinicial perspective

“…genes from the dopaminergic and serotonergic pathways as well as genes encoding proteins involved in hormonal pathways and membrane phospholipids (Arranz et al, 1998; Carlsson et al, 2001; Chowdari et al, 2001; Greenwood et al, 2011; Laruelle et al, 1999; Lieberman et al, 1998; Nielsen et al, 1998; Rotondo et al, 1999; Seeman, 2010; Semwal et al, 2002; Talkowski et al, 2006, 2008; Tandon et al, 2008b; Weinberger, 1987). Several meta-analyses were published (Allan et al, 2008; Chen et al, 2011a, 2011c); but consistent findings have been limited (Alkelai et al, 2009; Sanders et al, 2008; Sullivan et al, 2008). …”

TCF7L2 polymorphisms and the risk of schizophrenia in the Chinese Han population

“…It also appears that chromosome 10q is remarkably rich in linkages to SCZ [9]. TCF7L2 also known as TCF4 locus on chromosome 10q25.2-25.3 and encodes a high mobility group box-containing transcription factor that plays a key role in the WNT signaling pathway [10].…”