Connexin50 gene on human chromosome 1q21 is associated with schizophrenia in matched case-control and family- based studies

Xingqun Ni ^1*, Jose Valente ², Maria Azevedo ², Michelle Pato ³, Carlos Pato ³ and James L Kennedy ¹

¹ Centre for Addiction and Mental Health, Canada
² Department of Psychiatry, University of Coimbra, Portugal
³ Veterans Administration Hospital, United States

^* To whom correspondence should be addressed. E-mail: xingqun_ni{at}camh.net.

Accepted 23 March 2007

Abstract

Background: Gap junction, its subunit called connexin (Cx), permits direct intercellular exchange of ions and molecules including glutamate, and plays important roles in central nervous system. Connexin40 and Connexin50 genes are located on chromosome 1q21.1, a region highly linked with schizophrenia. These lines of evidence suggest that Cx40 and Cx50 may play a role in schizophrenia.

Methods: Using TaqMan technique, we genotyped four polymorphisms in each of Cx40 and Cx50 in 190 Caucasian schizophrenia patients and matched (sex, age and ethnicity) controls. Following up, we checked Cx50 rs989192 and rs4950495 in 99 Toronto and 163 Portuguese trios and nuclear families with schizophrenia probands. Program HaploView was used to do Hardy-Weinberg equilibrium (HWE) test and linkage disequilibrium (LD) block identification. The program UNPHASED was used to perform association analysis for alleles and haplotypes with a permutation test of 10,000 simulations.

Results: Distributions of genotype frequencies of all markers were in HWE in Caucasian cases, controls and families. One rs989192-rs4950495 LD block was found in cases but not in controls. We found a significant association between Cx50 rs989192-rs4950495 haplotype and schizophrenia in case-control study (¦Ö2=29.55, p=0.001). The A-C haplotype showed a higher frequency in cases (¦Ö2=7.153, p=0.007). Family studies also showed that the A-C haplotype transmitted more to schizophrenia patients (¦Ö2=8.43, p=0.004). No association of Cx40 with schizophrenia was found for allele, genotype and haplotype analyses.

Conclusions: Our matched case-control and family study indicate that Cx50, but not Cx40, may play a role in the genetic susceptibility to schizophrenia.

Keywords: connexin40, connexin50, family-based study, matched case-control study, schizophrenia

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