Strong evidence that GNB1L is associated with schizophrenia

Abstract

Evidence that a gene or genes on chromosome 22 is involved in susceptibility to schizophrenia comes from two sources: the increased incidence of schizophrenia in individuals with 22q11 deletion syndrome (22q11DS) and genetic linkage studies. In mice, hemizygous deletion of either Tbx1 or Gnb1l can cause deficits in pre-pulse inhibition, a sensory motor gating defect which is associated with schizophrenia. We tested the hypothesis that variation at this locus confers risk of schizophrenia and related disorders in a series of case-control association studies. First, we found evidence for a male-specific genotypic association (P = 0.00017) TBX1/GNB1L in 662 schizophrenia cases and 1416 controls from the UK. Moreover, we replicated this finding in two independent case-control samples (additional 746 cases and 1330 controls) (meta analysis P = 1.8 x 10(-5)) and also observed significant evidence for genotypic association in an independent sample of 480 schizophrenia parent-proband trios from Bulgaria with markers at this locus, which was again strongest in the male probands (P = 0.004). Genotyping the most significant SNPs in a sample of 83 subjects with 22q11DS with and without psychosis again revealed a significant allelic association with psychosis in males with 22q11DS (P = 0.01). Finally, using allele specific expression analysis, we have shown that the markers associated with psychosis are also correlated with alterations in GNB1L expression, raising the hypothesis that the risk to develop psychosis at this locus could be mediated in a dose sensitive manner via gene expression. However, other explanations are possible, and further analyses will be required to clarify the correct functional mechanism.

Supportive Evidence for Reduced Expression of GNB1L in Schizophrenia

“…An allele of rs5748832 is correlated with high GNB1L expression in this study, while the previous study showed the opposite direction of correlation. 26 Significant deviation from HWE in the genotypic distributions was observed at rs4819523 in the control group. Lower proportions of heterozygotes than those expected by HWE seemed to cause these deviations.…”

“…Also no significant differences were found in distributions of homozygotes and heterozygotes between schizophrenics and controls (table 1). Williams et al 26 reported male-specific associations of rs5746832 and rs2269726 with schizophrenia and correlation between those markers and the gene expression. However, such malespecific associations of rs5746832 and rs2269726 were not observed in our sample (table 1).…”

“…Williams et al 26 reported excess homozygosity at rs5746832 and rs2269726 in male schizophrenia subjects and that the markers associated with male schizophrenia were related with cis-acting changes in GNB1L expression. Firstly in the present study, we failed to confirm the association in our Japanese case-control population.…”

“…9 In another study, however, Tbx1 heterozygous knockout mice showed normal locomotor activity, habituation, nesting, and locomotor responses to amphetamine. 25 Recently, Williams et al 26 reported associations between polymorphisms in the GNB1L gene region and schizophrenia in the United Kingdom, German, and Bulgarian population. They found excess homozygosity at rs5746832 and rs2269726 in male schizophrenia subjects and that the markers associated with male schizophrenia were related with cis-acting changes in GNB1L expression.…”

Implications of copy number variation in people with chromosomal abnormalities: potential for greater variation in copy number state may contribute to variability of phenotype

“…This disorder is also associated with variable phenotypes, such as cleft palate, congenital heart disease (Shprintzen et al 1978), renal anomalies (Czarnecki et al 1998) and increased risk of schizophrenia (Murphy et al 1999). Several CNV loci have been identified within the 22q11.2 deletion region in apparently healthy individuals: of interest, two of the candidate genes for the schizophrenia phenotype, PRODH (Li et al 2004) and GNB1L (Williams et al 2008), are overlapped by a number of CNVs, and these could potentially modify this phenotype in DiGeorge patients.…”