Failure to confirm genetic association between schizophrenia and markers on chromosome 1q23.3 in the region of the gene encoding the regulator of G‐protein signaling 4 protein (RGS4)

Abstract

The chromosome 1q23.3 region, which includes the RGS4 gene has been implicated in genetic susceptibility to schizophrenia by two linkage studies with lod scores of 6.35 and 3.20 and with positive lod between 2.00 and 3.00 scores in several other studies. Reduced post mortem RGS4 gene expression in the brain of schizophrenics was reported as well as positive allelic association between markers at the RGS4 gene locus and schizophrenia. We have attempted to replicate the finding of allelic association with schizophrenia in a UK based sample of 450 subjects with schizophrenia and 450 supernormal controls. We genotyped the same SNP marker alleles investigated in the earlier studies and also a di-nucleotide (GT)14 repeat microsatellite marker, which was 7 kb distal to RGS4. In the new UK sample there was no evidence for allelic or haplotypic association between RGS4 markers and schizophrenia. This might reflect genetic heterogeneity between the population samples, genotyping or other methodological problems. The finding weakens the evidence that mutations or variation in the RGS4 gene have an effect on schizophrenia susceptibility.

Adenylate Cyclase 7 Is Implicated in the Biology of Depression and Modulation of Affective Neural Circuitry

“…This is clear in the high frequency of replicated associations between polymorphisms and neural phenotypes through imaging genetics, including the current replication of ADCY7 rs1064448 effects on amygdala reactivity, even in relatively small samples (32, 42-43). In striking contrast, genetic associations with clinical phenotypes, even in large samples, seldom replicate (44-46). Second, the nosological category of MDD is quite heterogeneous and comprises cases with diverse clinical profiles that likely reflect distinct underlying neural alterations.…”

Ethnic Stratification of the Association of RGS4 Variants with Antipsychotic Treatment Response in Schizophrenia

“…The genetic association between RGS4 and schizophrenia was detected initially in three different populations by Chowdari et al (20), and confirmed in five subsequent replication studies (21)(22)(23)(24)(25). However, there have been four reports of failures to replicate an association of RGS4 and schizophrenia (26)(27)(28)(29). Further, while the same single nucleotide polymorphisms (SNPs) in the 5′ region provide the strongest signal in association studies, the specific haplotypes have not been consistent across sample populations, which can be a hallmark of a false positive finding.…”

PLC‐β1 knockout mice as a model of disrupted cortical development and plasticity: Behavioral endophenotypes and dysregulation of RGS4 gene expression

“…Since its initial identification, RGS4 has been the subject of numerous linkage and association studies and multiple polymorphisms in the RGS4 gene have been found to segregate with schizophrenia (Chowdari et al, 2002;Chen et al, 2004;Cordeiro et al, 2005;Sobell et al, 2005;Zhang et al, 2005;Rizig et al, 2006). In addition to genetic evidence, RGS4 is robustly expressed in brain regions implicated in the pathophysiology of schizophrenia (Larminie et al, 2004;Erdely et al, 2006), including the gyrus areas of the cortex and the hippocampus, and downregulation of RGS4 mRNA has been demonstrated in Brodmann's area 9, motor cortex, and visual cortex of schizophrenic individuals (Mirnics et al, 2001).…”