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The rs1344706, an intronic SNP within the zinc-finger protein 804A gene (ZNF804A), was identified as one of the most compelling risk SNPs for schizophrenia (SZ) and bipolar disorder (BD). It is however not clear by which molecular mechanisms ZNF804A increases disease risk. We evaluated the role of ZNF804A in SZ and BD by genotyping the originally associated rs1344706 SNP and an exonic SNP (rs12476147) located in exon four of ZNF804A in a sample of 422 SZ, 382 BD, and 507 controls from the isolated population of the Costa Rica Central Valley. We also investigated the rs1344706 SNP for allelic specific expression (ASE) imbalance in the dorsolateral prefrontal cortex (DLPFC) of 46 heterozygous postmortem brains. While no significant association between rs1344706 and SZ or BD was observed in the Costa Rica sample, we observed an increased risk of SZ for the minor allele (A) of the exonic rs12476147 SNP (p=0.026). Our ASE assay detected a significant over-expression of the rs12476147 A allele in DLPFC of rs1344706 heterozygous subjects. Interestingly, cDNA allele ratios were significantly different according to the intronic rs1344706 genotypes (p-value=0.03), with the rs1344706 A allele associated with increased ZNF804A rs12476147 A allele expression (average 1.06, p-value=0.02, for heterozygous subjects vs. genomic DNA). In conclusion, we have demonstrated a significant association of rs12476147 with SZ, and using a powerful within-subject design, an allelic expression imbalance of ZNF804A exonic SNP rs12476147 in the DLPFC. Although this data does not preclude the possibility of other functional variants in ZNF804A, it provides evidence that the rs1344706 SZ risk allele is the cis-regulatory variant directly responsible for this allelic expression imbalance in adult cortex., (Copyright © 2013 Elsevier B.V. All rights reserved.)

A missense polymorphism in the NRG1 gene, Val>Leu in exon 11, was reported to increase the risk of schizophrenia in selected families from the Central Valley region of Costa Rica (CVCR). The present study investigated the relationship between three NRG1 genetic variants, rs6994992, rs3924999, and Val>Leu missense polymorphism in exon 11, in cases and selected controls from an isolated population from the CVCR. Isolated populations can have less genetic heterogeneity and increase power to detect risk variants in candidate genes. Subjects with bipolar disorder (BD, n=358), schizophrenia (SZ, n=273), or unrelated controls (CO, n=479) were genotyped for three NRG1 variants. The NRG1 promoter polymorphism (rs6994992) was related to altered expression of NRG1 Type IV in other studies. The expression of NRG1 type IV in the dorsolateral prefrontal cortex (DLPFC) and the effect of the rs6994992 genotype on expression were explored in a postmortem cohort of BD, SZ, major depressive disorder (MDD) cases, and controls. The missense polymorphism Val>Leu in exon 11 was not significantly associated with schizophrenia as previously reported in a family sample from this population, the minor allele frequency is 4%, thus our sample size is not large enough to detect an association. We observed however an association of rs6994992 with NRG1 type IV expression in DLPFC and a significantly decreased expression in MDD compared to controls. The present results while negative do not rule out a genetic association of these SNPs with BD and SZ in CVCR, perhaps due to small risk effects that we were unable to detect and potential intergenic epistasis. The previous genetic relationship between expression of a putative brain-specific isoform of NRG1 type IV and SNP variation was replicated in postmortem samples in our preliminary study., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Objective: The understanding of complex heritable psychiatric disorders such as schizophrenia could be clarified by examining endophenotypes within genetically isolated populations, such as the one found in the Central Valley of Costa Rica. The reduction of familial variability within a sample could allow the relationship between the cognitive and symptomatic manifestations of the illness and the genetic underpinnings to become more observable. This study investigates the neuropsychological test performances of 41 family members from four extended multiplex families within the Spanish origin population of the Central Valley of Costa Rica as potential endophenotypes for genetic studies., Methods: Individuals with a diagnosis of schizophrenia or schizoaffective disorder were compared with unaffected relatives and 15 unrelated controls with no family history of schizophrenia., Results: Although the sample size is small, the results confirm previous reports in the literature of deficits in working memory, executive function, processing speed, and verbal fluency in individuals with schizophrenia compared with controls and intermediate performance in nonpsychotic family members compared with controls. We also found several suggestive quantitative cognitive trait loci with log of the odds greater than 1.75., Conclusion: These findings suggest that the cognitive deficits in schizophrenia are consistent aspects of the illness, although their usefulness as endophenotypes for genetic studies remains unclear.