Whole-genome-wide association study in the Bulgarian population reveals HHAT as schizophrenia susceptibility gene.

OBJECTIVE: Schizophrenia, the most common major psychiatric disorder (or group of disorders), entails severe decline of higher functions, principally with alterations in cognitive functioning and reality perception. Both genetic and environmental factors are involved in its pathogenesis; however, its genetic background still needs to be clarified. The objective of the study was to reveal genetic markers associated with schizophrenia in the Bulgarian population. METHODS: We have conducted a genome-wide association study using 554 496 single nucleotide polymorphisms (SNPs) in 188 affected and 376 unaffected Bulgarian individuals. Subsequently, the 100 candidate SNPs that revealed the smallest P-values were further evaluated in an additional set of 99 case and 328 control samples. RESULTS: We found a significant association between schizophrenia and the intronic SNP rs7527939 in the HHAT gene (P-value of 6.49×10 with an odds ratio of 2.63, 95% confidence interval of 1.89-3.66). We also genotyped additional SNPs within a 58-kb linkage disequilibrium block surrounding the landmark SNP. CONCLUSION: We suggest rs7527939 to be the strongest indicator of susceptibility to schizophrenia in the Bulgarian population within the HHAT locus.

Elevated anticardiolipin antibodies in schizophrenic patients before and during neuroleptic medication.

The objective of this study was to examine the prevalence of IgG and IgM anticardiolipin antibodies (aCL) in schizophrenic patients and to determine the relation of aCL levels with neuroleptic medication and psychotic symptoms. Twenty-three patients with acute episodes of chronic schizophrenia, drug-free for at least 3 months before entering the study, were tested for aCL at admission (T1) and 42 days (T2) after neuroleptic treatment started. Blood samples were taken from 20 healthy volunteers as well. Diagnosis was performed according to DSM-IV. Serum samples were analysed for IgG and IgM autoantibodies against beta2-glycoprotein-1-cardiolipin complex by commercially available ELISA kits (Binding-site, UK). Significantly higher levels of aCL antibodies of both isotypes were found in schizophrenic patients versus controls. In patients IgM-aCL positivity was significantly more frequent than in controls. The elevated IgM-aCL and IgG-aCL values were not associated with neuroleptic treatment and psychotic symptoms, as measured by the Positive and Negative Syndrome Scale and the Pentagonal Structural Model of Schizophrenic Symptoms. The negative correlation of IgM-aCL and IgG-aCL with the positive symptoms scale and the autistic preoccupation scale (Pentagonal Structural Model) may indicate the consumption of these antibodies in the exacerbation of the disease.

Case-control association study of 65 candidate genes revealed a possible association of a SNP of HTR5A to be a factor susceptible to bipolar disease in Bulgarian population.

BACKGROUND: Bipolar affective disorder (BAD) is a psychiatric illness characterized by episodes of mania and depression. Although the etiology is not clear, epidemiological studies suggest it is a result of an interaction of genetic and environmental factors. Despite of enormous efforts and abundant studies conducted, none has yet been identified definitively a gene susceptible to bipolar disorder. METHODS: Ninety-four Bulgarian patients diagnosed with bipolar disorder and 184 Bulgarian healthy individuals, were used for genotyping of 191 single nucleotide polymorphisms (SNPs) by TaqMan and/or Invader assays. Seventeen SNPs that revealed P value less than 0.05 in the first screening were genotyped using an additional independent set of samples, consisting of 78 BAD cases and 372 controls. RESULTS: After applying the Bonferonni correction on genotyping results of 172 cases and 556 controls, only one SNP, rs1800883, in the HTR5A gene revealed a significant level of P value (P=0.000097; odds ratio=1.80 (95%CI, 1.27-2.54); corrected P=0.017). CONCLUSIONS: Our findings suggest that HTR5A gene could play an important role in the pathogenesis of bipolar disorder in our population. However these findings should be viewed with caution and replication studies in other populations are necessary in support of these findings.

Case-control association study of 59 candidate genes reveals the DRD2 SNP rs6277 (C957T) as the only susceptibility factor for schizophrenia in the Bulgarian population.

The development of molecular psychiatry in the last few decades identified a number of candidate genes that could be associated with schizophrenia. A great number of studies often result with controversial and non-conclusive outputs. However, it was determined that each of the implicated candidates would independently have a minor effect on the susceptibility to that disease. Herein we report results from our replication study for association using 255 Bulgarian patients with schizophrenia and schizoaffective disorder and 556 Bulgarian healthy controls. We have selected from the literatures 202 single nucleotide polymorphisms (SNPs) in 59 candidate genes, which previously were implicated in disease susceptibility, and we have genotyped them. Of the 183 SNPs successfully genotyped, only 1 SNP, rs6277 (C957T) in the DRD2 gene (P=0.0010, odds ratio=1.76), was considered to be significantly associated with schizophrenia after the replication study using independent sample sets. Our findings support one of the most widely considered hypotheses for schizophrenia etiology, the dopaminergic hypothesis.

Association analysis of the HOPA12bp polymorphism in schizophrenia and manic depressive illness.

Variations in exon 42 of the HOPA (human opposite paired) gene have been associated with mental retardation, hypothyroidism and psychiatric disorders. We attempted to replicate the association with schizophrenia using 309 parent-offspring trios from Bulgaria and 367 unrelated cases and 368 blood donors from the UK. We also tested 125 bipolar trios from Bulgaria, 112 bipolar trios from the UK and a sample of 178 unrelated bipolar cases and 188 blood donors from the UK. The frequency of HOPA(12bp) in the 556 UK blood donors was 2.6% and it was not significantly different in the UK patients groups, where it ranged from 1.2 to 3.8%. Sixteen mothers transmitted the HOPA(12bp) allele to schizophrenic offspring, while 12 did not transmit, a non-significant difference. There was a trend for under-transmission of the rare allele to bipolar patients (T/NT = 4/10) and they had a lower rate of that allele than schizophrenic patients in the Bulgarian population (1% vs. 4.2%, P = 0.043). However the two diagnostic groups had similar allele frequencies in the UK populations: 2% versus 2.6%, P = 0.6. We conclude that the HOPA polymorphism is unlikely to be a major risk factor in the pathogenesis of these major psychiatric disorders although there could be a small effect in schizophrenia.