Brain-derived neurotrophic factor (BDNF) influences dopamine and serotonin neurotransmission in the brain, both of which are involved in the reward system of addiction. The BDNF gene is located in a genomic region on chromosome 11p where we and others have found 'significant' linkage to nicotine dependence (ND). We tested the potential role of variants within BDNF in vulnerability to ND, which was assessed by Smoking Quantity (SQ), the Heaviness of Smoking Index (HSI), and the Fagerström Test for ND (FTND). Six single nucleotide polymorphisms (SNPs) in BDNF were analyzed in an extensively phenotyped cohort of 602 nuclear families with smokers and non-smokers of African-American (AA) or European-American (EA) ancestry. Individual SNP analysis revealed that two SNPs in the pooled male and three SNPs in the EA male samples were significantly associated with at least one adjusted ND measure. However, none of these associations remained significant after correction for multiple testing. Haplotype analysis of rs6484320-rs988748-rs2030324-rs7934165 revealed that a major T-C-T-G haplotype was significantly associated, even after Bonferroni correction, with the three ND measures in the pooled and EA male samples (maximum Z = 3.00, P = 0.002 and maximum Z = 3.13, P = 0.0009 for SQ, respectively). No significant association of a major haplotype with ND was found in the AA or EA female smokers. The significant association of BDNF variants with ND implies that this gene plays a role in the etiology of ND in EAs and that its involvement is gender specific. BDNF may warrant further investigation in ND.

Functional alterations of components of the endogenous cannabinoid system, in particular of the cannabinoid receptor 1 protein (CB1), are hypothetical contributors to many of the symptoms seen in schizophrenia. Variants within the cannabinoid receptor 1 gene (CNR1) have been shown to be directly associated with the hebephrenic form of schizophrenia in a Japanese population. This finding, however, has yet to be replicated. In the present study we sought to study the same (AAT)n-repeat microsatellite of the CNR1 gene which showed association to hebephrenic schizophrenia in Japan, and to investigate whether this microsatellite showed association to a hebephrenic type of schizophrenia in a family-based association study in a population of the Central Valley of Costa Rica. The Lifetime Dimensions of Psychosis Scale and a best estimate consensus process were utilized to identify subjects with schizophrenia who had an elevated lifetime dimensional score for negative and disorganized symptoms, which we used as a proxy for "hebephrenia." Using the Family Based Association Test we found association of these hebephrenic subjects and the (AAT)n-repeat marker of the CNR1 (multi-allelic P = 0.0368). Our hypothesis that an association with the (AAT)n-repeat marker of CNR1 would not be found with the more general type of schizophrenia was also confirmed. Schizophrenic subjects with prominent lifetime scores for disorganization and negative symptoms (dimension for hebephrenia) are associated with the CNR1 gene and present a type of symptomatology that resembles chronic cannabinoid-induced psychosis. The current finding points to the possibility of different genetic and pathophysiologic mechanisms underlying different types of schizophrenia.

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Schizophrenia (SC) and bipolar disorder (BP) share many clinical features, among them psychosis. We previously identified a putative gene locus for psychosis on chromosome 18p in a sample from the Central Valley of Costa Rica (CVCR) population. The present study replicated the association to a specific allele of microsatellite marker D18S63 on 18p11.3, using a newly collected sample from the CVCR. A combined analysis of both samples, plus additional subjects, showed that this specific allele on D18S63, which lies within an intron on the TGFB-induced factor (TGIF ) gene, is strongly associated (P-value = 0.0005) with psychosis. Eleven additional SNP markers, spanning five genes in the region, were analyzed in the combined sample from the CVCR. Only the four SNPs within the TGIF gene were in strong linkage disequilibrium with D18S63 (D 0 = 1.00). A specific haplotype for all five markers within the TGIF gene showed evidence of association (P-value = 0.011) to psychosis. A second, distinct haplotype, containing a newly identified nonsynonymous polymorphism in exon 5 of the TGIF gene, showed a nonsignificant trend towards association to psychosis (P-value = 0.077). TGIF is involved in neurodevelopment, neuron survival and controls the expression of dopamine receptors. Altogether, our results point to the possible involvement of TGIF in the pathophysiology of psychotic disorders in the CVCR population.

Depression and suicidal behavior are frequently observed in patients with schizophrenia. The serotonin transporter protein regulates serotonergic signaling at synapses and is encoded by a single gene (SLC6A4; Locus Link ID: 6532), located at 17q11.1-q12 with two polymorphic variants (the short and the long allele). The short allele of serotonin transporter gene has been associated with depression and suicidality in individuals who suffered negative life events and with depression in individuals with chronic psychosis.. Subjects were recruited from a genetic study of schizophrenia conducted in Costa Rica. The authors replicated their previous research, using a more narrow phenotype (only schizophrenic subjects) and a more ethnically homogenous sample (only Costa Rican schizophrenic individuals who were not included in the previous study). The authors hypothesized that subjects with at least one copy of the serotonin transporter promoter gene polymorphism (5-HTTLPR) "s" allele would have a greater history of lifetime depression and suicidability rate than those who had an "l/l" genotype. The authors analyzed 155 subjects with a DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) diagnosis of schizophrenia (73% male, age at interview 38.3, SD = 11.23). The genotype distribution was "ss" 58 (37%), "sl" 69 (45%), and "ll" 28 (18%). In the secondary analysis, the authors explored association of the "s" allele with lifetime history of suicide behavior in 173 subjects (18 more subjects than primary analysis because schizophrenic individuals were included regardless of history of depression). The authors found that subjects carrying at least one short allele had a significant increased lifetime risk for depressive syndromes (chi(2) = 5.4, df = 1, P = 0.02; odds ratio [OR] = 2.7, 95% confidence interval [CI] = 1.15-6.3). No association was found for suicidal behavior in the same sample (chi(2) = 0.928, P = 0.629). In conclusion, the genotype at the 5-HTTLPR promoter polymorphic locus increases the risk of developing major depression but not suicidal behavior during the course of the schizophrenia in these patients. Due to the small sample size, these results should be followed by definitive replication.