Response to fluoxetine in children and adolescents: a weighted gene co-expression network analysis of peripheral blood.

The inconclusive and non-replicated results of pharmacogenetic studies of antidepressant response could be related to the lack of acknowledgement of its mechanism of action. In this scenario, gene expression studies provide and interesting framework to reveal new candidate genes for pharmacogenetic studies or peripheral biomarkers of fluoxetine response. We propose a system biology approach to analyse changes in gene expression induced by eight weeks of treatment with fluoxetine in peripheral blood. 21 naïve child and adolescents participated in the present study. Our analysis include the identification of gene co-expression modules, using Weighted Gene Co-expression Network Analysis (WGCNA), followed by protein-protein interaction (PPi) network construction coupled with functional annotation. Our results revealed two modules of co-expression genes related to fluoxetine treatment. The constructed networks from these modules were enriched for biological processes related to cellular and metabolic processes, cell communication, immune system processes, cell death, response to stimulus and neurogenesis. Some of these processes, such as immune system, replicated previous findings in the literature, whereas, neurogenesis, a mechanism proposed to be involved in fluoxetine response, had been identified for first time using peripheral tissues. In conclusion, our study identifies several biological processes in relation to fluoxetine treatment in peripheral blood, offer new candidate genes for pharmacogenetic studies and valuable markers for peripheral moderator biomarkers discovery.

Identifying key transcription factors for pharmacogenetic studies of antipsychotics induced extrapyramidal symptoms.

INTRODUCTION: We explore the transcription factors involved in the molecular mechanism of antipsychotic (AP)-induced acute extrapyramidalsymptoms (EPS) in order to identify new candidate genes for pharmacogenetic studies. METHODS: Protein-protein interaction (PPI) networks previously created from three pharmacogenomic models (in vitro, animal, and peripheral blood inhumans) were used to, by means of several bioinformatic tools; identify key transcription factors (TFs) that regulate each network. Once the TFs wereidentified, SNPs disrupting the binding sites (TFBS) of these TFs in the genes of each network were selected for genotyping. Finally, SNP-basedassociations with EPS were analyzed in a sample of 356 psychiatric patients receiving AP. RESULTS: Our analysis identified 33 TFs expressed in the striatum, and 125 SNPs disrupting TFBS in 50 genes of our initial networks. Two SNPs (rs938112,rs2987902) in two genes (LSMAP and ABL1) were significantly associated with AP induced EPS (p < 0.001). These SNPs disrupt TFBS regulated byPOU2F1. CONCLUSION: Our results highlight the possible role of the disruption of TFBS by SNPs in the pharmacological response to AP.

The positive allosteric modulator of the mGlu2 receptor JNJ-46356479 partially improves neuropathological deficits and schizophrenia-like behaviors in a postnatal ketamine mice model.

Current antipsychotics have limited efficacy in controlling cognitive and negative symptoms of schizophrenia (SZ). Glutamatergic dysregulation has been implicated in the pathophysiology of SZ, based on the capacity of N-methyl-D-aspartate receptor (NMDAR) antagonists such as ketamine (KET) to induce SZ-like behaviors. This could be related to their putative neuropathological effect on gamma-aminobutyric (GABAergic) interneurons expressing parvalbumin (PV), which would lead to a hyperglutamatergic condition. Metabotropic glutamate receptor 2 (mGluR2) negatively modulates glutamate release and has been considered a potential clinical target for novel antipsychotics drugs. Our aim was to evaluate the efficacy of JNJ-46356479 (JNJ), a positive allosteric modulator (PAM) of the mGluR2, in reversing neuropathological and behavioral deficits induced in a postnatal KET mice model of SZ. These animals presented impaired spontaneous alternation in the Y-maze test, suggesting deficits in spatial working memory, and a decrease in social motivation and memory, assessed in both the Three-Chamber and the Five Trial Social Memory tests. Interestingly, JNJ treatment of adult mice partially reversed these deficits. Mice treated with KET also showed a reduction in PV+ in the mPFC and dentate gyrus together with an increase in c-Fos expression in this hippocampal area. Compared to the control group, mice treated with KET + JNJ showed a similar PV density and c-Fos activity pattern. Our results suggest that pharmacological treatment with a PAM of the mGluR2 such as JNJ could help improve cognitive and negative symptoms related to SZ.

Examining Gene-Environment Interactions Using Aggregate Scores in a First-Episode Psychosis Cohort.

Gene-environment (GxE) interactions have been related to psychosis spectrum disorders, involving multiple common genetic variants in multiple genes with very small effect sizes, and several environmental factors that constitute a dense network of exposures named the exposome. Here, we aimed to analyze GxE in a cohort of 310 first-episode psychotic (FEP) and 236 healthy controls, by using aggregate scores estimated in large populations such as the polygenic risk score for schizophrenia and (PRS-SCZ) and the Maudsley environmental risk score (ERS). In contrast to previous findings, in our study, the PRS-SCZ did not discriminate cases from controls, but the ERS score explained a similar percentage of the variance as in other studies using similar approaches. Our study supports a positive additive interaction, indicating synergy between genetic susceptibility to schizophrenia (PRS-SCZ dichotomized according to the highest quartile distribution of the control population) and the exposome (ERS > 75% of the controls). This additive interaction showed genetic and environmental dose dependence. Our study shows that the use of aggregate scores derived from large and powered studies instead of statistics derived from specific sample characteristics is a powerful tool for the study of the effects of GxE on the risk of psychotic spectrum disorders. In conclusion, by using a genetic risk score and an ERS we have provided further evidence for the role of GxE in psychosis.

Association study of candidate genes with obesity and metabolic traits in antipsychotic-treated patients with first-episode psychosis over a 2-year period.

AIMS: Patients with a first episode of psychosis (FEP) often display different metabolic disturbances even independently of drug therapy. However, antipsychotic (AP) treatment, especially with second-generation APs, is strongly linked to weight gain, which increases patients' risk of developing obesity and other metabolic diseases. There is an important genetic risk component that can contribute to the appearance of these disturbances. The aim of the present study was to evaluate the effect of polymorphisms in selected candidate genes on obesity and other anthropometric and metabolic traits in 320 AP-treated FEP patients over the course of a 2-year follow-up. METHODS: These patients were recruited in the multicentre PEPs study (Phenotype-genotype and environmental interaction; Application of a predictive model in first psychotic episodes). A total of 127 validated single nucleotide polymorphisms (SNPs) in 18 candidate genes were included in the genetic analysis. RESULTS: After Bonferroni correction, SNPs in ADRA2A, FTO, CNR1, DRD2, DRD3, LEPR and BDNF were associated with obesity, abdominal circumference, triglycerides, HDL cholesterol, and/or percentage of glycated haemoglobin. CONCLUSIONS: Although our results should be interpreted as exploratory, they support previous evidence of the impact of these candidate genes on obesity and metabolic status. Further research is required to gain a better knowledge of the genetic variants that can be considered relevant metabolic risk factors. The ability to identify FEP patients at higher risk for these metabolic disturbances would enable clinicians to better select and control their AP treatment.

RPGeNet v2.0: expanding the universe of retinal disease gene interactions network.

RPGeNet offers researchers a user-friendly queriable tool to visualize the interactome network of visual disorder genes, thus enabling the identification of new potential causative genes and the assignment of novel candidates to specific retinal or cellular pathways. This can be highly relevant for clinical applications as retinal dystrophies affect 1:3000 people worldwide, and the causative genes are still unknown for 30% of the patients. RPGeNet is a refined interaction network interface that limits its skeleton network to the shortest paths between each and every known causative gene of inherited syndromic and non-syndromic retinal dystrophies. RPGeNet integrates interaction information from STRING, BioGRID and PPaxe, along with retina-specific expression data and associated genetic variants, over a Cytoscape.js web interface. For the new version, RPGeNet v2.0, the database engine was migrated to Neo4j graph database manager, which speeds up the initial queries and can handle whole interactome data for new ways to query the network. Further, user facilities have been introduced as the capability of saving and restoring a researcher customized network layout or as novel features to facilitate navigation and data projection on the network explorer interface. Responsiveness has been further improved by transferring some functionality to the client side.

Altered frequencies of Th17 and Treg cells in children and adolescents with obsessive-compulsive disorder.

OBJECTIVE: Obsessive-compulsive disorder (OCD) is a debilitating neuropsychiatric disorder with an etiopathophysiology that seems to include immune alterations. Previous studies have suggested that variations in the levels of circulating T cell subpopulations may be involved in psychiatric diseases. However, the role of these cells in OCD remains unexplored. Hence, the present study aimed to examine the levels of T helper 1 (Th1), Th2, Th17 and regulatory T (Treg) cells in patients with early-onset OCD and healthy controls. METHODS: The assessment was performed in 99 children and adolescents with OCD and 46 control subjects. The percentages of circulating Th1, Th2, Th17 and Treg cells were evaluated using flow cytometry. RESULTS: OCD patients had significantly higher levels of Th17 cells and lower percentages of Treg cells than healthy controls (p = 0.001 and p = 0.005, respectively). Furthermore, levels of Th17 cells progressively increased with the duration (p = 0.005) and severity of OCD (p = 0.008), whereas the percentages of Treg cells significantly declined with the duration of the disorder (p = 1.8 × 10-5). CONCLUSIONS: These results provide more evidence of the involvement of immune dysregulation, specifically an imbalance in the levels of circulating T helper and regulatory T cells, in the pathophysiology of early-onset OCD.

Author Correction: Improving pharmacogenetic prediction of extrapyramidal symptoms induced by antipsychotics.

One of the funding sources (FEDER-Unión Europea) was not previously acknowledged in this Article. This study was supported by the Spanish Ministry of Health, Instituto de Salud Carlos III (FIS, Fondo de Investigacion Sanitaria PI13/00812, PI16/0122) and FEDER-Unión Europea.

Human-leukocyte antigen class II genes in early-onset obsessive-compulsive disorder.

Objective: The exact aetiology of obsessive-compulsive disorder (OCD) is unknown, although there is evidence to suggest a gene-environment interaction model. Several lines of evidence support a possible role of the immune system in this model. Methods: The present study explores the allele variability in HLA genes of class II (HLA-DRB1, HLA-DQB1) in a sample of 144 early-onset OCD compared with reference samples of general population in the same geographical area. Results: None of the 39 alleles identified (allele frequency >1%) showed significant differences between OCD and reference populations. Pooling the different alleles that comprised HLA-DR4 (including DRB1*04:01, DRB1*04:04 and DRB1*04:05 alleles) we observed a significantly higher frequency (X21 = 5.53, P = 0.018; OR = 1.64, 95% CI 1.08-2.48) of these alleles in the early-onset OCD sample (10.8%) than in the reference population (6.8%). Conclusions: Taking into account the role of HLA class II genes in the central nervous system, the results presented here support a role of the immune system in the pathophysiological model of OCD.

Genetic Associations of Serotoninergic and GABAergic Genes in an Extended Collection of Early-Onset Obsessive-Compulsive Disorder Trios.

OBJECTIVE: Obsessive-compulsive disorder (OCD) is a debilitating neuropsychiatric disorder whose etiology includes important genetic contributions. In a previous transmission disequilibrium study in which 75 complete trios were included, single-nucleotide polymorphisms (SNPs) in serotoninergic and GABAergic genes were associated with early-onset OCD. Our aim was to assess those findings in an extended collection of early-onset OCD trios. METHODS: A transmission disequilibrium test for SNPs in HTR1B (rs2000292), SLC18A1 (rs6586896), GAD1 (rs3791860), and GAD2 (rs8190748) was performed in a total of 101 early-onset OCD trios, from which 26 trios were newly recruited for the purpose of the present analysis. RESULTS: All the SNPs were overtransmitted from parents to OCD probands (p < 0.012, significant after Bonferroni correction). CONCLUSIONS: These results are consistent with the previous findings and constitute more evidence of the role of genetic factors related to serotoninergic and GABAergic pathways in the pathophysiology of early-onset OCD.

Genetic variability in the serotoninergic system and age of onset in anorexia nervosa and obsessive-compulsive disorder.

The age of onset of some psychiatric disorders may have etiopathogenic and clinical effects and may influence outcome. Following on from previous work by our group where we showed that early onset anorexia nervosa (AN) and obsessive-compulsive disorder (OCD) shared a common genetic background, the aim of the present study is to assess genetic pleiotropy related to the serotonergic system (SLC6A4, 5HTR2A, 5HTR2C, TPH2, SLC18A1), in a common phenotype such as very-early age of onset. One hundred and sixteen adolescents diagnosed with AN and 74 adolescents diagnosed with OCD participated in the present study. We confirmed the existence of a genetic overlap between OCD and AN. Specifically, we described genetic pleiotropy for age at onset across these disorders, associating two SNPs (rs6311, rs4942587) of the HTR2A with the very-early onset phenotype.

Improving pharmacogenetic prediction of extrapyramidal symptoms induced by antipsychotics.

In previous work we developed a pharmacogenetic predictor of antipsychotic (AP) induced extrapyramidal symptoms (EPS) based on four genes involved in mTOR regulation. The main objective is to improve this predictor by increasing its biological plausibility and replication. We re-sequence the four genes using next-generation sequencing. We predict functionality "in silico" of all identified SNPs and test it using gene reporter assays. Using functional SNPs, we develop a new predictor utilizing machine learning algorithms (Discovery Cohort, N = 131) and replicate it in two independent cohorts (Replication Cohort 1, N = 113; Replication Cohort 2, N = 113). After prioritization, four SNPs were used to develop the pharmacogenetic predictor of AP-induced EPS. The model constructed using the Naive Bayes algorithm achieved a 66% of accuracy in the Discovery Cohort, and similar performances in the replication cohorts. The result is an improved pharmacogenetic predictor of AP-induced EPS, which is more robust and generalizable than the original.

Further Support for the Involvement of Genetic Variants Related to the Serotonergic Pathway in the Antidepressant Response in Children and Adolescents After a 12-Month Follow-Up: Impact of the HTR2A rs7997012 Polymorphism.

Objective: Fluoxetine is an effective and well-tolerated pharmacological treatment for children and adolescents with major depressive disorder (MDD). However, a high percentage of patients do not respond. There is a substantial genetic contribution to this variable clinical outcome. Based on previous genetic results of our group and given the lack of pharmacogenetics studies of antidepressant response with a long follow-up period, we evaluated the influence of single nucleotide polymorphisms (SNPs) in genes related to the serotonergic pathway on remission and recovery in children and adolescents diagnosed with MDD after 12 months of initiating fluoxetine treatment. Methods: The assessment was performed in 46 patients. All of them were visited at least once a month during the 12-month follow-up. Psychiatrists interviewed patients and their parents to explore clinical improvement. A total of 75 genotyped SNPs in 10 candidate genes were included in the genetic association analysis with remission and recovery. Bonferroni correction for multiple testing was applied to avoid false positive results. Results: The HTR2A rs7997012 SNP was significantly associated after Bonferroni correction with clinical improvement. Particularly, the homozygotes for the major allele (GG) showed the highest percentage of remitters and the highest score reductions on the Clinical Global Impressions-Severity (CGI-S) scale. Moreover, although the results were on the border of statistical significance, the GG homozygotes also tended to experience fewer readmissions during the follow-up period Conclusions: These results provide more evidence of the involvement of genetic variants related to the serotonergic pathway in the antidepressant response. Studies with larger cohorts are needed to integrate all relevant variants into clinical predictors of antidepressant response.

SiNoPsis: Single Nucleotide Polymorphisms selection and promoter profiling.

MOTIVATION: The selection of a single nucleotide polymorphism (SNP) using bibliographic methods can be a very time-consuming task. Moreover, a SNP selected in this way may not be easily visualized in its genomic context by a standard user hoping to correlate it with other valuable information. Here we propose a web form built on top of Circos that can assist SNP-centered screening, based on their location in the genome and the regulatory modules they can disrupt. Its use may allow researchers to prioritize SNPs in genotyping and disease studies. RESULTS: SiNoPsis is bundled as a web portal. It focuses on the different structures involved in the genomic expression of a gene, especially those found in the core promoter upstream region. These structures include transcription factor binding sites (for promoter and enhancer signals), histones and promoter flanking regions. Additionally, the tool provides eQTL and linkage disequilibrium (LD) properties for a given SNP query, yielding further clues about other indirectly associated SNPs. Possible disruptions of the aforementioned structures affecting gene transcription are reported using multiple resource databases. SiNoPsis has a simple user-friendly interface, which allows single queries by gene symbol, genomic coordinates, Ensembl gene identifiers, RefSeq transcript identifiers and SNPs. It is the only portal providing useful SNP selection based on regulatory modules and LD with functional variants in both textual and graphic modes (by properly defining the arguments and parameters needed to run Circos). AVAILABILITY AND IMPLEMENTATION: SiNoPsis is freely available at https://compgen.bio.ub.edu/SiNoPsis/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Inflammatory dysregulation of monocytes in pediatric patients with obsessive-compulsive disorder.

BACKGROUND: Although the exact etiology of obsessive-compulsive disorder (OCD) is unknown, there is growing evidence of a role for immune dysregulation in the pathophysiology of the disease, especially in the innate immune system including the microglia. To test this hypothesis, we studied inflammatory markers in monocytes from pediatric patients with OCD and from healthy controls. METHODS: We determined the percentages of total monocytes, CD16+ monocytes, and classical (CD14highCD16-), intermediate (CD14highCD16low), and non-classical (CD14lowCD16high) monocyte subsets in 102 patients with early-onset OCD and in 47 healthy controls. Moreover, proinflammatory cytokine production (GM-CSF, IL-1ß, IL-6, IL-8, and TNF-α) was measured by multiplex Luminex analysis in isolated monocyte cultures, in basal conditions, after exposure to lipopolysaccharide (LPS) to stimulate immune response or after exposure to LPS and the immunosuppressant dexamethasone. RESULTS: OCD patients had significantly higher percentages of total monocytes and CD16+ monocytes than healthy controls, mainly due to an increase in the intermediate subset but also in the non-classical monocytes. Monocytes from OCD patients released higher amounts of GM-CSF, IL-1ß, IL-6, IL-8, and TNF-α than healthy controls after exposure to LPS. However, there were no significant differences in basal cytokine production or the sensitivity of monocytes to dexamethasone treatment between both groups. Based on monocyte subset distribution and cytokine production after LPS stimulation, patients receiving psychoactive medications seem to have an intermediate inflammatory profile, that is, lower than non-medicated OCD individuals and higher than healthy controls. CONCLUSIONS: These results strongly support the involvement of an enhanced proinflammatory innate immune response in the etiopathogenesis of early-onset OCD.

Microarray gene-expression study in fibroblast and lymphoblastoid cell lines from antipsychotic-naïve first-episode schizophrenia patients.

Schizophrenia (SZ) is a chronic psychiatric disorder whose onset of symptoms occurs in late adolescence and early adulthood. The etiology is complex and involves important gene-environment interactions. Microarray gene-expression studies on SZ have identified alterations in several biological processes. The heterogeneity in the results can be attributed to the use of different sample types and other important confounding factors including age, illness chronicity and antipsychotic exposure. The aim of the present microarray study was to analyze, for the first time to our knowledge, differences in gene expression profiles in 18 fibroblast (FCLs) and 14 lymphoblastoid cell lines (LCLs) from antipsychotic-naïve first-episode schizophrenia (FES) patients and healthy controls. We used an analytical approach based on protein-protein interaction network construction and functional annotation analysis to identify the biological processes that are altered in SZ. Significant differences in the expression of 32 genes were found when LCLs were assessed. The network and gene set enrichment approach revealed the involvement of similar biological processes in FCLs and LCLs, including apoptosis and related biological terms such as cell cycle, autophagy, cytoskeleton organization and response to stress and stimulus. Metabolism and other processes, including signal transduction, kinase activity and phosphorylation, were also identified. These results were replicated in two independent cohorts using the same analytical approach. This provides more evidence for altered apoptotic processes in antipsychotic-naïve FES patients and other important biological functions such as cytoskeleton organization and metabolism. The convergent results obtained in both peripheral cell models support their usefulness for transcriptome studies on SZ.

Association of regulatory TPH2 polymorphisms with higher reduction in depressive symptoms in children and adolescents treated with fluoxetine.

Genetic variability related to the brain serotonergic system has a significant impact on both the susceptibility to psychiatric disorders, such as major depressive disorder (MDD), and the response to antidepressant drugs, such as fluoxetine. TPH2 is one of the most important serotonergic candidate genes in selective serotonin reuptake inhibitors (SSRIs) pharmacogenetic studies. The aim of the present study was to evaluate the influence of regulatory polymorphisms that are specifically located in human TPH2 transcription factor binding sites (TFBSs), and therefore could be functional by altering gene expression, on clinical improvement in children and adolescents treated with fluoxetine. The selection of SNPs was also based on their linkage disequilibrium with TPH2 rs4570625, a genetic variant with questionable functionality, which was previously associated with clinical response in our pediatric population. A total of 83 children and adolescents were clinically evaluated 12weeks after initiating antidepressant treatment with fluoxetine for the first time. Clinical improvement was assessed by reductions in depressive symptoms measured using the Children's Depression Inventory (CDI) scale. The polymorphisms rs11179002, rs60032326 and rs34517220 were, for the first time in the literature, significantly associated with higher clinical improvement. The strongest association was found for rs34517220. In particular, minor allele homozygotes showed higher score reductions on the CDI scale compared with the major allele carriers. Interestingly, this polymorphism is located in a human TPH2 TFBS for two relevant transcription factors in the serotoninergic neurons, Foxa1 and Foxa2, which together with the high level of significance found for this SNP, could indicate that rs34517220 is in fact the crucial functional genetic variant related to the fluoxetine response. These results provide new evidence for the role of regulatory genetic variants that could modulate human TPH2 expression in the SSRI antidepressant response.

Epigenetic and genetic variants in the HTR1B gene and clinical improvement in children and adolescents treated with fluoxetine.

The serotonin 1B receptor (5-HT1B) is important to both the pathogenesis of major depressive disorder and the antidepressant effects of selective serotonin reuptake inhibitors. Although fluoxetine has been shown to be effective and safe in children and adolescents, not all patients experience a proper clinical response, which has led to further study into the main factors involved in this inter-individual variability. Our aim was to study the effect of epigenetic and genetic factors that could affect 5-hydroxytryptamine receptor 1B (HTR1B) gene expression, and thereby response to fluoxetine. A total of 83 children and adolescents were clinically assessed 12weeks after of initiating an antidepressant treatment with fluoxetine for the first time. We evaluated the influence of single nucleotide polymorphisms (SNPs) specifically located in transcription factor binding sites (TFBSs) on their clinical improvement. A combined genetic analysis considering the significant SNPs together with the functional variant rs130058 previously associated in our population was also performed. Moreover, we assessed, for the first time in the literature, whether methylation levels of the HTR1B promoter region could be associated with the pharmacological response. Two, rs9361233 and rs9361235, were significantly associated with clinical improvement after treatment with fluoxetine. The heterozygous genotype combination analysis showed a negative correlation with clinical improvement. The lowest improvement was experienced by patients who were heterozygous for all three SNPs. Moreover, a negative correlation was found between clinical improvement and the average methylation level of the HTR1B promoter. These results give new evidence for the role of epigenetic and genetic factors which could modulate HTR1B expression in the pharmacological response to antidepressants.

Pharmacogenetic study focused on fluoxetine pharmacodynamics in children and adolescent patients: impact of the serotonin pathway.

OBJECTIVE: Pharmacogenetic studies of fluoxetine in children and adolescents are scarce. After reporting the effect of genetic variants in genes related to the fluoxetine pharmacokinetics on clinical response in a pediatric population, we now evaluate the impact of genetic markers involved in its pharmacodynamics. PATIENTS AND METHODS: The assessment was performed in 83 patients after 12 weeks of fluoxetine treatment. The genetic association analysis included a total of 316 validated single nucleotide polymorphisms in 45 candidate genes involved in six different pathways. RESULTS: Clinical improvement after treatment with fluoxetine in our pediatric population was associated significantly with two polymorphisms located in genes related to the serotonergic system: the 5-hydroxytryptamine receptor 1B (HTR1B) and the tryptophan 5-hydroxylase 2 (TPH2). CONCLUSION: Although a wide range of candidate genes related to different pathways were assessed, the results show that genetic markers directly related to serotonin have an important effect on fluoxetine response.

Association of CACNA1C and SYNE1 in offspring of patients with psychiatric disorders.

Schizophrenia (SZ) and bipolar disorder (BD) are severe mental diseases associated with cognitive impairment, mood disturbance, and psychosis. Both disorders are highly heritable and share a common genetic background. The present study assesses, for the first time, differences in genotype frequencies of polymorphisms located in genes involved in neurodevelopment and synaptic plasticity between genetic high-risk individuals (offspring of patients with SZ or BD; N=100: 31 and 69, respectively) and control subjects (offspring of community controls; N=96). Individuals from both groups had similar ages, around 12 years. A higher percentage of men were included in the genetic high-risk group (58%) compared with the control group (40.6%). A total of 244 validated SNPs located in 35 candidate gene regions were analyzed in 196 participants. Multivariate methods based on logistic regression analysis were performed to assess differences in genotype frequencies. Bonferroni correction was applied for the multiple comparisons performed. Two polymorphisms, CACNA1C rs10848683 and SYNE1 rs214950, showed significant differences. The frequency of heterozygotes for CACNA1C rs10848683 in genetic high-risk individuals was double that in controls (OR=3.15; P=0.00016). For SYNE1 rs214950, higher frequencies of heterozygotes (OR=1.97) and homozygotes for the minor allele (OR=17.89; P=0.00020) were found in the genetic high-risk group than in the control group. In conclusion, polymorphisms in CACNA1C and SYNE1 could confer a greater risk of developing SZ and BD in individuals who are already at high risk because of their family history. This could help identify subjects with a very high genetic risk, in whom early detection and early intervention could lead to better prognosis.