BACKGROUND: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. METHODS: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. RESULTS: Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10-8), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10-6) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10-7; rs73033497, p = 8.8 × 10-7; rs7914279, p = 6.4 × 10-7), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10-7) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10-7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10-7) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). CONCLUSIONS: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.

• Klíčová slova
• Bipolar disorder, Genome-wide association study, Genotype-by-sex interaction, Major depressive disorder, Schizophrenia, Sex differences,
• MeSH
• bipolární porucha genetika   MeSH
• celogenomová asociační studie MeSH
• depresivní porucha unipolární * genetika   MeSH
• endoteliální buňky MeSH
• genetická predispozice k nemoci MeSH
• jednonukleotidový polymorfismus MeSH
• lidé MeSH
• pohlavní dimorfismus * MeSH
• psychotické poruchy * genetika   MeSH
• receptory vaskulárního endoteliálního růstového faktoru MeSH
• schizofrenie genetika   MeSH
• sulfurtransferasy MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• MOCOS protein, human MeSH Prohlížeč
• receptory vaskulárního endoteliálního růstového faktoru MeSH
• sulfurtransferasy MeSH

Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P < 1 × 10-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P < 5 × 10-8) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder.

• MeSH
• bipolární porucha klasifikace   genetika   MeSH
• celogenomová asociační studie MeSH
• depresivní porucha unipolární genetika   MeSH
• genetická predispozice k nemoci MeSH
• genetické lokusy * MeSH
• jednonukleotidový polymorfismus MeSH
• lidé MeSH
• psychotické poruchy genetika   MeSH
• schizofrenie genetika   MeSH
• studie případů a kontrol MeSH
• systémová biologie MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Intramural MeSH

Currently, patients are evaluated by a psychiatrist using the phenomenological classification then, first-line treatment is initiated according to the diagnosis; however, this approach is associated with a high rate of etiopathogenetic heterogeneity. The development of mental disorders is likely determined by combined effects of genetic predisposition and environmental adversity. Inter-mutual interaction is regulated by epigenetics processes which determine transcription and translation of gens to corresponding proteins. Choosing the optimal drug among available we strive for individualized approach based upon a patient's clinical characteristics. Personalized medicine including psychiatry considers measurable indicators of pathogenic processes (biomarkers) enabling identification of patients with common biological changes. Although personalized and precision medicine are often used synonymously, they describe two different approaches. Personalized psychiatry refers to the approach to an individual patient, precision psychiatry empowers decision- making process by measurable indicators and becomes the indispensable vehicle to achieve personalized treatment. An example is schizophrenia, the most severe mental disorder and prototype of psychotic disorder. The current definition of schizophrenia lacks a biological validity, which is stimulating an effort to alternatively define the psychotic disorders on the base of biomarkers. The goal of integration knowledge from biomedical research and clinical practice is providing more accurate diagnosis and the tailored treatment for each individual patient.

• Klíčová slova
• biomarkers, epigenetics., genetics, personalized medicine, precision psychiatry, schizophrenia,
• MeSH
• biologické markery MeSH
• genetická predispozice k nemoci MeSH
• individualizovaná medicína * MeSH
• lidé MeSH
• psychiatrie * MeSH
• psychotické poruchy * farmakoterapie   genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• biologické markery MeSH

Severe 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency is caused by mutations in the MTHFR gene and results in hyperhomocysteinemia and varying severity of disease, ranging from neonatal lethal to adult onset. Including those described here, 109 MTHFR mutations have been reported in 171 families, consisting of 70 missense mutations, 17 that primarily affect splicing, 11 nonsense mutations, seven small deletions, two no-stop mutations, one small duplication, and one large duplication. Only 36% of mutations recur in unrelated families, indicating that most are "private." The most common mutation is c.1530A>G (numbered from NM_005957.4, p.Lys510 = ) causing a splicing defect, found in 13 families; the most common missense mutation is c.1129C>T (p.Arg377Cys) identified in 10 families. To increase disease understanding, we report enzymatic activity, detected mutations, and clinical onset information (early, <1 year; or late, >1 year) for all published patients available, demonstrating that patients with early onset have less residual enzyme activity than those presenting later. We also review animal models, diagnostic approaches, clinical presentations, and treatment options. This is the first large review of mutations in MTHFR, highlighting the wide spectrum of disease-causing mutations.

• Klíčová slova
• MTHFR, genotype-phenotype correlation, homocystinuria, remethylation defects,
• MeSH
• databáze genetické MeSH
• homocystinurie genetika   MeSH
• katalytická doména MeSH
• lidé MeSH
• methylentetrahydrofolátreduktasa (NADPH2) chemie   nedostatek   genetika   metabolismus   MeSH
• modely nemocí na zvířatech MeSH
• mutace * MeSH
• novorozenec MeSH
• novorozenecký screening MeSH
• psychotické poruchy genetika   MeSH
• svalová spasticita genetika   MeSH
• věk při počátku nemoci MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• novorozenec MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• methylentetrahydrofolátreduktasa (NADPH2) MeSH
• MTHFR protein, human MeSH Prohlížeč

BACKGROUND: Severe methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare inborn defect disturbing the remethylation of homocysteine to methionine (<200 reported cases). This retrospective study evaluates clinical, biochemical genetic and in vitro enzymatic data in a cohort of 33 patients. METHODS: Clinical, biochemical and treatment data was obtained from physicians by using a questionnaire. MTHFR activity was measured in primary fibroblasts; genomic DNA was extracted from cultured fibroblasts. RESULTS: Thirty-three patients (mean age at follow-up 11.4 years; four deceased; median age at first presentation 5 weeks; 17 females) were included. Patients with very low (<1.5%) mean control values of enzyme activity (n = 14) presented earlier and with a pattern of feeding problems, encephalopathy, muscular hypotonia, neurocognitive impairment, apnoea, hydrocephalus, microcephaly and epilepsy. Patients with higher (>1.7-34.8%) residual enzyme activity had mainly psychiatric symptoms, mental retardation, myelopathy, ataxia and spasticity. Treatment with various combinations of betaine, methionine, folate and cobalamin improved the biochemical and clinical phenotype. During the disease course, patients with very low enzyme activity showed a progression of feeding problems, neurological symptoms, mental retardation, and psychiatric disease while in patients with higher residual enzyme activity, myelopathy, ataxia and spasticity increased. All other symptoms remained stable or improved in both groups upon treatment as did brain imaging in some cases. No clear genotype-phenotype correlation was obvious. DISCUSSION: MTHFR deficiency is a severe disease primarily affecting the central nervous system. Age at presentation and clinical pattern are correlated with residual enzyme activity. Treatment alleviates biochemical abnormalities and clinical symptoms partially.

• MeSH
• ataxie genetika   MeSH
• betain terapeutické užití   MeSH
• dítě MeSH
• fenotyp MeSH
• genetické asociační studie metody   MeSH
• homocystinurie farmakoterapie   enzymologie   genetika   MeSH
• kyselina listová terapeutické užití   MeSH
• lidé MeSH
• mentální retardace genetika   MeSH
• methionin terapeutické užití   MeSH
• methylentetrahydrofolátreduktasa (NADPH2) nedostatek   genetika   MeSH
• mutace genetika   MeSH
• nemoci míchy genetika   MeSH
• psychotické poruchy farmakoterapie   enzymologie   genetika   MeSH
• retrospektivní studie MeSH
• svalová spasticita farmakoterapie   enzymologie   genetika   MeSH
• vitamin B 12 terapeutické užití   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• betain MeSH
• kyselina listová MeSH
• methionin MeSH
• methylentetrahydrofolátreduktasa (NADPH2) MeSH
• vitamin B 12 MeSH

5,10-Methylenetetrahydrofolate reductase (MTHFR) deficiency is the most common inherited disorder of folate metabolism and causes severe hyperhomocysteinaemia. To better understand the relationship between mutation and function, we performed molecular genetic analysis of 76 MTHFR deficient patients, followed by extensive enzymatic characterization of fibroblasts from 72 of these. A deleterious mutation was detected on each of the 152 patient alleles, with one allele harboring two mutations. Sixty five different mutations (42 novel) were detected, including a common splicing mutation (c.1542G>A) found in 21 alleles. Using an enzyme assay in the physiological direction, we found residual activity (1.7%-42% of control) in 42 cell lines, of which 28 showed reduced affinity for nicotinamide adenine dinucleotide phosphate (NADPH), one reduced affinity for methylenetetrahydrofolate, five flavin adenine dinucleotide-responsiveness, and 24 abnormal kinetics of S-adenosylmethionine inhibition. Missense mutations causing virtually absent activity were found exclusively in the N-terminal catalytic domain, whereas missense mutations in the C-terminal regulatory domain caused decreased NADPH binding and disturbed inhibition by S-adenosylmethionine. Characterization of patients in this way provides a basis for improved diagnosis using expanded enzymatic criteria, increases understanding of the molecular basis of MTHFR dysfunction, and points to the possible role of cofactor or substrate in the treatment of patients with specific mutations.

• Klíčová slova
• MTHFR, enzyme kinetics, homocystinuria, methylenetetrahydrofolate,
• MeSH
• aktivace enzymů MeSH
• alely MeSH
• alternativní sestřih MeSH
• exony MeSH
• fibroblasty metabolismus   MeSH
• genetické asociační studie * MeSH
• homocystinurie diagnóza   genetika   metabolismus   MeSH
• introny MeSH
• jednonukleotidový polymorfismus MeSH
• kinetika MeSH
• lidé MeSH
• methylentetrahydrofolátreduktasa (NADPH2) nedostatek   genetika   metabolismus   MeSH
• mutace MeSH
• psychotické poruchy diagnóza   genetika   metabolismus   MeSH
• stabilita proteinů MeSH
• svalová spasticita diagnóza   genetika   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• methylentetrahydrofolátreduktasa (NADPH2) MeSH

OBJECTIVE: The objective of this prospective, naturalistic study, conducted in first-episode psychosis patients from a Central-European population, was to assess the utility of Cytochrome P-450 2D6 (CYP2D6) genotype testing under normal clinical setting. METHODS: A total of 35 patients diagnosed for the first time with schizophrenia or acute schizophrenia-like psychotic disorder and treated with risperidone were enrolled in the study. These patients underwent sequentiation of the CYP2D6 gene and evaluations of symptoms and severity of adverse effects using the PANSS and UKU scales, respectively. Doses of antipsychotics and other co-medication were monitored as well. In statistical analysis, Fisher's exact test was used to compare ratios and the Wilcoxon rank-sum test was used in the comparison of continual variables. RESULTS: PM patients showed a significantly lower reduction in psychotic symptoms and a greater severity of psychotic symptoms following risperidone treatment and higher doses of antipsychotics not metabolized by CYP2D6, which were used as co-medication. CONCLUSIONS: Based on these results, patients with the PM genotype experiencing first-episode schizophrenia don't appear to be optimal recipients of risperidone treatment. However, as the main limitation of this study was the relatively small sample-size, replication with a larger scale study is needed to confirm these findings.

• MeSH
• alely MeSH
• antipsychotika škodlivé účinky   terapeutické užití   MeSH
• cytochrom P-450 CYP2D6 genetika   MeSH
• dospělí MeSH
• genotyp MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• prospektivní studie MeSH
• psychiatrické posuzovací škály statistika a číselné údaje   MeSH
• psychotické poruchy farmakoterapie   genetika   MeSH
• risperidon škodlivé účinky   terapeutické užití   MeSH
• schizofrenie diagnóza   farmakoterapie   genetika   MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antipsychotika MeSH
• cytochrom P-450 CYP2D6 MeSH
• risperidon MeSH

OBJECTIVES: About 25,000 serious methamphetamine abusers live in the Czech Republic among the total population of 10 million. Dependence on methamphetamine is markedly related to the brain neurotransmitter dopamine, metabolised by catechol-O-methyltransferase enzyme. The main aim of the study was to ascertain whether the Val158Met catechol-O-methyltransferase gene polymorphism is associated with methamphetamine dependence in this Central European country. METHODS: One hundred and twenty-three subjects dependent on methamphetamine (women N=44), parents of sixty-seven dependent individuals, and four hundred healthy controls (women N=250) were involved into the study. We performed a population-based as well as family-based genetic association studies. RESULTS: We did not find any significant association between the Val158Met catechol-O-methyltransferase gene polymorphism and methamphetamine dependence using the population-based or family-based design (p=0.41-0.66; Chi-Square Test or UNPHASED program, Version 3.1.4, respectively). We found a trend toward a statistically significant difference between the Val allele carriers and Met/Met homozygotes in the frequence of psychotic symptoms induced by methamphetamine (more frequent in Val carriers; p=0.062; Chi-Square Test). CONCLUSION: Further research involving haplotype analysis and other dopamine-related genetic polymorphisms in large populations is needed. More attention should also be paid to possible role of the Val158Met catechol-O-methyl-transferase gene polymorphism in individual clinical subtypes of dependence on methamphetamine involving e.g. psychotic features or violence.

• MeSH
• bodová mutace * MeSH
• dospělí MeSH
• frekvence genu MeSH
• genetická predispozice k nemoci genetika   MeSH
• haplotypy MeSH
• katechol-O-methyltransferasa genetika   MeSH
• lidé MeSH
• methamfetamin škodlivé účinky   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• polymorfismus genetický * MeSH
• poruchy spojené s užíváním amfetaminu genetika   MeSH
• psychotické poruchy genetika   MeSH
• stimulanty centrálního nervového systému škodlivé účinky   MeSH
• zdraví rodiny MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• katechol-O-methyltransferasa MeSH
• methamfetamin MeSH
• stimulanty centrálního nervového systému MeSH

We found no differences in clinical symptoms among chronic schizophrenics with a family history of psychosis (n = 18) and without any affected relatives (n = 22). The lifetime morbidity risks of psychosis in the former group were 0.59 +/- 0.13 for children and 0.33 +/- 0.07 for siblings.

• MeSH
• chromozomální aberace genetika   MeSH
• chromozomální poruchy MeSH
• chronická nemoc MeSH
• dominantní geny genetika   MeSH
• frekvence genu genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• psychotické poruchy diagnóza   genetika   psychologie   MeSH
• rizikové faktory MeSH
• schizofrenie (psychologie) * MeSH
• schizofrenie diagnóza   genetika   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

The author gives an account of the problem of psychotic diseases in the practice of a genetic department. She mentions the specificity of decision taking on the reproduction in psychotic subjects, where in addition to the empirical risk of affection of the offspring and the possible teratogenic effect of medication, the load associated with the disease from the medical and socio-economical aspect must be considered. These factors are subject to the subjective interpretation by the family. The task of the geneticist is to help a rational solution of the situation in close cooperation with the psychiatrist.

• MeSH
• abnormality vyvolané léky etiologie   MeSH
• genetické poradenství * MeSH
• lidé MeSH
• psychotické poruchy farmakoterapie   genetika   MeSH
• psychotropní léky škodlivé účinky   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• Názvy látek
• psychotropní léky MeSH