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1.
Mol Psychiatry ; 27(9): 3842-3856, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35546635

RESUMO

Bipolar disorder is an often-severe mental health condition characterized by alternation between extreme mood states of mania and depression. Despite strong heritability and the recent identification of 64 common variant risk loci of small effect, pathophysiological mechanisms remain unknown. Here, we analyzed genome sequences from 41 multiply-affected pedigrees and identified variants in 741 genes with nominally significant linkage or association with bipolar disorder. These 741 genes overlapped known risk genes for neurodevelopmental disorders and clustered within gene networks enriched for synaptic and nuclear functions. The top variant in this analysis - prioritized by statistical association, predicted deleteriousness, and network centrality - was a missense variant in the gene encoding D-amino acid oxidase (DAOG131V). Heterologous expression of DAOG131V in human cells resulted in decreased DAO protein abundance and enzymatic activity. In a knock-in mouse model of DAOG131, DaoG130V/+, we similarly found decreased DAO protein abundance in hindbrain regions, as well as enhanced stress susceptibility and blunted behavioral responses to pharmacological inhibition of N-methyl-D-aspartate receptors (NMDARs). RNA sequencing of cerebellar tissue revealed that DaoG130V resulted in decreased expression of two gene networks that are enriched for synaptic functions and for genes expressed, respectively, in Purkinje neurons or granule neurons. These gene networks were also down-regulated in the cerebellum of patients with bipolar disorder compared to healthy controls and were enriched for additional rare variants associated with bipolar disorder risk. These findings implicate dysregulation of NMDAR signaling and of gene expression in cerebellar neurons in bipolar disorder pathophysiology and provide insight into its genetic architecture.


Assuntos
Transtorno Bipolar , Receptores de N-Metil-D-Aspartato , Camundongos , Animais , Humanos , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Transtorno Bipolar/genética , Transtorno Bipolar/metabolismo , D-Aminoácido Oxidase/genética , D-Aminoácido Oxidase/metabolismo , Redes Reguladoras de Genes/genética , Cerebelo/metabolismo
2.
Arch Sex Behav ; 50(8): 3371-3375, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34080073

RESUMO

Male sexual orientation is a scientifically and socially important trait shown by family and twin studies to be influenced by environmental and complex genetic factors. Individual genome-wide linkage studies (GWLS) have been conducted, but not jointly analyzed. Two main datasets account for > 90% of the published GWLS concordant sibling pairs on the trait and are jointly analyzed here: MGSOSO (Molecular Genetic Study of Sexual Orientation; 409 concordant sibling pairs in 384 families, Sanders et al. (2015)) and Hamer (155 concordant sibling pairs in 145 families, Mustanski et al. (2005)). We conducted multipoint linkage analyses with Merlin on the datasets separately since they were genotyped differently, integrated genetic marker positions, and combined the resultant LOD (logarithm of the odds) scores at each 1 cM grid position. We continue to find the strongest linkage support at pericentromeric chromosome 8 and chromosome Xq28. We also incorporated the remaining published GWLS dataset (on 55 families) by using meta-analytic approaches on published summary statistics. The meta-analysis has maximized the positional information from GWLS of currently available family resources and can help prioritize findings from genome-wide association studies (GWAS) and other approaches. Although increasing evidence highlights genetic contributions to male sexual orientation, our current understanding of contributory loci is still limited, consistent with the complexity of the trait. Further increasing genetic knowledge about male sexual orientation, especially via large GWAS, should help advance our understanding of the biology of this important trait.


Assuntos
Genoma Humano , Estudo de Associação Genômica Ampla , Feminino , Ligação Genética , Humanos , Escore Lod , Masculino , Comportamento Sexual
3.
Transl Psychiatry ; 9(1): 230, 2019 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-31530798

RESUMO

Schizophrenia, Schizoaffective, and Bipolar disorders share behavioral and phenomenological traits, intermediate phenotypes, and some associated genetic loci with pleiotropic effects. Volumetric abnormalities in brain structures are among the intermediate phenotypes consistently reported associated with these disorders. In order to examine the genetic underpinnings of these structural brain modifications, we performed genome-wide association analyses (GWAS) on 60 quantitative structural brain MRI phenotypes in a sample of 777 subjects (483 cases and 294 controls pooled together). Genotyping was performed with the Illumina PsychChip microarray, followed by imputation to the 1000 genomes multiethnic reference panel. Enlargement of the Temporal Horns of Lateral Ventricles (THLV) is associated with an intronic SNP of the gene NRXN1 (rs12467877, P = 6.76E-10), which accounts for 4.5% of the variance in size. Enlarged THLV is associated with psychosis in this sample, and with reduction of the hippocampus and enlargement of the choroid plexus and caudate. Eight other suggestively significant associations (P < 5.5E-8) were identified with THLV and 5 other brain structures. Although rare deletions of NRXN1 have been previously associated with psychosis, this is the first report of a common SNP variant of NRXN1 associated with enlargement of the THLV in psychosis.


Assuntos
Proteínas de Ligação ao Cálcio/genética , Ventrículos Laterais/diagnóstico por imagem , Moléculas de Adesão de Célula Nervosa/genética , Transtornos Psicóticos/genética , Adulto , Alelos , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neuroimagem , Polimorfismo de Nucleotídeo Único , Transtornos Psicóticos/diagnóstico por imagem , Adulto Jovem
4.
Nat Genet ; 51(5): 793-803, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31043756

RESUMO

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.


Assuntos
Transtorno Bipolar/genética , Loci Gênicos , Transtorno Bipolar/classificação , Estudos de Casos e Controles , Transtorno Depressivo Maior/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Transtornos Psicóticos/genética , Esquizofrenia/genética , Biologia de Sistemas
5.
Eur Neuropsychopharmacol ; 29(1): 156-170, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30503783

RESUMO

Genome-wide association studies of case-control status have advanced the understanding of the genetic basis of psychiatric disorders. Further progress may be gained by increasing sample size but also by new analysis strategies that advance the exploitation of existing data, especially for clinically important quantitative phenotypes. The functionally-informed efficient region-based test strategy (FIERS) introduced herein uses prior knowledge on biological function and dependence of genotypes within a powerful statistical framework with improved sensitivity and specificity for detecting consistent genetic effects across studies. As proof of concept, FIERS was used for the first genome-wide single nucleotide polymorphism (SNP)-based investigation on bipolar disorder (BD) that focuses on an important aspect of disease course, the functional outcome. FIERS identified a significantly associated locus on chromosome 15 (hg38: chr15:48965004 - 49464789 bp) with consistent effect strength between two independent studies (GAIN/TGen: European Americans, BOMA: Germans; n = 1592 BD patients in total). Protective and risk haplotypes were found on the most strongly associated SNPs. They contain a CTCF binding site (rs586758); CTCF sites are known to regulate sets of genes within a chromatin domain. The rs586758 - rs2086256 - rs1904317 haplotype is located in the promoter flanking region of the COPS2 gene, close to microRNA4716, and the EID1, SHC4, DTWD1 genes as plausible biological candidates. While implication with BD is novel, COPS2, EID1, and SHC4 are known to be relevant for neuronal differentiation and function and DTWD1 for psychopharmacological side effects. The test strategy FIERS that enabled this discovery is equally applicable for tag SNPs and sequence data.


Assuntos
Transtorno Bipolar/diagnóstico , Transtorno Bipolar/genética , Predisposição Genética para Doença/genética , Adolescente , Adulto , Idoso , Transtorno Bipolar/fisiopatologia , Transtorno Bipolar/psicologia , Estudos de Casos e Controles , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Haplótipos , Humanos , Desequilíbrio de Ligação/genética , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Polimorfismo de Nucleotídeo Único/genética , Prognóstico , Escalas de Graduação Psiquiátrica , População Branca/genética , Adulto Jovem
6.
Sci Transl Med ; 10(472)2018 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-30545964

RESUMO

Schizophrenia and bipolar disorder are complex psychiatric diseases with risks contributed by multiple genes. Dysregulation of gene expression has been implicated in these disorders, but little is known about such dysregulation in the human brain. We analyzed three transcriptome datasets from 394 postmortem brain tissue samples from patients with schizophrenia or bipolar disorder or from healthy control individuals without a known history of psychiatric disease. We built genome-wide coexpression networks that included microRNAs (miRNAs). We identified a coexpression network module that was differentially expressed in the brain tissue from patients compared to healthy control individuals. This module contained genes that were principally involved in glial and neural cell genesis and glial cell differentiation, and included schizophrenia risk genes carrying rare variants. This module included five miRNAs and 545 mRNAs, with six transcription factors serving as hub genes in this module. We found that the most connected transcription factor gene POU3F2, also identified on a genome-wide association study for bipolar disorder, could regulate the miRNA hsa-miR-320e and other putative target mRNAs. These regulatory relationships were replicated using PsychENCODE/BrainGVEX datasets and validated by knockdown and overexpression experiments in SH-SY5Y cells and human neural progenitor cells in vitro. Thus, we identified a brain gene expression module that was enriched for rare coding variants in genes associated with schizophrenia and that contained the putative bipolar disorder risk gene POU3F2 The transcription factor POU3F2 may be a key regulator of gene expression in this disease-associated gene coexpression module.


Assuntos
Encéfalo/metabolismo , Redes Reguladoras de Genes , Proteínas de Homeodomínio/metabolismo , Transtornos Mentais/genética , Fatores do Domínio POU/metabolismo , Diferenciação Celular/genética , Proliferação de Células/genética , Bases de Dados Genéticas , Regulação da Expressão Gênica , Predisposição Genética para Doença , Variação Genética , Estudo de Associação Genômica Ampla , Proteínas de Homeodomínio/genética , Humanos , Células-Tronco Neurais/metabolismo , Fatores do Domínio POU/genética , Mudanças Depois da Morte , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reprodutibilidade dos Testes
7.
Int J Bipolar Disord ; 6(1): 24, 2018 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-30415424

RESUMO

BACKGROUND: Disentangling the etiology of common, complex diseases is a major challenge in genetic research. For bipolar disorder (BD), several genome-wide association studies (GWAS) have been performed. Similar to other complex disorders, major breakthroughs in explaining the high heritability of BD through GWAS have remained elusive. To overcome this dilemma, genetic research into BD, has embraced a variety of strategies such as the formation of large consortia to increase sample size and sequencing approaches. Here we advocate a complementary approach making use of already existing GWAS data: a novel data mining procedure to identify yet undetected genotype-phenotype relationships. We adapted association rule mining, a data mining technique traditionally used in retail market research, to identify frequent and characteristic genotype patterns showing strong associations to phenotype clusters. We applied this strategy to three independent GWAS datasets from 2835 phenotypically characterized patients with BD. In a discovery step, 20,882 candidate association rules were extracted. RESULTS: Two of these rules-one associated with eating disorder and the other with anxiety-remained significant in an independent dataset after robust correction for multiple testing. Both showed considerable effect sizes (odds ratio ~ 3.4 and 3.0, respectively) and support previously reported molecular biological findings. CONCLUSION: Our approach detected novel specific genotype-phenotype relationships in BD that were missed by standard analyses like GWAS. While we developed and applied our method within the context of BD gene discovery, it may facilitate identifying highly specific genotype-phenotype relationships in subsets of genome-wide data sets of other complex phenotype with similar epidemiological properties and challenges to gene discovery efforts.

8.
Sci Rep ; 7(1): 16950, 2017 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-29217827

RESUMO

Family and twin studies suggest that genes play a role in male sexual orientation. We conducted a genome-wide association study (GWAS) of male sexual orientation on a primarily European ancestry sample of 1,077 homosexual men and 1,231 heterosexual men using Affymetrix single nucleotide polymorphism (SNP) arrays. We identified several SNPs with p < 10-5, including regions of multiple supporting SNPs on chromosomes 13 (minimum p = 7.5 × 10-7) and 14 (p = 4.7 × 10-7). The genes nearest to these peaks have functions plausibly relevant to the development of sexual orientation. On chromosome 13, SLITRK6 is a neurodevelopmental gene mostly expressed in the diencephalon, which contains a region previously reported as differing in size in men by sexual orientation. On chromosome 14, TSHR genetic variants in intron 1 could conceivably help explain past findings relating familial atypical thyroid function and male homosexuality. Furthermore, skewed X chromosome inactivation has been found in the thyroid condition, Graves' disease, as well as in mothers of homosexual men. On pericentromeric chromosome 8 within our previously reported linkage peak, we found support (p = 4.1 × 10-3) for a SNP association previously reported (rs77013977, p = 7.1 × 10-8), with the combined analysis yielding p = 6.7 × 10-9, i.e., a genome-wide significant association.


Assuntos
Homossexualidade Masculina/genética , Polimorfismo de Nucleotídeo Único , Cromossomos Humanos Par 13/genética , Cromossomos Humanos Par 14/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Proteínas de Membrana/genética , Receptores da Tireotropina/genética , Inativação do Cromossomo X
9.
Mol Neuropsychiatry ; 2(3): 145-150, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27867939

RESUMO

Whole-genome sequencing was performed on 3 bipolar I disorder (BPI) cases from a multiplex pedigree of European ancestry with 7 BPI cases. Within CACNA1D, a gene implicated by genome-wide association studies, a G to C nucleotide transversion at 53,835,340 base pairs (bps) was found predicting the substitution of proline for alanine at amino acid position 1751 (A1751P). Using Sanger sequencing, the DNA variant was shown to co-segregate with the remaining 4 BPI cases within the pedigree. A high-resolution DNA denaturing curve method was then used to screen for the presence of the A1751P change in 4,150 BPI cases from the NIMH Genetics Initiative. The A1751P variant was found in 4 BPI cases. A second variant within exon 43, a C to T nucleotide transition, was found in 1 case at 53,835,355 bps, predicting the substitution of tryptophan for arginine at amino acid position 1771 (R1771W). In the NHLBI Exome Sequencing Project database, the heterozygous A1751P variant was present in 3 of 4,300 subjects of European ancestry, and the R1771W change was not present in any subject. Given the rarity of these variants, large-scale case/control rare variant sequencing studies will be required for definitive conclusions.

10.
Hum Mol Genet ; 25(15): 3383-3394, 2016 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-27329760

RESUMO

Bipolar disorder (BD) is a genetically complex mental illness characterized by severe oscillations of mood and behaviour. Genome-wide association studies (GWAS) have identified several risk loci that together account for a small portion of the heritability. To identify additional risk loci, we performed a two-stage meta-analysis of >9 million genetic variants in 9,784 bipolar disorder patients and 30,471 controls, the largest GWAS of BD to date. In this study, to increase power we used ∼2,000 lithium-treated cases with a long-term diagnosis of BD from the Consortium on Lithium Genetics, excess controls, and analytic methods optimized for markers on the X-chromosome. In addition to four known loci, results revealed genome-wide significant associations at two novel loci: an intergenic region on 9p21.3 (rs12553324, P = 5.87 × 10 - 9; odds ratio (OR) = 1.12) and markers within ERBB2 (rs2517959, P = 4.53 × 10 - 9; OR = 1.13). No significant X-chromosome associations were detected and X-linked markers explained very little BD heritability. The results add to a growing list of common autosomal variants involved in BD and illustrate the power of comparing well-characterized cases to an excess of controls in GWAS.


Assuntos
Transtorno Bipolar/genética , Cromossomos Humanos X/genética , Estudo de Associação Genômica Ampla , Receptor ErbB-2/genética , Feminino , Humanos , Masculino
11.
Schizophr Res ; 169(1-3): 326-333, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26481615

RESUMO

Smooth pursuit eye tracking deficits are a promising intermediate phenotype for schizophrenia and possibly for psychotic disorders more broadly. The Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) consortium investigated the severity and familiality of different pursuit parameters across psychotic disorders. Probands with schizophrenia (N=265), schizoaffective disorder (N=178), psychotic bipolar disorder (N=231), their first-degree relatives (N=306, N=217, N=273, respectively) and healthy controls (N=305) performed pursuit tracking tasks designed to evaluate sensorimotor and cognitive/predictive aspects of pursuit. Probands from all diagnostic groups were impaired on all pursuit measures of interest compared to controls (p<0.001). Schizophrenia probands were more impaired than other proband groups on both early pursuit gain and predictive gain. Relatives with and without enhanced psychosis spectrum personality traits were impaired on initial eye acceleration, the most direct sensorimotor pursuit measure, but not on pursuit gain measures. This suggests that alterations in early sensorimotor function may track susceptibility to psychosis even in the absence of psychosis related personality traits. There were no differences in pursuit measures between relatives of the three proband groups. Familiality estimates of pursuit deficits indicate that early pursuit gain was more familial than predictive gain, which has been the most widely used measure in previous family studies of psychotic disorders. Thus, while disease-related factors may induce significant impairments of pursuit gain, especially in schizophrenia, the pattern of deficits in relatives and their familiality estimates suggest that alterations in sensorimotor function at pursuit onset may indicate increased susceptibility across psychotic disorders.


Assuntos
Transtorno Bipolar/fisiopatologia , Transtornos Psicóticos/fisiopatologia , Acompanhamento Ocular Uniforme/fisiologia , Esquizofrenia/fisiopatologia , Adulto , Análise de Variância , Processamento Eletrônico de Dados , Família , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Escalas de Graduação Psiquiátrica , Adulto Jovem
12.
Am J Med Genet B Neuropsychiatr Genet ; 168B(4): 247-57, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25832558

RESUMO

Attention deficit hyperactivity disorder (ADHD) is associated with substantial functional impairment in children and in adults. Many individuals with ADHD have clear neurocognitive deficits, including problems with visual attention, processing speed, and set shifting. ADHD is etiologically complex, and although genetic factors play a role in its development, much of the genetic contribution to ADHD remains unidentified. We conducted clinical and neuropsychological assessments of 294 individuals (269 with ADHD) from 163 families (48 multigenerational families created using genealogical reconstruction, 78 affected sib pair families, and 37 trios) from the Central Valley of Costa Rica (CVCR). We used principal components analysis (PCA) to group neurocognitive and behavioral variables using the subscales of the Child Behavior Checklist (CBCL) and 15 neuropsychological measures, and created quantitative traits for heritability analyses. We identified seven cognitive and two behavioral domains. Individuals with ADHD were significantly more impaired than their unaffected siblings on most behavioral and cognitive domains. The verbal IQ domain had the highest heritability (92%), followed by auditory attention (87%), visual processing speed and problem solving (85%), and externalizing symptoms (81%). The quantitative traits identified here have high heritabilities, similar to the reported heritability of ADHD (70-90%), and may represent appropriate alternative phenotypes for genetic studies. The use of multigenerational families from a genetically isolated population may facilitate the identification of ADHD risk genes in the face of phenotypic and genetic heterogeneity.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Comportamento , Irmãos , Adolescente , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Criança , Cognição , Costa Rica , Análise Fatorial , Feminino , Predisposição Genética para Doença , Humanos , Padrões de Herança/genética , Masculino , Modelos Genéticos , Testes Neuropsicológicos , Linhagem , Fenótipo , Análise de Componente Principal , Adulto Jovem
13.
Proc Natl Acad Sci U S A ; 112(11): 3576-81, 2015 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-25730879

RESUMO

We sequenced the genomes of 200 individuals from 41 families multiply affected with bipolar disorder (BD) to identify contributions of rare variants to genetic risk. We initially focused on 3,087 candidate genes with known synaptic functions or prior evidence from genome-wide association studies. BD pedigrees had an increased burden of rare variants in genes encoding neuronal ion channels, including subunits of GABAA receptors and voltage-gated calcium channels. Four uncommon coding and regulatory variants also showed significant association, including a missense variant in GABRA6. Targeted sequencing of 26 of these candidate genes in an additional 3,014 cases and 1,717 controls confirmed rare variant associations in ANK3, CACNA1B, CACNA1C, CACNA1D, CACNG2, CAMK2A, and NGF. Variants in promoters and 5' and 3' UTRs contributed more strongly than coding variants to risk for BD, both in pedigrees and in the case-control cohort. The genes and pathways identified in this study regulate diverse aspects of neuronal excitability. We conclude that rare variants in neuronal excitability genes contribute to risk for BD.


Assuntos
Transtorno Bipolar/genética , Transtorno Bipolar/fisiopatologia , Predisposição Genética para Doença , Variação Genética , Neurônios/fisiologia , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Humanos , Masculino , Linhagem , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Transdução de Sinais/genética , População Branca/genética
14.
Psychopharmacology (Berl) ; 232(1): 145-54, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25096017

RESUMO

RATIONALE: Type-3 metabotropic glutamate receptor gene (GRM3) single nucleotide polymorphisms (SNPs) have been associated with cognitive performance and prefrontal cortex brain activity in chronically treated schizophrenia patients. Whether these SNPs are associated with cognitive and symptom response to antipsychotic therapy has not been extensively evaluated. OBJECTIVES: The aim of the study was to examine pharmacogenetic relationships between GRM3 and selected variants in relevant dopamine genes with changes in spatial working memory and clinical symptoms after treatment. METHODS: Sixty-one untreated first-episode schizophrenia patients were assessed before and after 6 weeks of antipsychotic pharmacotherapy, primarily consisting of risperidone. Patients' level of cognitive performance on a spatial working memory task was assessed with a translational oculomotor paradigm. Changes after treatment in cognitive and clinical measures were examined in relationship to genetic polymorphisms in the GRM3, COMT, and DRD2/ANKK1 gene regions. RESULTS: Spatial working memory performance worsened after antipsychotic treatment. This worsening was associated with GRM3 rs1468412, with the genetic subgroup of patients known to have altered glutamate activity having greater adverse changes in working memory performance after antipsychotic treatment. Negative symptom improvement was associated with GRM3 rs6465084. There were no pharmacogenetic associations between DRD2/ANKK1 and COMT with working memory changes or symptom response to treatment. CONCLUSIONS: These findings suggest important pharmacogenetic relationships between GRM3 variants and changes in cognition and symptom response with exposure to antipsychotics. This information may be useful in identifying patients susceptible to adverse cognitive outcomes associated with antipsychotic treatment and suggest that glutamatergic mechanisms contribute to such effects.


Assuntos
Antipsicóticos/uso terapêutico , Memória de Curto Prazo/efeitos dos fármacos , Farmacogenética/métodos , Receptores de Glutamato Metabotrópico/genética , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética , Adolescente , Adulto , Antipsicóticos/farmacologia , Feminino , Variação Genética/genética , Humanos , Masculino , Memória de Curto Prazo/fisiologia , Polimorfismo de Nucleotídeo Único/genética , Esquizofrenia/diagnóstico , Resultado do Tratamento , Adulto Jovem
15.
Nat Commun ; 4: 2739, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24253340

RESUMO

Schizophrenia and bipolar disorder are major psychiatric disorders with high heritability and overlapping genetic variance. Here we perform a genome-wide association study in an ethnically homogeneous cohort of 904 schizophrenia cases and 1,640 controls drawn from the Ashkenazi Jewish population. We identify a novel genome-wide significant risk locus at chromosome 4q26, demonstrating the potential advantages of this founder population for gene discovery. The top single-nucleotide polymorphism (SNP; rs11098403) demonstrates consistent effects across 11 replication and extension cohorts, totalling 23, 191 samples across multiple ethnicities, regardless of diagnosis (schizophrenia or bipolar disorder), resulting in Pmeta=9.49 × 10(-12) (odds ratio (OR)=1.13, 95% confidence interval (CI): 1.08-1.17) across both disorders and Pmeta=2.67 × 10(-8) (OR=1.15, 95% CI: 1.08-1.21) for schizophrenia alone. In addition, this intergenic SNP significantly predicts postmortem cerebellar gene expression of NDST3, which encodes an enzyme critical to heparan sulphate metabolism. Heparan sulphate binding is critical to neurite outgrowth, axon formation and synaptic processes thought to be aberrant in these disorders.


Assuntos
Transtorno Bipolar/genética , Esquizofrenia/genética , Sulfotransferases/metabolismo , Regulação da Expressão Gênica , Predisposição Genética para Doença , Genoma Humano , Humanos , Judeus/genética , Razão de Chances , Polimorfismo de Nucleotídeo Único , Sulfotransferases/genética
16.
Nat Genet ; 45(9): 984-94, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23933821

RESUMO

Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17-29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 ± 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 ± 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 ± 0.06 s.e.), and ADHD and major depressive disorder (0.32 ± 0.07 s.e.), low between schizophrenia and ASD (0.16 ± 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohn's disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.


Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Transtornos Mentais/genética , Polimorfismo de Nucleotídeo Único , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno Bipolar/genética , Criança , Transtornos Globais do Desenvolvimento Infantil/genética , Doença de Crohn/genética , Transtorno Depressivo Maior/genética , Heterogeneidade Genética , Genoma Humano , Humanos , Padrões de Herança , Esquizofrenia/genética
17.
J Affect Disord ; 151(2): 748-755, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23972719

RESUMO

BACKGROUND: The many attempts that have been made to identify genes for bipolar disorder (BD) have met with limited success, which may reflect an inadequacy of diagnosis as an informative and biologically relevant phenotype for genetic studies. Here we have explored aspects of personality as quantitative phenotypes for bipolar disorder through the use of the Temperament and Character Inventory (TCI), which assesses personality in seven dimensions. Four temperament dimensions are assessed: novelty seeking (NS), harm avoidance (HA), reward dependence (RD), and persistence (PS). Three character dimensions are also included: self-directedness (SD), cooperativeness (CO), and self-transcendence (ST). METHODS: We compared personality scores between diagnostic groups and assessed heritability in a sample of 101 families collected for genetic studies of BD. A genome-wide SNP linkage analysis was then performed in the subset of 51 families for which genetic data was available. RESULTS: Significant group differences were observed between BD subjects, their first-degree relatives, and independent controls for all but RD and PS, and all but HA and RD were found to be significantly heritable in this sample. Linkage analysis of the heritable dimensions produced several suggestive linkage peaks for NS (chromosomes 7q21 and 10p15), PS (chromosomes 6q16, 12p13, and 19p13), and SD (chromosomes 4q35, 8q24, and 18q12). LIMITATIONS: The relatively small size of our linkage sample likely limited our ability to reach genome-wide significance in this study. CONCLUSIONS: While not genome-wide significant, these results suggest that aspects of personality may prove useful in the identification of genes underlying BD susceptibility.


Assuntos
Transtorno Bipolar/genética , Transtorno Bipolar/psicologia , Personalidade/genética , Adulto , Transtorno Depressivo Maior/genética , Endofenótipos , Família , Feminino , Ligação Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Inventário de Personalidade , Polimorfismo de Nucleotídeo Único , Temperamento
18.
J Affect Disord ; 150(3): 1031-40, 2013 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-23759419

RESUMO

BACKGROUND: The many attempts to identify genes for bipolar disorder (BD) have met with limited success, which has generally been attributed to genetic heterogeneity and small gene effects. However, it is also possible that the categorical phenotypes used in genetic studies of BD are not the most informative or biologically relevant. We have explored aspects of temperament as quantitative phenotypes for BD through the use of the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego Auto-questionnaire (TEMPS-A), which is designed to assess lifelong, milder aspects of bipolar symptomatology and defines five temperaments: hyperthymic, dysthymic, cyclothymic, irritable, and anxious. METHODS: We compared temperament scores between diagnostic groups and assessed heritability in a sample of 101 families collected for genetic studies of BD. A genome-wide SNP linkage study was then performed in the subset of 51 families for which genetic data was available. RESULTS: Significant group differences were observed between BD subjects, their first-degree relatives, and independent controls, and all five temperaments were found to be significantly heritable, with heritabilities ranging from 21% for the hyperthymic to 52% for the irritable temperaments. Suggestive evidence for linkage was observed for the hyperthymic (chromosomes 1q44, 2p16, 6q16, and 14q23), dysthymic (chromosomes 3p21 and 13q34), and irritable (chromosome 6q24) temperaments. LIMITATIONS: The relatively small size of our linkage sample likely limited our ability to reach genome-wide significance in this study. CONCLUSIONS: While not genome-wide significant, these results suggest that aspects of temperament may prove useful in the identification of genes underlying BD susceptibility.


Assuntos
Transtorno Bipolar/genética , Transtorno Bipolar/psicologia , Ligação Genética , Temperamento , Adulto , Comparação Transcultural , Feminino , Estudo de Associação Genômica Ampla , Humanos , Humor Irritável , Masculino , Inventário de Personalidade/estatística & dados numéricos , Polimorfismo de Nucleotídeo Único , Psicometria/estatística & dados numéricos , Reprodutibilidade dos Testes , Inquéritos e Questionários
19.
Am J Med Genet B Neuropsychiatr Genet ; 159B(8): 941-50, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23038240

RESUMO

We have previously reported genome-wide significant linkage of bipolar disorder to a region on 22q12.3 near the marker D22S278. Towards identifying the susceptibility gene, we have conducted a fine-mapping association study of the region in two independent family samples, an independent case-control sample and a genome-wide association dataset. Two hundred SNPs were first examined in a 5 Mb region surrounding the D22S278 marker in a sample of 169 families and analyzed using PLINK. The peak of association was a haplotype near the genes stargazin (CACNG2), intraflagellar transport protein homolog 27 (IFT27) and parvalbumin (PVALB; P = 4.69 × 10(-4)). This peak overlapped a significant haplotype in a family based association study of a second independent sample of 294 families (P = 1.42 × 10(-5)). Analysis of the combined family sample yielded statistically significant evidence of association to a rare three SNP haplotype in the gene IFT27 (P = 8.89 × 10(-6)). Twelve SNPs comprising these haplotypes were genotyped in an independent sample of 574 bipolar I cases and 550 controls. Statistically significant association was found for a haplotype window that overlapped the region from the first two family samples (P = 3.43 × 10(-4)). However, analyses of the two family samples using the program LAMP, found no evidence for association in this region, but did yield significant evidence for association to a haplotype 3' of CACNG2 (P = 1.76 × 10(-6)). Furthermore, no evidence for association was found in a large genome-wide association dataset. The replication of association to overlapping haplotypes in three independent datasets suggests the presence of a bipolar disorder susceptibility gene in this region.


Assuntos
Transtorno Bipolar/genética , Cromossomos Humanos Par 22/genética , Haplótipos , Polimorfismo de Nucleotídeo Único , Canais de Cálcio/genética , Estudos de Casos e Controles , Mapeamento Cromossômico , Ligação Genética , Marcadores Genéticos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Repetições de Microssatélites/genética , Parvalbuminas/genética
20.
Transl Psychiatry ; 2: e165, 2012 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-23010768

RESUMO

Research suggests that clinical symptom dimensions may be more useful in delineating the genetics of bipolar disorder (BD) than standard diagnostic models. To date, no study has applied this concept to data from genome-wide association studies (GWAS). We performed a GWAS of factor dimensions in 927 clinically well-characterized BD patients of German ancestry. Rs9875793, which is located in an intergenic region of 3q26.1 and in the vicinity of the solute carrier family 2 (facilitated glucose transporter), member 2 gene (SLC2A2), was significantly associated with the factor analysis-derived dimension 'negative mood delusions' (n=927; P=4.65 × 10(-8), odds ratio (OR)=2.66). This dimension was comprised of the symptoms delusions of poverty, delusions of guilt and nihilistic delusions. In case-control analyses, significant association with the G allele of rs9875793 was only observed in the subgroup of BD patients who displayed symptoms of 'negative mood delusions' (allelic χ(2) model: P(G)=0.0001, OR=1.92; item present, n=89). Further support for the hypothesis that rs9875793 is associated with BD in patients displaying 'negative mood delusions' symptom, such as delusions of guilt, was obtained from an European American sample (GAIN/TGEN), which included 1247 BD patients and 1434 controls (P(EA)=0.028, OR=1.27).


Assuntos
Transtorno Bipolar/genética , Delusões/genética , Estudo de Associação Genômica Ampla , Transportador de Glucose Tipo 2/genética , Adulto , Alelos , Transtorno Bipolar/diagnóstico , Transtorno Bipolar/psicologia , Estudos de Casos e Controles , Análise Fatorial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
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