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1.
Mol Psychiatry ; 2021 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-33483693

RESUMO

Although large genome-wide association studies (GWAS) of major depressive disorder (MDD) have identified many significant loci, the SNP-based heritability remains notably low, which might be due to etiological heterogeneity in existing samples. Here, we test the utility of targeting the severe end of the MDD spectrum through genome-wide SNP genotyping of 2725 cases who received electroconvulsive therapy (ECT) for a major depressive episode (MDE) and 4035 controls. A subset of cases (n = 1796) met a narrow case definition (MDE occurring in the context of MDD). Standard GWAS quality control procedures and imputation were conducted. SNP heritability and genetic correlations with other traits were estimated using linkage disequilibrium score regression. Results were compared with MDD cases of mild-moderate severity receiving internet-based cognitive behavioral therapy (iCBT) and summary results from the Psychiatric Genomics Consortium (PGC). The SNP-based heritability was estimated at 29-34% (SE: 6%) for the narrow case definition, considerably higher than the 6.5-8.0% estimate in the most recent PGC MDD study. Our severe MDE cases had smaller genetic correlations with neurodevelopmental disorders and neuroticism than PGC MDD cases but higher genetic risk scores for bipolar disorder than iCBT MDD cases. One genome-wide significant locus was identified (rs114583506, P = 5e-8) in an intron of HLA-B in the major histocompatibility locus on chr6. These results indicate that individuals receiving ECT for an MDE have higher burden of common variant risk loci than individuals with mild-moderate MDD. Furthermore, severe MDE shows stronger relations with other severe adult-onset psychiatric disorders but weaker relations with personality and stress-related traits than mild-moderate MDD. These findings suggest a different genetic architecture at the severest end of the spectrum, and support further study of the severest MDD cases as an extreme phenotype approach to understand the etiology of MDD.

2.
Am J Med Genet B Neuropsychiatr Genet ; 183(1): 38-50, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31424634

RESUMO

Obsessive-compulsive disorder (OCD) is a debilitating psychiatric disorder, yet its etiology is unknown and treatment outcomes could be improved if biological targets could be identified. Unfortunately, genetic findings for OCD are lagging behind other psychiatric disorders. Thus, there is a pressing need to understand the causal mechanisms implicated in OCD in order to improve clinical outcomes and to reduce morbidity and societal costs. Specifically, there is a need for a large-scale, etiologically informative genetic study integrating genetic and environmental factors that presumably interact to cause the condition. The Nordic countries provide fertile ground for such a study, given their detailed population registers, national healthcare systems and active specialist clinics for OCD. We thus formed the Nordic OCD and Related Disorders Consortium (NORDiC, www.crowleylab.org/nordic), and with the support of NIMH and the Swedish Research Council, have begun to collect a large, richly phenotyped and genotyped sample of OCD cases. Our specific aims are geared toward answering a number of key questions regarding the biology, etiology, and treatment of OCD. This article describes and discusses the rationale, design, and methodology of NORDiC, including details on clinical measures and planned genomic analyses.

3.
Transl Psychiatry ; 9(1): 150, 2019 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-31123309

RESUMO

Major depressive disorder and the anxiety disorders are highly prevalent, disabling and moderately heritable. Depression and anxiety are also highly comorbid and have a strong genetic correlation (rg ≈ 1). Cognitive behavioural therapy is a leading evidence-based treatment but has variable outcomes. Currently, there are no strong predictors of outcome. Therapygenetics research aims to identify genetic predictors of prognosis following therapy. We performed genome-wide association meta-analyses of symptoms following cognitive behavioural therapy in adults with anxiety disorders (n = 972), adults with major depressive disorder (n = 832) and children with anxiety disorders (n = 920; meta-analysis n = 2724). We estimated the variance in therapy outcomes that could be explained by common genetic variants (h2SNP) and polygenic scoring was used to examine genetic associations between therapy outcomes and psychopathology, personality and learning. No single nucleotide polymorphisms were strongly associated with treatment outcomes. No significant estimate of h2SNP could be obtained, suggesting the heritability of therapy outcome is smaller than our analysis was powered to detect. Polygenic scoring failed to detect genetic overlap between therapy outcome and psychopathology, personality or learning. This study is the largest therapygenetics study to date. Results are consistent with previous, similarly powered genome-wide association studies of complex traits.


Assuntos
Transtornos de Ansiedade/genética , Transtornos de Ansiedade/terapia , Terapia Cognitivo-Comportamental/estatística & dados numéricos , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/terapia , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Adulto , Criança , Humanos
4.
Mol Psychiatry ; 24(4): 484-490, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30410065

RESUMO

Major depressive disorder is heritable and a leading cause of disability. Cognitive behavior therapy is an effective treatment for major depression. By quantifying genetic risk scores based on common genetic variants, the aim of this report was to explore the utility of psychiatric and cognitive trait genetic risk scores, for predicting the response of 894 adults with major depressive disorder to cognitive behavior therapy. The participants were recruited in a psychiatric setting, and the primary outcome score was measured using the Montgomery Åsberg Depression Rating Scale-Self Rated. Single-nucleotide polymorphism genotyping arrays were used to calculate the genomic risk scores based on large genetic studies of six phenotypes: major depressive disorder, bipolar disorder, attention-deficit/hyperactivity disorder, autism spectrum disorder, intelligence, and educational attainment. Linear mixed-effect models were used to test the relationships between the six genetic risk scores and cognitive behavior therapy outcome. Our analyses yielded one significant interaction effect (B = 0.09, p < 0.001): the autism spectrum disorder genetic risk score correlated with Montgomery Åsberg Depression Rating Scale-Self Rated changes during treatment, and the higher the autism spectrum disorder genetic load, the less the depressive symptoms decreased over time. The genetic risk scores for the other psychiatric and cognitive traits were not related to depressive symptom severity or change over time. Our preliminary results indicated, as expected, that the genomics of the response of patients with major depression to cognitive behavior therapy were complex and that future efforts should aim to maximize sample size and limit subject heterogeneity in order to gain a better understanding of the use of genetic risk factors to predict treatment outcome.


Assuntos
Terapia Cognitivo-Comportamental/métodos , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/terapia , Adulto , Transtorno do Deficit de Atenção com Hiperatividade , Transtorno do Espectro Autista , Biomarcadores , Depressão/genética , Transtorno Depressivo Maior/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Herança Multifatorial/genética , Dados Preliminares , Prognóstico , Escalas de Graduação Psiquiátrica , Resultado do Tratamento
5.
Behav Ther ; 48(3): 391-402, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28390501

RESUMO

Worry is a common phenotype in both psychiatric patients and the normal population. Worry can be seen as a covert behavior with primary function to avoid aversive emotional experiences. Our research group has developed a treatment protocol based on an operant model of worry, where we use exposure-based strategies to extinguish the catastrophic worry thoughts. The aim of this study was to test this treatment delivered via the Internet in a large-scale randomized controlled trial. We randomized 140 high-worriers (defined as > 56 on the Penn State Worry Questionnaire [PSWQ]) to either Internet-based extinction therapy (IbET) or to a waiting-list condition (WL). Results showed that IbET was superior to WL with an overall large between-group effect size of d = 1.39 (95% confidence interval [1.04,1.73]) on the PSWQ. In the IbET group, 58% were classified as responders. The corresponding figure for WL participants was 7%. IbET was also superior to the WL on secondary outcome measures of anxiety, depression, meta-cognitions, cognitive avoidance, and quality of life. Overall treatment results were maintained for the IbET group at 4- and 12-month follow-up. The results from this trial are encouraging as they indicate that worry can be targeted with an accessible and novel intervention for worry. Replication trials with active control group are needed.


Assuntos
Ansiedade/terapia , Terapia Comportamental/métodos , Extinção Psicológica , Internet , Telemedicina/métodos , Terapia Assistida por Computador/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Ansiedade/diagnóstico , Ansiedade/psicologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Resultado do Tratamento , Adulto Jovem
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