Polygenic determinants of white matter volume derived from GWAS lack reproducibility in a replicate sample

A recent publication reported an exciting polygenic effect of schizophrenia (SCZ) risk variants, identified by a large genome-wide association study (GWAS), on total brain and white matter volumes in schizophrenic patients and, even more prominently, in healthy subjects. The aim of the present work was to replicate and then potentially extend these findings. According to the original publication, polygenic risk scores using single nucleotide polymorphism (SNP) information of SCZ GWAS (polygenic SCZ risk scores; PSS) were calculated in 122 healthy subjects, enrolled in a structural magnetic resonance imaging (MRI) study. These scores were computed based on P-values and odds ratios available through the Psychiatric GWAS Consortium. In addition, polygenic white matter scores (PWM) were calculated, using the respective SNP subset in the original publication. None of the polygenic scores, either PSS or PWM, were found to be associated with total brain, white matter or gray matter volume in our replicate sample. Minor differences between the original and the present study that might have contributed to lack of reproducibility (but unlikely explain it fully), are number of subjects, ethnicity, age distribution, array technology, SNP imputation quality and MRI scanner type. In contrast to the original publication, our results do not reveal the slightest signal of association of the described sets of GWAS-identified SCZ risk variants with brain volumes in adults. Caution is indicated in interpreting studies building on polygenic risk scores without replication sample

Genetic Architecture of ADHD and Overlap With Other Psychiatric Disorders And Cognition-Related Phenotypes

Attention-deficit/hyperactivity disorder (ADHD) co-occurs with many other psychiatric disorders and traits. In this review, we summarize and interpret the existing literature on the genetic architecture of these comorbidities based on hypothesis-generating approaches. Quantitative genetic studies indicate that genetic factors play a substantial role in the observed co-occurrence of ADHD with many different disorders and traits. Molecular genetic correlations derived from genome-wide association studies and results of studies based on polygenic risk scores confirm the general pattern but provide effect estimates that are smaller than those from twin studies. The identification of the specific genetic variants and biological pathways underlying co-occurrence using genome-wide approaches is still in its infancy. The first analyses of causal inference using genetic data support causal relationships between ADHD and comorbid disorders, although bidirectional effects identified in some instances point to complex relationships. While several issues in the methodology and inferences from the results are still to be overcome, this review shows that the co-occurrence of ADHD with many psychiatric disorders and traits is genetically interpretable

Smoking cessation improves clinical outcome in severe mental disorders and is modulated by genetic variability at CHRNA5 gene

Smoking has been traditionally tolerated for patients with mental disorders due to its hypothesized self-medication function (Schroeder and Morris, 2010).[...

Combining schizophrenia and depression polygenic risk scores improves the genetic prediction of lithium response in bipolar disorder patients

Lithium is the gold standard therapy for Bipolar Disorder (BD) but its effectiveness differs widely between individuals. The molecular mechanisms underlying treatment response heterogeneity are not well understood, and personalized treatment in BD remains elusive. Genetic analyses of the lithium treatment response phenotype may generate novel molecular insights into lithium's therapeutic mechanisms and lead to testable hypotheses to improve BD management and outcomes. We used fixed effect meta-analysis techniques to develop meta-analytic polygenic risk scores (MET-PRS) from combinations of highly correlated psychiatric traits, namely schizophrenia (SCZ), major depression (MD) and bipolar disorder (BD). We compared the effects of cross-disorder MET-PRS and single genetic trait PRS on lithium response. For the PRS analyses, we included clinical data on lithium treatment response and genetic information for n = 2283 BD cases from the International Consortium on Lithium Genetics (ConLi+Gen; www.ConLiGen.org). Higher SCZ and MD PRSs were associated with poorer lithium treatment response whereas BD-PRS had no association with treatment outcome. The combined MET2-PRS comprising of SCZ and MD variants (MET2-PRS) and a model using SCZ and MD-PRS sequentially improved response prediction, compared to single-disorder PRS or to a combined score using all three traits (MET3-PRS). Patients in the highest decile for MET2-PRS loading had 2.5 times higher odds of being classified as poor responders than patients with the lowest decile MET2-PRS scores. An exploratory functional pathway analysis of top MET2-PRS variants was conducted. Findings may inform the development of future testing strategies for personalized lithium prescribing in BD

HLA-DRB1 and HLA-DQB1 genetic diversity modulates response to lithium in bipolar affective disorders

Bipolar afective disorder (BD) is a severe psychiatric illness, for which lithium (Li) is the gold standard for acute and maintenance therapies. The therapeutic response to Li in BD is heterogeneous and reliable biomarkers allowing patients stratifcation are still needed. A GWAS performed by the International Consortium on Lithium Genetics (ConLiGen) has recently identifed genetic markers associated with treatment responses to Li in the human leukocyte antigens (HLA) region. To better understand the molecular mechanisms underlying this association, we have genetically imputed the classical alleles of the HLA region in the European patients of the ConLiGen cohort. We found our best signal for amino-acid variants belonging to the HLA-DRB1*11:01 classical allele, associated with a better response to Li (p < 1 × ­10−3; FDR< 0.09 in the recessive model). Alanine or Leucine at position 74 of the HLA-DRB1 heavy chain was associated with a good response while Arginine or Glutamic acid with a poor response. As these variants have been implicated in common infammatory/autoimmune processes, our fndings strongly suggest that HLA-mediated low infammatory background may contribute to the efcient response to Li in BD patients, while an infammatory status overriding Li anti-infammatory properties would favor a weak response

Genetic Risk Factors for the Lack of Response to Clinical Treatment in Mental Disorders: an Approach from Pharmacogenetics

[spa] Los trastornos mentales graves, como son la depresión mayor (DM), el trastorno bipolar (TB) y la esquizofrenia (SCZ), se han convertido en los últimos años en un importante problema de salud en los países desarrollados. Aunque el avance alcanzado en el desarrollo de tratamientos farmacológicos ha constituido uno de los grandes logros de la psiquiatría moderna, no debemos olvidar que hay un porcentaje muy alto de pacientes que no reciben el tratamiento adecuado para su enfermedad. En este sentido, la farmacogenética tiene como objetivo identificar y caracterizar los factores genéticos que se encuentran en la base de las diferencias existentes entre individuos en la respuesta clínica al tratamiento farmacológico. La presente tesis pretende estudiar variación genética basada en genes que codifican para moléculas implicadas directamente o indirectamente en los mecanismos de acción del tratamiento con citalopram (DM), carbonato de litio (TB) y clozapina (SCZ) que nos explicará parte del riesgo para la no respuesta clínica y la no remisión del episodio tratado farmacológicamente. Los resultados nos permitieron identificar variación genética asociada a la respuesta al tratamiento. Concretamente, nuestros resultados indicaron que variabilidad genética relacionada con el sistema endocannabinoide se asociaba con la respuesta a citalopram en DM. Por otro lado, genes involucrados con el sistema de fosfoinositoles podrían explican parte de la variación en la respuesta al litio en el TB. En referencia al estudio de la respuesta a clozapina en pacientes con SCZ, los resultados sugieren que variantes genéticas en los genes FKBP5 y NTRK2 pueden jugar un papel en la respuesta. En este sentido, nuestro estudio proporciona evidencia de la implicación del eje hipotálamo-pituitario-adrenal (HPA) y de factores neurotróficos en la modulación de la respuesta a clozapina. La detección de diferencias genéticas individuales en la respuesta a los fármacos psicotrópicos puede proporcionar nuevas estrategias para el tratamiento de trastornos mentales, así como, nuevos conocimientos sobre la etiología de estos trastornos.[eng] Severe mental disorders, such as Major Depressive Disorder (MDD), Bipolar Disorder (BD) and Schizophrenia (SCZ), represent a huge burden to society, reflecting the limited efficacy of current drug treatments. Although the progress in development of pharmacological treatments is one of the great successes of modern psychiatry, it should not be forgotten that a very high percentage of patients do not receive and/or seek the proper treatment for their disease. Individual differences in clinical response to psychotropic drugs have long been recognized as a fundamental problem in the treatment of the seriously mentally ill patient. This variability in individual response ranges from patients who experience complete symptom remission to a subset of patients often describes as “treatment refractory”, as well as a marked variability in susceptibility to adverse drug effects. In this sense, the overall objective of pharmacogenetics is to determine the genetic basis of the variability in drug efficacy and safety, and to use this information to benefit the patient detecting a priori those patients that could not respond to a drug and/or present drug side effects. The present dissertation hypothesizes that lack of response to psychotropic drugs will be associated to genetic variability at genes coding for proteins involved directly or indirectly in the mechanism of action of these drugs. In this sense three different studies have been carried out. The first study analyses genetic variability at genes of the endocannabinoid system in clinical response and/or remission to citalopram treatment in MDD patients. The second study analyses genetic variability at genes related to phosphoinositide (PI), glycogen synthetase kinase-3 (GSK3), hypothalamic-pituitary-adrenal (HPA) and glutamatergic pathways in clinical response to lithium in BD patients. The third study analyses genetic variability at genes related to neurotrophic factors and HPA in clinical response to clozapine in patients with SCZ. Our results focused in the analyses of genetic variability at genes coding for proteins involved in the mechanism of action of psychotropic drugs let us to detect some minor and moderate effects of genetic variants that could explain, at least, part of the lack of response to these drugs. The results of our study in relation to citalopram response in MDD showed that genetic variability at genes related to the endocannabinoid system could play a role in the understanding of clinical response to this drug treatment. Specifically, we found an association between CNR1 gene and clinical remission at 12th week and an effect of CNR1 gene on longitudinal response (along the 12th week follow-up). The results of our study in relation to lithium response in BD showed that genetic variability at INPP1, IMPA2, GSK3B and GRIK2 genes could play a role in the understanding of lithium response. Finally, the results in relation to clozapine response in SCZ showed that genetic variants at FKBP5 and NTRK2 genes may play a role in clozapine response. The detection of individual genetic differences in the response to psychotropic drugs may provide new strategies for the treatment of mental disorders, as well as, new knowledge about the aetiology of these disorders

Polygenic determinants of white matter volume derived from GWAS lack reproducibility in a replicate sample

A recent publication reported an exciting polygenic effect of schizophrenia (SCZ) risk variants, identified by a large genome-wide association study (GWAS), on total brain and white matter volumes in schizophrenic patients and, even more prominently, in healthy subjects. The aim of the present work was to replicate and then potentially extend these findings. According to the original publication, polygenic risk scores using single nucleotide polymorphism (SNP) information of SCZ GWAS (polygenic SCZ risk scores; PSS) were calculated in 122 healthy subjects, enrolled in a structural magnetic resonance imaging (MRI) study. These scores were computed based on P-values and odds ratios available through the Psychiatric GWAS Consortium. In addition, polygenic white matter scores (PWM) were calculated, using the respective SNP subset in the original publication. None of the polygenic scores, either PSS or PWM, were found to be associated with total brain, white matter or gray matter volume in our replicate sample. Minor differences between the original and the present study that might have contributed to lack of reproducibility (but unlikely explain it fully), are number of subjects, ethnicity, age distribution, array technology, SNP imputation quality and MRI scanner type. In contrast to the original publication, our results do not reveal the slightest signal of association of the described sets of GWAS-identified SCZ risk variants with brain volumes in adults. Caution is indicated in interpreting studies building on polygenic risk scores without replication sample

Predicting Response Trajectories during Cognitive-Behavioural Therapy for Panic Disorder: No Association with the BDNF Gene or Childhood Maltreatment.

BACKGROUND: Anxiety disorders are highly prevalent and result in low quality of life and a high social and economic cost. The efficacy of cognitive-behavioural therapy (CBT) for anxiety disorders is well established, but a substantial proportion of patients do not respond to this treatment. Understanding which genetic and environmental factors are responsible for this differential response to treatment is a key step towards 'personalized medicine'. Based on previous research, our objective was to test whether the BDNF Val66Met polymorphism and/or childhood maltreatment are associated with response trajectories during exposure-based CBT for panic disorder (PD). METHOD: We used Growth Mixture Modeling to identify latent classes of change (response trajectories) in patients with PD (N = 97) who underwent group manualized exposure-based CBT. We conducted logistic regression to investigate the effect on these trajectories of the BDNF Val66Met polymorphism and two different types of childhood maltreatment, abuse and neglect. RESULTS: We identified two response trajectories ('high response' and 'low response'), and found that they were not significantly associated with either the genetic (BDNF Val66Met polymorphism) or childhood trauma-related variables of interest, nor with an interaction between these variables. CONCLUSIONS: We found no evidence to support an effect of the BDNF gene or childhood trauma-related variables on CBT outcome in PD. Future studies in this field may benefit from looking at other genotypes or using different (e.g. whole-genome) approaches