Constitutive serotonin transporter reduction resembles maternal separation with regard to stress-related gene expression

Interactive effects between allelic variants of the serotonin transporter (5-HTT) promoter-linked polymorphic region (5-HTTLPR) and stressors on depression symptoms have been documented, as well as questioned, by meta-analyses. Translational models of constitutive 5-htt reduction and experimentally controlled stressors often led to inconsistent behavioral and molecular findings, and often did not include females. The present study sought to investigate the effect of 5-htt genotype, maternal separation, and sex on the expression of stress-related candidate genes in the rat hippocampus and frontal cortex. The mRNA expression levels of Avp, Pomc, Crh, Crhbp, Crhr1, Bdnf, Ntrk2, Maoa, Maob, and Comt were assessed in the hippocampus and frontal cortex of 5-htt +/- and 5-htt +/+ male and female adult rats exposed, or not, to daily maternal separation for 180 minutes during the first two postnatal weeks. Gene- and brain region-dependent, but sex-independent, interactions between 5-htt genotype and maternal separation were found. Gene expression levels were higher in 5-htt +/+ rats not exposed to maternal separation compared to the other experimental groups. Maternal separation and 5-htt +/- genotype did not yield additive effects on gene expression. Correlative relationships, mainly positive, were observed within, but not across, brain regions in all groups, except in non-maternally separated 5-htt +/+ rats. Gene expression patterns in the hippocampus and frontal cortex of rats exposed to maternal separation resembled the ones observed in rats with reduced 5-htt expression, regardless of sex. These results suggest that floor effects of 5-htt reduction and maternal separation might explain inconsistent findings in humans and rodents.</p

Analysis of shared common genetic risk between amyotrophic lateral sclerosis and epilepsy

Peer reviewe

Phenome-wide and genome-wide analyses of quality of life in schizophrenia

This article has been published in a revised form in BJPsych Open [http://doi.org/10.1192/bjo.2020.140]. This version is free to view and download for private research and study only. Not for re-distribution or re-use. © copyright holder.Background Schizophrenia negatively affects quality of life (QoL). A handful of variables from small studies have been reported to influence QoL in patients with schizophrenia, but a study comprehensively dissecting the genetic and non-genetic contributing factors to QoL in these patients is currently lacking. Aims We adopted a hypothesis-generating approach to assess the phenotypic and genotypic determinants of QoL in schizophrenia. Method The study population comprised 1119 patients with a psychotic disorder, 1979 relatives and 586 healthy controls. Using linear regression, we tested >100 independent demographic, cognitive and clinical phenotypes for their association with QoL in patients. We then performed genome-wide association analyses of QoL and examined the association between polygenic risk scores for schizophrenia, major depressive disorder and subjective well-being and QoL. Results We found nine phenotypes to be significantly and independently associated with QoL in patients, the most significant ones being negative (β = −1.17; s.e. 0.05; P = 1 × 10–83; r2 = 38%), depressive (β = −1.07; s.e. 0.05; P = 2 × 10–79; r2 = 36%) and emotional distress (β = −0.09; s.e. 0.01; P = 4 × 10–59, r2 = 25%) symptoms. Schizophrenia and subjective well-being polygenic risk scores, using various P-value thresholds, were significantly and consistently associated with QoL (lowest association P-value = 6.8 × 10–6). Several sensitivity analyses confirmed the results. Conclusions Various clinical phenotypes of schizophrenia, as well as schizophrenia and subjective well-being polygenic risk scores, are associated with QoL in patients with schizophrenia and their relatives. These may be targeted by clinicians to more easily identify vulnerable patients with schizophrenia for further social and clinical interventions to improve their QoL.Dutch Health Research Council; Lundbeck; AstraZeneca; Eli Lilly; Janssen Cilag;Amsterdam: Academic Psychiatric Centre of the Academic Medical Center and the mental health institutions at Geestelijke Gezondheidszorg (GGZ) Ingeest; Arkin; Dijk en Duin; GGZ Rivierduinen; Erasmus Medical Centre and GGZ Noord Holland Noord; Groningen: University Medical Center Groningen and the mental health institutions at Lentis; GGZ Friesland; GGZ Drenthe; Dimence; Mediant; GGNet Warnsveld; Yulius Dordrecht and Parnassia Psycho-Medical Center The Hague; Maastricht: Maastricht University Medical Centre and the mental health institutions at GGZ Eindhoven en De Kempen; GGZ Breburg; GGZ Oost-Brabant; Vincent van Gogh voor Geestelijke Gezondheid; Mondriaan; Virenze riagg; Zuyderland GGZ; MET ggz; Universitair Centrum Sint-Jozef Kortenberg; Collaborative Antwerp Psychiatric Research Institute University of Antwerp; Psychiatrisch Centrum Ziekeren Sint-Truiden; Psychiatrisch Ziekenhuis Sancta Maria Sint-Truiden; GGZ Overpelt and Openbaar Psychiatrisch Zorgcentrum Rekem; Utrecht: University Medical Center Utrecht and the mental health institutions Altrecht; GGZ Centraal and Delt

Inherited variants in CHD3 show variable expressivity in Snijders Blok-Campeau syndrome

Purpose: Common diagnostic next-generation sequencing strategies are not optimized to identify inherited variants in genes associated with dominant neurodevelopmental disorders as causal when the transmitting parent is clinically unaffected, leaving a significant number of cases with neurodevelopmental disorders undiagnosed. Methods: We characterized 21 families with inherited heterozygous missense or protein-truncating variants in CHD3, a gene in which de novo variants cause Snijders Blok-Campeau syndrome. Results: Computational facial and Human Phenotype Ontology–based comparisons showed that the phenotype of probands with inherited CHD3 variants overlaps with the phenotype previously associated with de novo CHD3 variants, whereas heterozygote parents are mildly or not affected, suggesting variable expressivity. In addition, similarly reduced expression levels of CHD3 protein in cells of an affected proband and of healthy family members with a CHD3 protein-truncating variant suggested that compensation of expression from the wild-type allele is unlikely to be an underlying mechanism. Notably, most inherited CHD3 variants were maternally transmitted. Conclusion: Our results point to a significant role of inherited variation in Snijders Blok-Campeau syndrome, a finding that is critical for correct variant interpretation and genetic counseling and warrants further investigation toward understanding the broader contributions of such variation to the landscape of human disease

Enhancing Discovery of Genetic Variants for Posttraumatic Stress Disorder Through Integration of Quantitative Phenotypes and Trauma Exposure Information

Funding Information: This work was supported by the National Institute of Mental Health / U.S. Army Medical Research and Development Command (Grant No. R01MH106595 [to CMN, IL, MBS, KJRe, and KCK], National Institutes of Health (Grant No. 5U01MH109539 to the Psychiatric Genomics Consortium ), and Brain & Behavior Research Foundation (Young Investigator Grant [to KWC]). Genotyping of samples was provided in part through the Stanley Center for Psychiatric Genetics at the Broad Institute supported by Cohen Veterans Bioscience . Statistical analyses were carried out on the LISA/Genetic Cluster Computer ( https://userinfo.surfsara.nl/systems/lisa ) hosted by SURFsara. This research has been conducted using the UK Biobank resource (Application No. 41209). This work would have not been possible without the financial support provided by Cohen Veterans Bioscience, the Stanley Center for Psychiatric Genetics at the Broad Institute, and One Mind. Funding Information: MBS has in the past 3 years received consulting income from Actelion, Acadia Pharmaceuticals, Aptinyx, Bionomics, BioXcel Therapeutics, Clexio, EmpowerPharm, GW Pharmaceuticals, Janssen, Jazz Pharmaceuticals, and Roche/Genentech and has stock options in Oxeia Biopharmaceuticals and Epivario. In the past 3 years, NPD has held a part-time paid position at Cohen Veterans Bioscience, has been a consultant for Sunovion Pharmaceuticals, and is on the scientific advisory board for Sentio Solutions for unrelated work. In the past 3 years, KJRe has been a consultant for Datastat, Inc., RallyPoint Networks, Inc., Sage Pharmaceuticals, and Takeda. JLM-K has received funding and a speaking fee from COMPASS Pathways. MU has been a consultant for System Analytic. HRK is a member of the Dicerna scientific advisory board and a member of the American Society of Clinical Psychopharmacology Alcohol Clinical Trials Initiative, which during the past 3 years was supported by Alkermes, Amygdala Neurosciences, Arbor Pharmaceuticals, Dicerna, Ethypharm, Indivior, Lundbeck, Mitsubishi, and Otsuka. HRK and JG are named as inventors on Patent Cooperative Treaty patent application number 15/878,640, entitled “Genotype-guided dosing of opioid agonists,” filed January 24, 2018. RP and JG are paid for their editorial work on the journal Complex Psychiatry. OAA is a consultant to HealthLytix. All other authors report no biomedical financial interests or potential conflicts of interest. Funding Information: This work was supported by the National Institute of Mental Health/ U.S. Army Medical Research and Development Command (Grant No. R01MH106595 [to CMN, IL, MBS, KJRe, and KCK], National Institutes of Health (Grant No. 5U01MH109539 to the Psychiatric Genomics Consortium), and Brain & Behavior Research Foundation (Young Investigator Grant [to KWC]). Genotyping of samples was provided in part through the Stanley Center for Psychiatric Genetics at the Broad Institute supported by Cohen Veterans Bioscience. Statistical analyses were carried out on the LISA/Genetic Cluster Computer (https://userinfo.surfsara.nl/systems/lisa) hosted by SURFsara. This research has been conducted using the UK Biobank resource (Application No. 41209). This work would have not been possible without the financial support provided by Cohen Veterans Bioscience, the Stanley Center for Psychiatric Genetics at the Broad Institute, and One Mind. This material has been reviewed by the Walter Reed Army Institute of Research. There is no objection to its presentation and/or publication. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting true views of the U.S. Department of the Army or the Department of Defense. We thank the investigators who comprise the PGC-PTSD working group and especially the more than 206,000 research participants worldwide who shared their life experiences and biological samples with PGC-PTSD investigators. We thank Mark Zervas for his critical input. Full acknowledgments are in Supplement 1. MBS has in the past 3 years received consulting income from Actelion, Acadia Pharmaceuticals, Aptinyx, Bionomics, BioXcel Therapeutics, Clexio, EmpowerPharm, GW Pharmaceuticals, Janssen, Jazz Pharmaceuticals, and Roche/Genentech and has stock options in Oxeia Biopharmaceuticals and Epivario. In the past 3 years, NPD has held a part-time paid position at Cohen Veterans Bioscience, has been a consultant for Sunovion Pharmaceuticals, and is on the scientific advisory board for Sentio Solutions for unrelated work. In the past 3 years, KJRe has been a consultant for Datastat, Inc. RallyPoint Networks, Inc. Sage Pharmaceuticals, and Takeda. JLM-K has received funding and a speaking fee from COMPASS Pathways. MU has been a consultant for System Analytic. HRK is a member of the Dicerna scientific advisory board and a member of the American Society of Clinical Psychopharmacology Alcohol Clinical Trials Initiative, which during the past 3 years was supported by Alkermes, Amygdala Neurosciences, Arbor Pharmaceuticals, Dicerna, Ethypharm, Indivior, Lundbeck, Mitsubishi, and Otsuka. HRK and JG are named as inventors on Patent Cooperative Treaty patent application number 15/878,640, entitled ?Genotype-guided dosing of opioid agonists,? filed January 24, 2018. RP and JG are paid for their editorial work on the journal Complex Psychiatry. OAA is a consultant to HealthLytix. All other authors report no biomedical financial interests or potential conflicts of interest. Publisher Copyright: © 2021 Society of Biological PsychiatryBackground: Posttraumatic stress disorder (PTSD) is heritable and a potential consequence of exposure to traumatic stress. Evidence suggests that a quantitative approach to PTSD phenotype measurement and incorporation of lifetime trauma exposure (LTE) information could enhance the discovery power of PTSD genome-wide association studies (GWASs). Methods: A GWAS on PTSD symptoms was performed in 51 cohorts followed by a fixed-effects meta-analysis (N = 182,199 European ancestry participants). A GWAS of LTE burden was performed in the UK Biobank cohort (N = 132,988). Genetic correlations were evaluated with linkage disequilibrium score regression. Multivariate analysis was performed using Multi-Trait Analysis of GWAS. Functional mapping and annotation of leading loci was performed with FUMA. Replication was evaluated using the Million Veteran Program GWAS of PTSD total symptoms. Results: GWASs of PTSD symptoms and LTE burden identified 5 and 6 independent genome-wide significant loci, respectively. There was a 72% genetic correlation between PTSD and LTE. PTSD and LTE showed largely similar patterns of genetic correlation with other traits, albeit with some distinctions. Adjusting PTSD for LTE reduced PTSD heritability by 31%. Multivariate analysis of PTSD and LTE increased the effective sample size of the PTSD GWAS by 20% and identified 4 additional loci. Four of these 9 PTSD loci were independently replicated in the Million Veteran Program. Conclusions: Through using a quantitative trait measure of PTSD, we identified novel risk loci not previously identified using prior case-control analyses. PTSD and LTE have a high genetic overlap that can be leveraged to increase discovery power through multivariate methods.publishersversionpublishe

Genetic correlation between amyotrophic lateral sclerosis and schizophrenia

A. Palotie on työryhmän Schizophrenia Working Grp Psychiat jäsen.We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05-21.6; P = 1 x 10(-4)) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P = 8.4 x 10(-7)). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08-1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies.Peer reviewe

Rare copy number variation in posttraumatic stress disorder

Posttraumatic stress disorder (PTSD) is a heritable (h2 = 24-71%) psychiatric illness. Copy number variation (CNV) is a form of rare genetic variation that has been implicated in the etiology of psychiatric disorders, but no large-scale investigation of CNV in PTSD has been performed. We present an association study of CNV burden and PTSD symptoms in a sample of 114,383 participants (13,036 cases and 101,347 controls) of European ancestry. CNVs were called using two calling algorithms and intersected to a consensus set. Quality control was performed to remove strong outlier samples. CNVs were examined for association with PTSD within each cohort using linear or logistic regression analysis adjusted for population structure and CNV quality metrics, then inverse variance weighted meta-analyzed across cohorts. We examined the genome-wide total span of CNVs, enrichment of CNVs within specified gene-sets, and CNVs overlapping individual genes and implicated neurodevelopmental regions. The total distance covered by deletions crossing over known neurodevelopmental CNV regions was significant (beta = 0.029, SE = 0.005, P = 6.3 × 10-8). The genome-wide neurodevelopmental CNV burden identified explains 0.034% of the variation in PTSD symptoms. The 15q11.2 BP1-BP2 microdeletion region was significantly associated with PTSD (beta = 0.0206, SE = 0.0056, P = 0.0002). No individual significant genes interrupted by CNV were identified. 22 gene pathways related to the function of the nervous system and brain were significant in pathway analysis (FDR q < 0.05), but these associations were not significant once NDD regions were removed. A larger sample size, better detection methods, and annotated resources of CNV are needed to explore this relationship further

Single- and cross-disorder genome-wide studies in psychiatry and neurology

Most psychiatric and neurological disorders are characterized by a complex genetic background where many common variants (single-nucleotide polymorphisms, SNPs) show an association to disease. Nowadays, we are able to obtain the genotypes of millions of SNPs through array-based genotyping and genotype imputation, and compare allele frequencies between large groups of cases and healthy controls in a statistical framework called a genome-wide association study (GWAS). With GWAS, genetic variation can be linked to – and ultimately provide insight into – the development of disease. This thesis aims to further unravel the role of common genetic variation in complex psychiatric and neurological diseases and describes a variety of findings. First, using results from large GWAS in schizophrenia, further insight was provided into the role of common genetic variants in the synapse through comprehensive gene set and pathway enrichment analyses. Second, in a multivariate GWAS of quantitative phenotypes related to stress and trauma-induced psychopathology, a genetic locus was discovered that is possibly involved in the stress response. Additionally, this locus was functionally linked to genes involved in various stress-related conditions. This study furthermore shows the potential of using accurately measured quantitative phenotypes instead of a binary clinical diagnosis as a phenotype in GWAS. Third, it was found that using polygenic risk scores capturing the combined effect of SNPs associated with posttraumatic stress disorder and depression, we are currently unable to predict the risk for developing these disorders after exposure to deployment stress, also when assessing the interaction between genetic risk and exposure to traumatic events. Finally, the genetic overlap between diseases was explored and the clinical relevance of genetic cross-disorder studies was outlined. Cross-disorder genetic analysis showed that common genetic risk for amyotrophic lateral sclerosis (ALS) partly overlaps with common genetic risk for schizophrenia. This genetic correlation is relevant in light of an increased neuropsychiatric burden in families of ALS patients and the occurrence of cognitive impairment as a symptom in ALS. Furthermore, ALS patients can suffer from cramps and fasciculations, caused by hyperexcitability in motor neurons. Similarly, hyperexcitability of the nervous system plays a major role in epilepsy. We therefore assessed the genetic overlap between these two neurological conditions, but found that ALS and epilepsy do not share polygenic risk

Single- and cross-disorder genome-wide studies in psychiatry and neurology

Most psychiatric and neurological disorders are characterized by a complex genetic background where many common variants (single-nucleotide polymorphisms, SNPs) show an association to disease. Nowadays, we are able to obtain the genotypes of millions of SNPs through array-based genotyping and genotype imputation, and compare allele frequencies between large groups of cases and healthy controls in a statistical framework called a genome-wide association study (GWAS). With GWAS, genetic variation can be linked to – and ultimately provide insight into – the development of disease. This thesis aims to further unravel the role of common genetic variation in complex psychiatric and neurological diseases and describes a variety of findings. First, using results from large GWAS in schizophrenia, further insight was provided into the role of common genetic variants in the synapse through comprehensive gene set and pathway enrichment analyses. Second, in a multivariate GWAS of quantitative phenotypes related to stress and trauma-induced psychopathology, a genetic locus was discovered that is possibly involved in the stress response. Additionally, this locus was functionally linked to genes involved in various stress-related conditions. This study furthermore shows the potential of using accurately measured quantitative phenotypes instead of a binary clinical diagnosis as a phenotype in GWAS. Third, it was found that using polygenic risk scores capturing the combined effect of SNPs associated with posttraumatic stress disorder and depression, we are currently unable to predict the risk for developing these disorders after exposure to deployment stress, also when assessing the interaction between genetic risk and exposure to traumatic events. Finally, the genetic overlap between diseases was explored and the clinical relevance of genetic cross-disorder studies was outlined. Cross-disorder genetic analysis showed that common genetic risk for amyotrophic lateral sclerosis (ALS) partly overlaps with common genetic risk for schizophrenia. This genetic correlation is relevant in light of an increased neuropsychiatric burden in families of ALS patients and the occurrence of cognitive impairment as a symptom in ALS. Furthermore, ALS patients can suffer from cramps and fasciculations, caused by hyperexcitability in motor neurons. Similarly, hyperexcitability of the nervous system plays a major role in epilepsy. We therefore assessed the genetic overlap between these two neurological conditions, but found that ALS and epilepsy do not share polygenic risk