Genome-wide association study identifies new loci associated with OCD.

To date, four genome-wide association studies (GWAS) of obsessive-compulsive disorder (OCD) have been published, reporting a high single-nucleotide polymorphism (SNP)-heritability of 28% but finding only one significant SNP. A substantial increase in sample size will likely lead to further identification of SNPs, genes, and biological pathways mediating the susceptibility to OCD. We conducted a GWAS meta-analysis with a 2-3-fold increase in case sample size (OCD cases: N = 37,015, controls: N = 948,616) compared to the last OCD GWAS, including six previously published cohorts (OCGAS, IOCDF-GC, IOCDF-GC-trio, NORDiC-nor, NORDiC-swe, and iPSYCH) and unpublished self-report data from 23andMe Inc. We explored the genetic architecture of OCD by conducting gene-based tests, tissue and celltype enrichment analyses, and estimating heritability and genetic correlations with 74 phenotypes. To examine a potential heterogeneity in our data, we conducted multivariable GWASs with MTAG. We found support for 15 independent genome-wide significant loci (14 new) and 79 protein-coding genes. Tissue enrichment analyses implicate multiple cortical regions, the amygdala, and hypothalamus, while cell type analyses yielded 12 cell types linked to OCD (all neurons). The SNP-based heritability of OCD was estimated to be 0.08. Using MTAG we found evidence for specific genetic underpinnings characteristic of different cohort-ascertainment and identified additional significant SNPs. OCD was genetically correlated with 40 disorders or traits-positively with all psychiatric disorders and negatively with BMI, age at first birth and multiple autoimmune diseases. The GWAS meta-analysis identified several biologically informative genes as important contributors to the aetiology of OCD. Overall, we have begun laying the groundwork through which the biology of OCD will be understood and described.

Genome-Wide Association Study of Obsessive-Compulsive Symptoms including 33,943 individuals from the general population.

While 1-2% of individuals meet the criteria for a clinical diagnosis of obsessive-compulsive disorder (OCD), many more (~13-38%) experience subclinical obsessive-compulsive symptoms (OCS) during their life. To characterize the genetic underpinnings of OCS and its genetic relationship to OCD, we conducted the largest genome-wide association study (GWAS) meta-analysis of parent- or self-reported OCS to date (N = 33,943 with complete phenotypic and genome-wide data), combining the results from seven large-scale population-based cohorts from Sweden, the Netherlands, England, and Canada (including six twin cohorts and one cohort of unrelated individuals). We found no genome-wide significant associations at the single-nucleotide polymorphism (SNP) or gene-level, but a polygenic risk score (PRS) based on the OCD GWAS previously published by the Psychiatric Genetics Consortium (PGC-OCD) was significantly associated with OCS (Pfixed = 3.06 × 10-5). Also, one curated gene set (Mootha Gluconeogenesis) reached Bonferroni-corrected significance (Ngenes = 28, Beta = 0.79, SE = 0.16, Pbon = 0.008). Expression of genes in this set is high at sites of insulin mediated glucose disposal. Dysregulated insulin signaling in the etiology of OCS has been suggested by a previous study describing a genetic overlap of OCS with insulin signaling-related traits in children and adolescents. We report a SNP heritability of 4.1% (P = 0.0044) in the meta-analyzed GWAS, and heritability estimates based on the twin cohorts of 33-43%. Genetic correlation analysis showed that OCS were most strongly associated with OCD (rG = 0.72, p = 0.0007) among all tested psychiatric disorders (N = 11). Of all 97 tested phenotypes, 24 showed a significant genetic correlation with OCS, and 66 traits showed concordant directions of effect with OCS and OCD. OCS have a significant polygenic contribution and share genetic risk with diagnosed OCD, supporting the hypothesis that OCD represents the extreme end of widely distributed OCS in the population.

The Relationship of Attention-Deficit/Hyperactivity Disorder With Posttraumatic Stress Disorder: A Two-Sample Mendelian Randomization and Population-Based Sibling Comparison Study.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) and posttraumatic stress disorder (PTSD) are associated, but it is unclear if this is a causal relationship or confounding. We used genetic analyses and sibling comparisons to clarify the direction of this relationship. METHODS: Linkage disequilibrium score regression and 2-sample Mendelian randomization were used to test for genetic correlation (rg) and bidirectional causal effects using European ancestry genome-wide association studies of ADHD (20,183 cases and 35,191 controls) and 6 PTSD definitions (up to 320,369 individuals). Several additional variables were included in the analysis to verify the independence of the ADHD-PTSD relationship. In a population-based sibling comparison (N = 2,082,118 individuals), Cox regression models were fitted to account for time at risk, a range of sociodemographic factors, and unmeasured familial confounders (via sibling comparisons). RESULTS: ADHD and PTSD had consistent rg (rg range, 0.43-0.52; p < .001). ADHD genetic liability was causally linked with increased risk for PTSD (ß = 0.367; 95% CI, 0.186-0.552; p = 7.68 × 10-5). This result was not affected by heterogeneity, horizontal pleiotropy (Mendelian randomization Egger intercept = 4.34 × 10-4, p = .961), or other phenotypes and was consistent across PTSD datasets. However, we found no consistent associations between PTSD genetic liability and ADHD risk. Individuals diagnosed with ADHD were at a higher risk for developing PTSD than their undiagnosed sibling (hazard ratio = 2.37; 95% CI, 1.98-3.53). CONCLUSIONS: Our findings add novel evidence supporting the need for early and effective treatment of ADHD, as patients with this diagnosis are at significantly higher risk to develop PTSD later in life.

Meta-analysis of genome-wide association studies of hoarding symptoms in 27,537 individuals.

Hoarding Disorder (HD) is a mental disorder characterized by persistent difficulties discarding or parting with possessions, often resulting in cluttered living spaces, distress, and impairment. Its etiology is largely unknown, but twin studies suggest that it is moderately heritable. In this study, we pooled phenotypic and genomic data from seven international cohorts (N = 27,537 individuals) and conducted a genome wide association study (GWAS) meta-analysis of parent- or self-reported hoarding symptoms (HS). We followed up the results with gene-based and gene-set analyses, as well as leave-one-out HS polygenic risk score (PRS) analyses. To examine a possible genetic association between hoarding symptoms and other phenotypes we conducted cross-trait PRS analyses. Though we did not report any genome-wide significant SNPs, we report heritability estimates for the twin-cohorts between 26-48%, and a SNP-heritability of 11% for an unrelated sub-cohort. Cross-trait PRS analyses showed that the genetic risk for schizophrenia and autism spectrum disorder were significantly associated with hoarding symptoms. We also found suggestive evidence for an association with educational attainment. There were no significant associations with other phenotypes previously linked to HD, such as obsessive-compulsive disorder, depression, anxiety, or attention-deficit hyperactivity disorder. To conclude, we found that HS are heritable, confirming and extending previous twin studies but we had limited power to detect any genome-wide significant loci. Much larger samples will be needed to further extend these findings and reach a "gene discovery zone". To move the field forward, future research should not only include genetic analyses of quantitative hoarding traits in larger samples, but also in samples of individuals meeting strict diagnostic criteria for HD, and more ethnically diverse samples.

Genetic architecture of 11 major psychiatric disorders at biobehavioral, functional genomic and molecular genetic levels of analysis.

We interrogate the joint genetic architecture of 11 major psychiatric disorders at biobehavioral, functional genomic and molecular genetic levels of analysis. We identify four broad factors (neurodevelopmental, compulsive, psychotic and internalizing) that underlie genetic correlations among the disorders and test whether these factors adequately explain their genetic correlations with biobehavioral traits. We introduce stratified genomic structural equation modeling, which we use to identify gene sets that disproportionately contribute to genetic risk sharing. This includes protein-truncating variant-intolerant genes expressed in excitatory and GABAergic brain cells that are enriched for genetic overlap across disorders with psychotic features. Multivariate association analyses detect 152 (20 new) independent loci that act on the individual factors and identify nine loci that act heterogeneously across disorders within a factor. Despite moderate-to-high genetic correlations across all 11 disorders, we find little utility of a single dimension of genetic risk across psychiatric disorders either at the level of biobehavioral correlates or at the level of individual variants.

Polygenic Heterogeneity Across Obsessive-Compulsive Disorder Subgroups Defined by a Comorbid Diagnosis.

Among patients with obsessive-compulsive disorder (OCD), 65-85% manifest another psychiatric disorder concomitantly or at some other time point during their life. OCD is highly heritable, as are many of its comorbidities. A possible genetic heterogeneity of OCD in relation to its comorbid conditions, however, has not yet been exhaustively explored. We used a framework of different approaches to study the genetic relationship of OCD with three commonly observed comorbidities, namely major depressive disorder (MDD), attention-deficit hyperactivity disorder (ADHD), and autism spectrum disorder (ASD). First, using publicly available summary statistics from large-scale genome-wide association studies, we compared genetic correlation patterns for OCD, MDD, ADHD, and ASD with 861 somatic and mental health phenotypes. Secondly, we examined how polygenic risk scores (PRS) of eight traits that showed heterogeneous correlation patterns with OCD, MDD, ADHD, and ASD partitioned across comorbid subgroups in OCD using independent unpublished data from the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH). The comorbid subgroups comprised of patients with only OCD (N = 366), OCD and MDD (N = 1,052), OCD and ADHD (N = 443), OCD and ASD (N = 388), and OCD with more than 1 comorbidity (N = 429). We found that PRS of all traits but BMI were significantly associated with OCD across all subgroups (neuroticism: p = 1.19 × 10-32, bipolar disorder: p = 7.51 × 10-8, anorexia nervosa: p = 3.52 × 10-20, age at first birth: p = 9.38 × 10-5, educational attainment: p = 1.56 × 10-4, OCD: p = 1.87 × 10-6, insomnia: p = 2.61 × 10-5, BMI: p = 0.15). For age at first birth, educational attainment, and insomnia PRS estimates significantly differed across comorbid subgroups (p = 2.29 × 10-4, p = 1.63 × 10-4, and p = 0.045, respectively). Especially for anorexia nervosa, age at first birth, educational attainment, insomnia, and neuroticism the correlation patterns that emerged from genetic correlation analysis of OCD, MDD, ADHD, and ASD were mirrored in the PRS associations with the respective comorbid OCD groups. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across OCD comorbid subgroups.

Chronicity and Sex Affect Genetic Risk Prediction in Schizophrenia.

Schizophrenia (SCZ) is a severe mental disorder with immense personal and societal costs; identifying individuals at risk is therefore of utmost importance. Genomic risk profile scores (GRPS) have been shown to significantly predict cases-control status. Making use of a large-population based sample from Sweden, we replicate a previous finding demonstrating that the GRPS is strongly associated with admission frequency and chronicity of SCZ. Furthermore, we were able to show a substantial gap in prediction accuracy between males and females. In sum, our results indicate that prediction accuracy by GRPS depends on clinical and demographic characteristics.

Familial confounding of the association between maternal smoking in pregnancy and autism spectrum disorder in offspring.

Evidence supports no link between maternal smoking in pregnancy and autism spectrum disorder (autism) overall. To address remaining questions about the unexplained heterogeneity between study results and the possibility of risk for specific autism sub-phenotypes, we conducted a whole-population cohort study in Denmark. We followed births 1991-2011 (1,294,906 persons, including 993,301 siblings in 728,271 families), from 1 year of age until an autism diagnosis (13,547), death, emigration, or December 31, 2012. Autism, with and without attention deficit hyperactivity disorder (ADHD) and with and without intellectual disability (ID) were based on ICD-8 and ICD-10 codes from Danish national health registers, including 3,319 autism + ADHD, 10,228 autism - no ADHD, 2,205 autism + ID, and 11,342 autism - no ID. We estimated hazard ratios (HRs) and 95% confidence intervals (95% CIs) between any maternal smoking (from birth records) and autism (or sub-phenotypes) using survival models with robust standard errors, stratifying by birth year and adjusting for child sex, parity, and parental age, education, income, and psychiatric history. To additionally address confounding using family designs, we constructed a maternal cluster model (adjusting for the smoking proportion within the family), and a stratified sibling model. Associations with maternal smoking and autism were elevated in conventional adjusted analyses (HR of 1.17 [1.13-1.22]) but attenuated in the maternal cluster (0.98 [0.88-1.09]) and sibling (0.86 [0.64-1.15]) models. Similarly, risks of autism sub-phenotypes with maternal smoking were attenuated in the family-based models. Together these results support that smoking in pregnancy is not linked with autism or select autism comorbid sub-phenotypes after accounting for familial confounding. Autism Res 2020, 13: 134-144. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Smoking during pregnancy has many harmful impacts, which may include harming the baby's developing brain. However, in a study of thousands of families in Denmark, it does not appear that smoking in pregnancy leads to autism or autism in combination with intellectual problems or attention deficits, once you account for the way smoking patterns and developmental disabilities run in families.

A major role for common genetic variation in anxiety disorders.

Anxiety disorders are common, complex psychiatric disorders with twin heritabilities of 30-60%. We conducted a genome-wide association study of Lifetime Anxiety Disorder (ncase = 25 453, ncontrol = 58 113) and an additional analysis of Current Anxiety Symptoms (ncase = 19 012, ncontrol = 58 113). The liability scale common variant heritability estimate for Lifetime Anxiety Disorder was 26%, and for Current Anxiety Symptoms was 31%. Five novel genome-wide significant loci were identified including an intergenic region on chromosome 9 that has previously been associated with neuroticism, and a locus overlapping the BDNF receptor gene, NTRK2. Anxiety showed significant positive genetic correlations with depression and insomnia as well as coronary artery disease, mirroring findings from epidemiological studies. We conclude that common genetic variation accounts for a substantive proportion of the genetic architecture underlying anxiety.

Genetic Variants Associated With Anxiety and Stress-Related Disorders: A Genome-Wide Association Study and Mouse-Model Study.

Importance: Anxiety and stress-related disorders are among the most common mental disorders. Although family and twin studies indicate that both genetic and environmental factors play an important role underlying their etiology, the genetic underpinnings of anxiety and stress-related disorders are poorly understood. Objectives: To estimate the single-nucleotide polymorphism-based heritability of anxiety and stress-related disorders; to identify novel genetic risk variants, genes, or biological pathways; to test for pleiotropic associations with other psychiatric traits; and to evaluate the association of psychiatric comorbidities with genetic findings. Design, Setting, Participants: This genome-wide association study included individuals with various anxiety and stress-related diagnoses and controls derived from the population-based Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH) study. Lifetime diagnoses of anxiety and stress-related disorders were obtained through the national Danish registers. Genes of interest were further evaluated in mice exposed to chronic social defeat. The study was conducted between June 2016 and November 2018. Main Outcomes and Measures: Diagnoses of a relatively broad diagnostic spectrum of anxiety and stress-related disorders. Results: The study sample included 12 655 individuals with various anxiety and stress-related diagnoses and 19 225 controls. Overall, 17 740 study participants (55.6%) were women. A total of 7308 participants (22.9%) were born between 1981-1985, 8840 (27.7%) between 1986-1990, 8157 (25.6%) between 1991-1995, 5918 (18.6%) between 1996-2000, and 1657 (5.2%) between 2001-2005. Standard association analysis revealed variants in PDE4B to be associated with anxiety and stress-related disorder (rs7528604; P = 5.39 × 10-11; odds ratio = 0.89; 95% CI, 0.86-0.92). A framework of sensitivity analyses adjusting for mental comorbidity supported this result showing consistent association of PDE4B variants with anxiety and stress-related disorder across analytical scenarios. In mouse models, alterations in Pde4b expression were observed in those mice displaying anxiety-like behavior after exposure to chronic stress in the prefrontal cortex (P = .002; t = -3.33) and the hippocampus (P = .001; t = -3.72). We also found a single-nucleotide polymorphism heritability of 28% (standard error = 0.027) and that the genetic signature of anxiety and stress-related overlapped with psychiatric traits, educational outcomes, obesity-related phenotypes, smoking, and reproductive success. Conclusions and Relevance: This study highlights anxiety and stress-related disorders as complex heritable phenotypes with intriguing genetic correlations not only with psychiatric traits, but also with educational outcomes and multiple obesity-related phenotypes. Furthermore, we highlight the candidate gene PDE4B as a robust risk locus pointing to the potential of PDE4B inhibitors in treatment of these disorders.

Genetics of Anxiety Disorders.

PURPOSE OF REVIEW: Anxiety disorders are among the most common mental disorders with a lifetime prevalence of over 20%. Clinically, anxiety is not thought of as a homogenous disorder, but is subclassified in generalized, panic, and phobic anxiety disorder. Anxiety disorders are moderately heritable. This review will explore recent genetic and epigenetic approaches to anxiety disorders explaining differential susceptibility risk. RECENT FINDINGS: A substantial portion of the variance in susceptibility risk can be explained by differential inherited and acquired genetic and epigenetic risk. Available data suggest that anxiety disorders are highly complex and polygenic. Despite the substantial progress in genetic research over the last decade, only few risk loci for anxiety disorders have been identified so far. This review will cover recent findings from large-scale genome-wide association studies as well as newer epigenome-wide studies. Progress in this area will likely require analysis of much larger sample sizes than have been reported to date. We discuss prospects for clinical translation of genetic findings and future directions for research.

Efficient region-based test strategy uncovers genetic risk factors for functional outcome in bipolar disorder.

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.

Attention-deficit hyperactivity disorder and anxiety disorders as precursors of bipolar disorder onset in adulthood.

BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) and anxiety disorders have been proposed as precursors of bipolar disorder, but their joint and relative roles in the development of bipolar disorder are unknown.AimsTo test the prospective relationship of ADHD and anxiety with onset of bipolar disorder. METHOD: We examined the relationship between ADHD, anxiety disorders and bipolar disorder in a birth cohort of 2 409 236 individuals born in Denmark between 1955 and 1991. Individuals were followed from their sixteenth birthday or from January 1995 to their first clinical contact for bipolar disorder or until December 2012. We calculated incidence rates per 10 000 person-years and tested the effects of prior diagnoses on the risk of bipolar disorder in survival models. RESULTS: Over 37 394 865 person-years follow-up, 9250 onsets of bipolar disorder occurred. The incidence rate of bipolar disorder was 2.17 (95% CI 2.12-2.19) in individuals with no prior diagnosis of ADHD or anxiety, 23.86 (95% CI 19.98-27.75) in individuals with a prior diagnosis of ADHD only, 26.05 (95% CI 24.47-27.62) in individuals with a prior diagnosis of anxiety only and 66.16 (95% CI 44.83-87.47) in those with prior diagnoses of both ADHD and anxiety. The combination of ADHD and anxiety increased the risk of bipolar disorder 30-fold (95% CI 21.66-41.40) compared with those with no prior ADHD or anxiety. CONCLUSIONS: Early manifestations of both internalising and externalising psychopathology indicate liability to bipolar disorder. The combination of ADHD and anxiety is associated with a very high risk of bipolar disorder.Declaration of interestNone.

Mortality risk in a nationwide cohort of individuals with tic disorders and with tourette syndrome.

BACKGROUND: Few studies have investigated mortality risk in individuals with tic disorders. METHODS: We thus measured the risk of premature death in individuals with tic disorders and with Tourette syndrome in a prospective cohort study with 80 million person-years of follow-up. We estimated mortality rate ratios and adjusted for calendar year, age, sex, urbanicity, maternal and paternal age, and psychiatric disorders to compare individuals with and without tic disorders. RESULTS: The risk of premature death was higher among individuals with tic disorders (mortality rate ratio, 2.02; 95% CI, 1.49-2.66) and with Tourette syndrome (mortality rate ratio, 1.63; 95% CI, 1.11-2.28) compared with controls. After the exclusion of individuals with comorbid attention-deficit/hyperactivity disorder, obsessive-compulsive disorder, and substance abuse, tic disorder remained associated with increased mortality risk (mortality rate ratio, 2.30; 95% CI, 1.57-3.23), as did also Tourette Syndrome (mortality rate ratio, 1.81; 95% CI, 1.11-2.75). CONCLUSIONS: These results are of clinical significance for clinicians and advocacy organizations. Several factors may contribute to this increased risk of premature death, and more research mapping out these factors is needed. © 2017 International Parkinson and Movement Disorder Society.

Association of the polygenic risk score for schizophrenia with mortality and suicidal behavior - A Danish population-based study.

BACKGROUND: It is unknown whether an increased genetic liability to schizophrenia influences the risk of dying early. The aim of the study was to determine whether the genetic predisposition to schizophrenia is associated with the risk of dying early and experience a suicide attempt. METHOD: Case control study, Denmark. The main measure was the mortality rate ratios (MRR) for deaths and odds ratios (OR) for multiple suicide attempts, associated with one standard deviations increase of the polygenic risk-score for schizophrenia (PRS). RESULTS: We replicated the high mortality MRR=9.01 (95% CI: 3.56-22.80), and high risk of multiple suicide attempts OR=33.16 (95% CI: 20.97-52.43) associated with schizophrenia compared to the general population. However, there was no effect of the PRS on mortality MRR=1.00 (95% CI 0.71-1.40) in the case-control setup or in cases only, MRR=1.05 (95% CI 0.73-1.51). Similar, no association between the PRS and multiple suicide attempts was found in the adjusted models, but in contrast, family history of mental disorders was associated with both outcomes. CONCLUSIONS: A genetic predisposition for schizophrenia, measured by PRS, has little influence on the excess mortality or the risk of suicide attempts. In contrast there is a strong significant effect of family history of mental disorders. Our findings could reflect that the common variants detected by recent PRS only explain a small proportion of risk of schizophrenia, and that future, more powerful PRS instruments may be able to predict excess mortality within this disorder.

Increased mortality among people with anxiety disorders: total population study.

BACKGROUND: Anxiety disorders and depression are the most common mental disorders worldwide and have a striking impact on global disease burden. Although depression has consistently been found to increase mortality; the role of anxiety disorders in predicting mortality risk is unclear. AIMS: To assess mortality risk in people with anxiety disorders. METHOD: We used nationwide Danish register data to conduct a prospective cohort study with over 30 million person-years of follow-up. RESULTS: In total, 1066 (2.1%) people with anxiety disorders died during an average follow-up of 9.7 years. The risk of death by natural and unnatural causes was significantly higher among individuals with anxiety disorders (natural mortality rate ratio (MRR) = 1.39, 95% CI 1.28-1.51; unnatural MRR = 2.46, 95% CI 2.20-2.73) compared with the general population. Of those who died from unnatural causes, 16.5% had comorbid diagnoses of depression (MRR = 11.72, 95% CI 10.11-13.51). CONCLUSIONS: Anxiety disorders significantly increased mortality risk. Comorbidity of anxiety disorders and depression played an important part in the increased mortality.