Evaluation of polygenic prediction methodology within a reference-standardized framework.

The predictive utility of polygenic scores is increasing, and many polygenic scoring methods are available, but it is unclear which method performs best. This study evaluates the predictive utility of polygenic scoring methods within a reference-standardized framework, which uses a common set of variants and reference-based estimates of linkage disequilibrium and allele frequencies to construct scores. Eight polygenic score methods were tested: p-value thresholding and clumping (pT+clump), SBLUP, lassosum, LDpred1, LDpred2, PRScs, DBSLMM and SBayesR, evaluating their performance to predict outcomes in UK Biobank and the Twins Early Development Study (TEDS). Strategies to identify optimal p-value thresholds and shrinkage parameters were compared, including 10-fold cross validation, pseudovalidation and infinitesimal models (with no validation sample), and multi-polygenic score elastic net models. LDpred2, lassosum and PRScs performed strongly using 10-fold cross-validation to identify the most predictive p-value threshold or shrinkage parameter, giving a relative improvement of 16-18% over pT+clump in the correlation between observed and predicted outcome values. Using pseudovalidation, the best methods were PRScs, DBSLMM and SBayesR. PRScs pseudovalidation was only 3% worse than the best polygenic score identified by 10-fold cross validation. Elastic net models containing polygenic scores based on a range of parameters consistently improved prediction over any single polygenic score. Within a reference-standardized framework, the best polygenic prediction was achieved using LDpred2, lassosum and PRScs, modeling multiple polygenic scores derived using multiple parameters. This study will help researchers performing polygenic score studies to select the most powerful and predictive analysis methods.

Imputed gene expression risk scores: a functionally informed component of polygenic risk.

Integration of functional genomic annotations when estimating polygenic risk scores (PRS) can provide insight into aetiology and improve risk prediction. This study explores the predictive utility of gene expression risk scores (GeRS), calculated using imputed gene expression and transcriptome-wide association study (TWAS) results. The predictive utility of GeRS was evaluated using 12 neuropsychiatric and anthropometric outcomes measured in two target samples: UK Biobank and the Twins Early Development Study. GeRS were calculated based on imputed gene expression levels and TWAS results, using 53 gene expression-genotype panels, termed single nucleotide polymorphism (SNP)-weight sets, capturing expression across a range of tissues. We compare the predictive utility of elastic net models containing GeRS within and across SNP-weight sets, and models containing both GeRS and PRS. We estimate the proportion of SNP-based heritability attributable to cis-regulated gene expression. GeRS significantly predicted a range of outcomes, with elastic net models combining GeRS across SNP-weight sets improving prediction. GeRS were less predictive than PRS, but models combining GeRS and PRS improved prediction for several outcomes, with relative improvements ranging from 0.3% for height (P = 0.023) to 4% for rheumatoid arthritis (P = 5.9 × 10-8). The proportion of SNP-based heritability attributable to cis-regulated expression was modest for most outcomes, even when restricting GeRS to colocalized genes. GeRS represent a component of PRS and could be useful for functional stratification of genetic risk. Only in specific circumstances can GeRS substantially improve prediction over PRS alone. Future research considering functional genomic annotations when estimating genetic risk is warranted.

Using major depression polygenic risk scores to explore the depressive symptom continuum.

BACKGROUND: Major depression (MD) is often characterised as a categorical disorder; however, observational studies comparing sub-threshold and clinical depression suggest MD is continuous. Many of these studies do not explore the full continuum and are yet to consider genetics as a risk factor. This study sought to understand if polygenic risk for MD could provide insight into the continuous nature of depression. METHODS: Factor analysis on symptom-level data from the UK Biobank (N = 148 957) was used to derive continuous depression phenotypes which were tested for association with polygenic risk scores (PRS) for a categorical definition of MD (N = 119 692). RESULTS: Confirmatory factor analysis showed a five-factor hierarchical model, incorporating 15 of the original 18 items taken from the PHQ-9, GAD-7 and subjective well-being questionnaires, produced good fit to the observed covariance matrix (CFI = 0.992, TLI = 0.99, RMSEA = 0.038, SRMR = 0.031). MD PRS associated with each factor score (standardised ß range: 0.057-0.064) and the association remained when the sample was stratified into case- and control-only subsets. The case-only subset had an increased association compared to controls for all factors, shown via a significant interaction between lifetime MD diagnosis and MD PRS (p value range: 2.23 × 10-3-3.94 × 10-7). CONCLUSIONS: An association between MD PRS and a continuous phenotype of depressive symptoms in case- and control-only subsets provides support against a purely categorical phenotype; indicating further insights into MD can be obtained when this within-group variation is considered. The stronger association within cases suggests this variation may be of particular importance.

Exploring the genetic heterogeneity in major depression across diagnostic criteria.

Major depressive disorder (MDD) is defined differently across genetic research studies and this may be a key source of heterogeneity. While previous literature highlights differences between minimal and strict phenotypes, the components contributing to this heterogeneity have not been identified. Using the cardinal symptoms (depressed mood/anhedonia) as a baseline, we build MDD phenotypes using five components-(1) five or more symptoms, (2) episode duration, (3) functional impairment, (4) episode persistence, and (5) episode recurrence-to determine the contributors to such heterogeneity. Thirty-two depression phenotypes which systematically incorporate different combinations of MDD components were created using the mental health questionnaire data within the UK Biobank. SNP-based heritabilities and genetic correlations with three previously defined major depression phenotypes were calculated (Psychiatric Genomics Consortium (PGC) defined depression, 23andMe self-reported depression and broad depression) and differences between estimates analysed. All phenotypes were heritable (h2SNP range: 0.102-0.162) and showed substantial genetic correlations with other major depression phenotypes (Rg range: 0.651-0.895 (PGC); 0.652-0.837 (23andMe); 0.699-0.900 (broad depression)). The strongest effect on SNP-based heritability was from the requirement for five or more symptoms (1.4% average increase) and for a long episode duration (2.7% average decrease). No significant differences were noted between genetic correlations. While there is some variation, the two cardinal symptoms largely reflect the genetic aetiology of phenotypes incorporating more MDD components. These components may index severity, however, their impact on heterogeneity in genetic results is likely to be limited.

Self-reported medication use as an alternate phenotyping method for anxiety and depression in the UK Biobank.

The requirement for large sample sizes for psychiatric genetic analyses necessitates novel approaches to derive cases. Anxiety and depression show substantial genetic overlap and share pharmacological treatments. Data on prescribed medication could be effective for inferring case status when other indicators of mental health are unavailable. We investigated self-reported current medication use in UK Biobank participants of European ancestry. Medication Status cases reported using antidepressant or anxiolytic medication (n = 22,218), controls did not report psychotropic medication use (n = 168,959). A subset, "Medication Only," additionally did not meet criteria for any other mental health indicator (case n = 2,643, control n = 107,029). We assessed genetic overlap between these phenotypes and two published genetic association studies of anxiety and depression, and an internalizing disorder trait derived from symptom-based questionnaires in UK Biobank. Genetic correlations between Medication Status and the three anxiety and depression phenotypes were significant (rg  = 0.60-0.73). In the Medication Only subset, the genetic correlation with depression was significant (rg  = 0.51). The three polygenic scores explained 0.33% - 0.80% of the variance in Medication Status and 0.07% - 0.19% of the variance in Medication Only. This study provides evidence that self-reported current medication use offers an alternate or supplementary anxiety or depression phenotype in genetic studies where diagnostic information is sparse or unavailable.

Studying individual risk factors for self-harm in the UK Biobank: A polygenic scoring and Mendelian randomisation study.

BACKGROUND: Identifying causal risk factors for self-harm is essential to inform preventive interventions. Epidemiological studies have identified risk factors associated with self-harm, but these associations can be subject to confounding. By implementing genetically informed methods to better account for confounding, this study aimed to better identify plausible causal risk factors for self-harm. METHODS AND FINDINGS: Using summary statistics from 24 genome-wide association studies (GWASs) comprising 16,067 to 322,154 individuals, polygenic scores (PSs) were generated to index 24 possible individual risk factors for self-harm (i.e., mental health vulnerabilities, substance use, cognitive traits, personality traits, and physical traits) among a subset of UK Biobank participants (N = 125,925, 56.2% female) who completed an online mental health questionnaire in the period from 13 July 2016 to 27 July 2017. In total, 5,520 (4.4%) of these participants reported having self-harmed in their lifetime. In binomial regression models, PSs indexing 6 risk factors (major depressive disorder [MDD], attention deficit/hyperactivity disorder [ADHD], bipolar disorder, schizophrenia, alcohol dependence disorder, and lifetime cannabis use) predicted self-harm, with effect sizes ranging from odds ratio (OR) = 1.05 (95% CI 1.02 to 1.07, q = 0.008) for lifetime cannabis use to OR = 1.20 (95% CI 1.16 to 1.23, q = 1.33 × 10-35) for MDD. No systematic differences emerged between suicidal and non-suicidal self-harm. To further probe causal relationships, two-sample Mendelian randomisation (MR) analyses were conducted, with MDD, ADHD, and schizophrenia emerging as the most plausible causal risk factors for self-harm. The genetic liabilities for MDD and schizophrenia were associated with self-harm independently of diagnosis and medication. Main limitations include the lack of representativeness of the UK Biobank sample, that self-harm was self-reported, and the limited power of some of the included GWASs, potentially leading to possible type II error. CONCLUSIONS: In addition to confirming the role of MDD, we demonstrate that ADHD and schizophrenia likely play a role in the aetiology of self-harm using multivariate genetic designs for causal inference. Among the many individual risk factors we simultaneously considered, our findings suggest that systematic detection and treatment of core psychiatric symptoms, including psychotic and impulsivity symptoms, may be beneficial among people at risk for self-harm.

Investigating the effects of genetic risk of schizophrenia on behavioural traits.

To characterise the trait-effects of increased genetic risk for schizophrenia, and highlight potential risk mediators, we test the association between schizophrenia polygenic risk scores (PRSs) and 529 behavioural traits (personality, psychological, lifestyle, nutritional) in the UK Biobank. Our primary analysis is performed on individuals aged 38-71 with no history of schizophrenia or related disorders, allowing us to report the effects of schizophrenia genetic risk in the sub-clinical general population. Higher schizophrenia PRSs were associated with a range of traits, including lower verbal-numerical reasoning (P = 6 × 10-61), higher nervous feelings (P = 1 × 10-46) and higher self-reported risk-taking (P = 3 × 10-38). We follow-up the risk-taking association, hypothesising that the association may be due to a genetic propensity for risk-taking leading to greater migration, urbanicity or drug-taking - reported environmental risk factors for schizophrenia, and all positively associated with risk-taking in these data. Next, to identify potential disorder or medication effects, we compare the PRS-trait associations in the general population to the trait values in 599 medicated and non-medicated individuals diagnosed with schizophrenia in the biobank. This analysis highlights, for example, levels of BMI, physical activity and risk-taking in cases in the opposite directions than expected from the PRS-trait associations in the general population. Our analyses offer simple yet potentially revealing insights into the possible causes of observed trait-disorder associations, which can complement approaches such as Mendelian Randomisation. While we urge caution in causal interpretations in PRS cross-trait studies that are highly powered to detect weak horizontal pleiotropy or population structure, we propose that well-designed polygenic score analyses have the potential to highlight modifiable risk factors that lie on the path between genetic risk and disorder.

The genetic case for cardiorespiratory fitness as a clinical vital sign and the routine prescription of physical activity in healthcare.

BACKGROUND: Cardiorespiratory fitness (CRF) and physical activity (PA) are well-established predictors of morbidity and all-cause mortality. However, CRF is not routinely measured and PA not routinely prescribed as part of standard healthcare. The American Heart Association (AHA) recently presented a scientific case for the inclusion of CRF as a clinical vital sign based on epidemiological and clinical observation. Here, we leverage genetic data in the UK Biobank (UKB) to strengthen the case for CRF as a vital sign and make a case for the prescription of PA. METHODS: We derived two CRF measures from the heart rate data collected during a submaximal cycle ramp test: CRF-vo2max, an estimate of the participants' maximum volume of oxygen uptake, per kilogram of body weight, per minute; and CRF-slope, an estimate of the rate of increase of heart rate during exercise. Average PA over a 7-day period was derived from a wrist-worn activity tracker. After quality control, 70,783 participants had data on the two derived CRF measures, and 89,683 had PA data. We performed genome-wide association study (GWAS) analyses by sex, and post-GWAS techniques to understand genetic architecture of the traits and prioritise functional genes for follow-up. RESULTS: We found strong evidence that genetic variants associated with CRF and PA influenced genetic expression in a relatively small set of genes in the heart, artery, lung, skeletal muscle and adipose tissue. These functionally relevant genes were enriched among genes known to be associated with coronary artery disease (CAD), type 2 diabetes (T2D) and Alzheimer's disease (three of the top 10 causes of death in high-income countries) as well as Parkinson's disease, pulmonary fibrosis, and blood pressure, heart rate, and respiratory phenotypes. Genetic variation associated with lower CRF and PA was also correlated with several disease risk factors (including greater body mass index, body fat and multiple obesity phenotypes); a typical T2D profile (including higher insulin resistance, higher fasting glucose, impaired beta-cell function, hyperglycaemia, hypertriglyceridemia); increased risk for CAD and T2D; and a shorter lifespan. CONCLUSIONS: Genetics supports three decades of evidence for the inclusion of CRF as a clinical vital sign. Given the genetic, clinical and epidemiological evidence linking CRF and PA to increased morbidity and mortality, regular measurement of CRF as a marker of health and routine prescription of PA could be a prudent strategy to support public health.

Investigating Pleiotropy Between Depression and Autoimmune Diseases Using the UK Biobank.

BACKGROUND: Epidemiological studies report increased comorbidity between depression and autoimmune diseases. The role of shared genetic influences in the observed comorbidity is unclear. We investigated the evidence for pleiotropy between these traits in the UK Biobank (UKB). METHODS: We defined autoimmune and depression cases using hospital episode statistics, self-reported conditions and medications, and mental health questionnaires. Pairwise comparisons of depression prevalence between autoimmune cases and controls, and vice versa, were performed. Cross-trait polygenic risk score (PRS) analyses tested for pleiotropy, i.e., whether PRSs for depression could predict autoimmune disease status, and vice versa. RESULTS: We identified 28,479 cases of autoimmune diseases (pooling across 14 traits) and 324,074 autoimmune controls, and 65,075 cases of depression and 232,552 depression controls. The prevalence of depression was significantly higher in autoimmune cases than in controls, and similarly, the prevalence of autoimmune disease was higher in depression cases than in controls. PRSs for myasthenia gravis and psoriasis were significantly higher in depression cases than in controls (p < 5.2 × 10-5, R 2 ≤ 0.04%). PRSs for depression were significantly higher in inflammatory bowel disease, psoriasis, psoriatic arthritis, rheumatoid arthritis, and type 1 diabetes cases than in controls (p < 5.8 × 10-5, R 2 range = 0.06%-0.27%), and lower in celiac disease cases than in controls (p < 5.4 × 10-7, R 2 range = 0.11%-0.15%). CONCLUSIONS: Consistent with the literature, depression was more common in individuals with autoimmune diseases than in controls, and vice versa. PRSs showed some evidence for involvement of shared genetic factors, but the modest R 2 values suggest that shared genetic architecture accounts for a small proportion of the increased risk across traits.

Elevated C-Reactive Protein in Patients With Depression, Independent of Genetic, Health, and Psychosocial Factors: Results From the UK Biobank.

OBJECTIVE: The authors investigated the pathways (genetic, environmental, lifestyle, medical) leading to inflammation in major depressive disorder using C-reactive protein (CRP), genetic, and phenotypic data from the UK Biobank. METHODS: This was a case-control study of 26,894 participants with a lifetime diagnosis of major depressive disorder from the Composite International Diagnostic Interview and 59,001 control subjects who reported no mental disorder and had not reported taking any antidepressant medication. Linear regression models of log CRP level were fitted to regress out the effects of age, sex, body mass index (BMI), and smoking and to test whether the polygenic risk score (PRS) for major depression was associated with log CRP level and whether the association between log CRP level and major depression remained after adjusting for early-life trauma, socioeconomic status, and self-reported health status. RESULTS: CRP levels were significantly higher in patients with depression relative to control subjects (2.4 mg/L compared with 2.1 mg/L, respectively), and more case than control subjects had CRP levels >3 mg/L (21.2% compared with 16.8%, respectively), indicating low-grade inflammation. The PRS for depression was positively and significantly associated with log CRP levels, but this association was no longer significant after adjustment for BMI and smoking. The association between depression and increased log CRP level was substantially reduced, but still remained significant, after adjustment for the aforementioned clinical and sociodemographic factors. CONCLUSIONS: The data indicate that the "genetic" contribution to increased inflammation in depression is due to regulation of eating and smoking habits rather than an "autoimmune" genetic predisposition. Moreover, the association between depression and increased inflammation even after full adjustment indicates either the presence of yet unknown or unmeasured psychosocial and clinical confounding factors or that a core biological association between depression and increased inflammation exists independently from confounders.

Multiple measures of depression to enhance validity of major depressive disorder in the UK Biobank.

BACKGROUND: The UK Biobank contains data with varying degrees of reliability and completeness for assessing depression. A third of participants completed a Mental Health Questionnaire (MHQ) containing the gold-standard Composite International Diagnostic Interview (CIDI) criteria for assessing mental health disorders. AIMS: To investigate whether multiple observations of depression from sources other than the MHQ can enhance the validity of major depressive disorder (MDD). METHOD: In participants who did not complete the MHQ, we calculated the number of other depression measures endorsed, for example from hospital episode statistics and interview data. We compared cases defined this way with CIDI-defined cases for several estimates: the variance explained by polygenic risk scores (PRS), area under the curve attributable to PRS, single nucleotide polymorphisms (SNPs)-based heritability and genetic correlations with summary statistics from the Psychiatric Genomics Consortium MDD genome-wide association study. RESULTS: The strength of the genetic contribution increased with the number of measures endorsed. For example, SNP-based heritability increased from 7% in participants who endorsed only one measure of depression, to 21% in those who endorsed four or five measures of depression. The strength of the genetic contribution to cases defined by at least two measures approximated that for CIDI-defined cases. Most genetic correlations between UK Biobank and the Psychiatric Genomics Consortium MDD study exceeded 0.7, but there was variability between pairwise comparisons. CONCLUSIONS: Multiple measures of depression can serve as a reliable approximation for case status where the CIDI measure is not available, indicating sample size can be optimised using the entire suite of UK Biobank data.

Cannabis use, depression and self-harm: phenotypic and genetic relationships.

BACKGROUND AND AIMS: The use of cannabis has previously been linked to both depression and self-harm; however, the role of genetics in this relationship is unclear. This study aimed to estimate the phenotypic and genetic associations between cannabis use and depression and self-harm. DESIGN: Cross-sectional data collected through UK Biobank were used to test the phenotypic association between cannabis use, depression and self-harm. UK Biobank genetic data were then combined with consortia genome-wide association study summary statistics to further test the genetic relationships between these traits using LD score regression, polygenic risk scoring and Mendelian randomization methods. SETTING: United Kingdom, with additional international consortia data. PARTICIPANTS: A total of 126 291 British adults aged between 40 and 70 years, recruited into UK Biobank. MEASUREMENTS: Phenotypic outcomes were life-time history of cannabis use (including initial and continued cannabis use), depression (including single-episode and recurrent depression) and self-harm. Genome-wide genetic data were used and assessment centre, batch and the first six principal components were included as key covariates when handling genetic data. FINDINGS: In UK Biobank, cannabis use is associated with an increased likelihood of depression [odds ratio (OR) = 1.64, 95% confidence interval (CI) = 1.59-1.70] and self-harm (OR = 2.85, 95% CI = 2.69-3.01). The strength of this phenotypic association is stronger when more severe trait definitions of cannabis use and depression are considered. Using consortia genome-wide summary statistics, significant genetic correlations are seen between cannabis use and depression [rg = 0.289, standard error (SE) = 0.036]. Polygenic risk scores for cannabis use and depression explain a small but significant proportion of variance in cannabis use, depression and self-harm within a UK Biobank target sample. However, two-sample Mendelian randomization analyses were not significant. CONCLUSIONS: Cannabis use appeared to be both phenotypically and genetically associated with depression and self-harm. Limitations in statistical power mean that conclusions could not be made on the direction of causality between these traits.

Genetic stratification of depression in UK Biobank.

Depression is a common and clinically heterogeneous mental health disorder that is frequently comorbid with other diseases and conditions. Stratification of depression may align sub-diagnoses more closely with their underling aetiology and provide more tractable targets for research and effective treatment. In the current study, we investigated whether genetic data could be used to identify subgroups within people with depression using the UK Biobank. Examination of cross-locus correlations were used to test for evidence of subgroups using genetic data from seven other complex traits and disorders that were genetically correlated with depression and had sufficient power (>0.6) for detection. We found no evidence for subgroups within depression for schizophrenia, bipolar disorder, attention deficit/hyperactivity disorder, autism spectrum disorder, anorexia nervosa, inflammatory bowel disease or obesity. This suggests that for these traits, genetic correlations with depression were driven by pleiotropic genetic variants carried by everyone rather than by a specific subgroup.

Classical Human Leukocyte Antigen Alleles and C4 Haplotypes Are Not Significantly Associated With Depression.

BACKGROUND: The prevalence of depression is higher in individuals with autoimmune diseases, but the mechanisms underlying the observed comorbidities are unknown. Shared genetic etiology is a plausible explanation for the overlap, and in this study we tested whether genetic variation in the major histocompatibility complex (MHC), which is associated with risk for autoimmune diseases, is also associated with risk for depression. METHODS: We fine-mapped the classical MHC (chr6: 29.6-33.1 Mb), imputing 216 human leukocyte antigen (HLA) alleles and 4 complement component 4 (C4) haplotypes in studies from the Psychiatric Genomics Consortium Major Depressive Disorder Working Group and the UK Biobank. The total sample size was 45,149 depression cases and 86,698 controls. We tested for association between depression status and imputed MHC variants, applying both a region-wide significance threshold (3.9 × 10-6) and a candidate threshold (1.6 × 10-4). RESULTS: No HLA alleles or C4 haplotypes were associated with depression at the region-wide threshold. HLA-B*08:01 was associated with modest protection for depression at the candidate threshold for testing in HLA genes in the meta-analysis (odds ratio = 0.98, 95% confidence interval = 0.97-0.99). CONCLUSIONS: We found no evidence that an increased risk for depression was conferred by HLA alleles, which play a major role in the genetic susceptibility to autoimmune diseases, or C4 haplotypes, which are strongly associated with schizophrenia. These results suggest that any HLA or C4 variants associated with depression either are rare or have very modest effect sizes.

Genetic influences on treatment-seeking for common mental health problems in the UK biobank.

The majority of those who experience clinical anxiety and/or depressive symptoms in the population do not receive treatment. Studies investigating inequalities in treatment outcomes rarely consider that individuals respond differently to their experience of the environment. Much of our environment is under genetic influence, via our behaviour, whereby individuals actively select their experiences. If genes influence who seeks and receives treatment, selection bias will confound genomic studies of treatment response. Furthermore, if some individuals are at high genetic risk of needing but not commencing treatment, then greater efforts could be made to engage them. The role of common genetic variation on four lifetime treatment-seeking behaviours (treatment-seeking, treatment-receipt, self-help, self-medication with alcohol/drugs) was examined in participants of the UK Biobank (sample size range: 48,106 - 75,322). Treatment-related behaviours were only modestly heritable in these data. Nonetheless, genetic correlations reveal substantial genetic overlap between lifetime treatment-related behaviours and psychiatric disorders, symptoms and behavioural traits. To our knowledge, this is the first study to examine genetic influences on treatment-related behaviours. Further work is required to determine whether genetic factors could be used alongside clinical, social and demographic factors to identify at risk groups and inform strategies which target early intervention.

Association of Polygenic Risk for Attention-Deficit/Hyperactivity Disorder With Co-occurring Traits and Disorders.

BACKGROUND: A recent large-scale mega genome-wide association study identified, for the first time, genetic variants at 12 loci significantly associated with attention-deficit/hyperactivity disorder (ADHD). In this study we use a powerful polygenic approach, with polygenic scores derived from the genome-wide association study, to investigate the etiological overlap between ADHD and frequently co-occurring traits and disorders. METHODS: Polygenic risk scores for ADHD derived from the mega genome-wide association study (20,183 cases and 35,191 control subjects) were computed in a large-scale adult population sample (N = 135,726) recruited by the UK Biobank. Regression analyses were conducted to investigate whether polygenic risk for ADHD is associated with related traits and disorders in this population sample. The effects of sex were investigated via inclusion of an interaction term in the models. RESULTS: Polygenic risk for ADHD significantly and positively predicted body mass index (R2 = .45%; p = 5 × 10-129), neuroticism (R2 = .09%; p = 2 × 10-24), depression (R2 = .11%; p = 2 × 10-13), anxiety (R2 = .06%; p = 3 × 10-4), risk taking (R2 = .12%; p = 9 × 10-25), alcohol intake (R2 = .09%; p = 8 × 10-29), smoking (R2 = .33%; p = 4 × 10-21), alcohol dependency (R2 = .21%; p = 5 × 10-6), and negatively predicted verbal-numerical reasoning (R2 = .38%; p = 5 × 10-36). Polygenic risk scores did not significantly predict schizophrenia or bipolar disorder, although this may be because of the small number of diagnostic cases. We found no interaction effects between polygenic risk for ADHD and sex on any phenotypes. CONCLUSIONS: Our findings suggest that common genetic variation underlying risk for clinically diagnosed ADHD also contributes to higher body mass index, neuroticism, anxiety and depressive disorders, alcohol and nicotine use, risk taking, and lower general cognitive ability in the general population. These findings suggest that the co-occurrence of several traits with ADHD is partly explained by the same common genetic variants.