Exploring the Genetic Risk of Childhood Daytime Urinary Incontinence: A Genome-Wide Association Study.

PURPOSE: Childhood incontinence is stigmatized and underprioritized, and a basic understanding of its pathogenesis is missing. Our goal was to identify risk-conferring genetic variants in daytime urinary incontinence (DUI). MATERIALS AND METHODS: We conducted a genome-wide association study in the Danish iPSYCH2015 cohort. Cases (3024) were identified through DUI diagnosis codes and redeemed prescriptions for DUI medication in children aged 5 to 20. Controls (30,240), selected from the same sample, were matched to cases on sex and psychiatric diagnoses, if any, and down-sampled to a 1:10 case:control ratio. Replication was performed in the Icelandic deCODE cohort (5475 cases/287,773 controls). Single-nucleotide polymorphism heritability was calculated using the genome-based restricted maximum likelihood method. Cross-trait genetic correlation was estimated using linkage disequilibrium score regression. Polygenic risk scores generated with LDpred2-auto and BOLT-LMM were assessed for association. RESULTS: Variants on chromosome 6 (rs12210989, OR = 1.24 [95% CI: 1.17-1.32], P = 3.21 × 10-12) and 20 (rs4809801, OR = 1.18 [95% CI: 1.11-1.25], P = 3.66 × 10-8) reached genome-wide significance and implicated the PRDM13 and RIPOR3 genes. Chromosome 6 findings were replicated (P = .024, OR = 1.09 [95% CI: 1.01-1.16]). Liability scale heritability ranged from 10.20% (95% CI: 6.40%-14.00%) to 15.30% (95% CI: 9.66%-20.94%). DUI and nocturnal enuresis showed positive genetic correlation (rg = 1.28 ± 0.38, P = .0007). DUI was associated with attention-deficit/hyperactivity disorder (OR = 1.098 [95% CI: 1.046-1.152], P < .0001) and body mass index (OR = 1.129 [95% CI: 1.081-1.178], P < .0001) polygenic risk. CONCLUSIONS: Common genetic variants contribute to the risk of childhood DUI and genes important in neuronal development and detrusor smooth muscle activity were implicated. These findings may help guide identification of new treatment targets.

The role of co-occurring conditions and genetics in the associations of eating disorders with attention-deficit/hyperactivity disorder and autism spectrum disorder.

Eating disorders (EDs) commonly co-occur with other psychiatric and neurodevelopmental disorders including attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD); however, the pattern of family history and genetic overlap among them requires clarification. This study investigated the diagnostic, familial, and genetic associations of EDs with ADHD and ASD. The nationwide population-based cohort study included all individuals born in Denmark, 1981-2008, linked to their siblings and cousins. Cox regression was used to estimate associations between EDs and ADHD or ASD, and mediation analysis was used to assess the effects of intermediate mood or anxiety disorders. Polygenic scores (PGSs) were used to investigate the genetic association between anorexia nervosa (AN) and ADHD or ASD. Significantly increased risk for any ED was observed following an ADHD [hazard ratio = 1.97, 95% confidence interval = 1.75-2.22] or ASD diagnosis [2.82, 2.48-3.19]. Mediation analysis suggested that intermediate mood or anxiety disorders could account for 44-100% of the association between ADHD or ASD and ED. Individuals with a full sibling or maternal halfsibling with ASD had increased risk of AN [1.54, 1.33-1.78; 1.45, 1.08-1.94] compared to those with siblings without ASD. A positive association was found between ASD-PGS and AN risk [1.06, 1.02-1.09]. In this study, positive phenotypic associations between EDs and ADHD or ASD, mediation by mood or anxiety disorder, and a genetic association between ASD-PGS and AN were observed. These findings could guide future research in the development of new treatments that can mitigate the development of EDs among individuals with ADHD or ASD.

Cross-ancestry genetic investigation of schizophrenia, cannabis use disorder, and tobacco smoking.

Individuals with schizophrenia frequently experience co-occurring substance use, including tobacco smoking and heavy cannabis use, and substance use disorders. There is interest in understanding the extent to which these relationships are causal, and to what extent shared genetic factors play a role. We explored the relationships between schizophrenia (Scz; European ancestry N = 161,405; African ancestry N = 15,846), cannabis use disorder (CanUD; European ancestry N = 886,025; African ancestry N = 120,208), and ever-regular tobacco smoking (Smk; European ancestry N = 805,431; African ancestry N = 24,278) using the largest available genome-wide studies of these phenotypes in individuals of African and European ancestries. All three phenotypes were positively genetically correlated (rgs = 0.17-0.62). Genetic instrumental variable analyses suggested the presence of shared heritable factors, but evidence for bidirectional causal relationships was also found between all three phenotypes even after correcting for these shared genetic factors. We identified 327 pleiotropic loci with 439 lead SNPs in the European ancestry data, 150 of which were novel (i.e., not genome-wide significant in the original studies). Of these pleiotropic loci, 202 had lead variants which showed convergent effects (i.e., same direction of effect) on Scz, CanUD, and Smk. Genetic variants convergent across all three phenotypes showed strong genetic correlations with risk-taking, executive function, and several mental health conditions. Our results suggest that both shared genetic factors and causal mechanisms may play a role in the relationship between CanUD, Smk, and Scz, but longitudinal, prospective studies are needed to confirm a causal relationship.

Genetic contribution to the comorbidity between attention-deficit/hyperactivity disorder and substance use disorders.

We characterized the genetic architecture of the attention-deficit hyperactivity disorder-substance use disorder (ADHD-SUD) relationship by investigating genetic correlation, causality, pleiotropy, and common polygenic risk. Summary statistics from genome-wide association studies (GWAS) were used to investigate ADHD (Neff = 51,568), cannabis use disorder (CanUD, Neff = 161,053), opioid use disorder (OUD, Neff = 57,120), problematic alcohol use (PAU, Neff = 502,272), and problematic tobacco use (PTU, Neff = 97,836). ADHD, CanUD, and OUD GWAS meta-analyses included cohorts with case definitions based on different diagnostic criteria. PAU GWAS combined information related to alcohol use disorder, alcohol dependence, and the items related to alcohol problematic consequences assessed by the alcohol use disorders identification test. PTU GWAS was generated a multi-trait analysis including information regarding Fagerström Test for Nicotine Dependence and cigarettes per day. Linkage disequilibrium score regression analyses indicated positive genetic correlation with CanUD, OUD, PAU, and PTU. Genomic structural equation modeling showed that these genetic correlations were related to two latent factors: one including ADHD, CanUD, and PTU and the other with OUD and PAU. The evidence of a causal effect of PAU and PTU on ADHD was stronger than the reverse in the two-sample Mendelian randomization analysis. Conversely, similar strength of evidence was found between ADHD and CanUD. CADM2 rs62250713 was a pleiotropic SNP between ADHD and all SUDs. We found seven, one, and twenty-eight pleiotropic variants between ADHD and CanUD, PAU, and PTU, respectively. Finally, OUD, CanUD, and PAU PRS were associated with increased odds of ADHD. Our findings demonstrated the contribution of multiple pleiotropic mechanisms to the comorbidity between ADHD and SUDs.

Cross-ancestry genetic investigation of schizophrenia, cannabis use disorder, and tobacco smoking.

Individuals with schizophrenia frequently experience co-occurring substance use, including tobacco smoking and heavy cannabis use, and substance use disorders. There is interest in understanding the extent to which these relationships are causal, and to what extent shared genetic factors play a role. We explored the relationships between schizophrenia (Scz), cannabis use disorder (CanUD), and ever-regular tobacco smoking (Smk) using the largest available genome-wide studies of these phenotypes in individuals of African and European ancestries. All three phenotypes were positively genetically correlated (rgs = 0.17 - 0.62). Causal inference analyses suggested the presence of horizontal pleiotropy, but evidence for bidirectional causal relationships was also found between all three phenotypes even after correcting for horizontal pleiotropy. We identified 439 pleiotropic loci in the European ancestry data, 150 of which were novel (i.e., not genome-wide significant in the original studies). Of these pleiotropic loci, 202 had lead variants which showed convergent effects (i.e., same direction of effect) on Scz, CanUD, and Smk. Genetic variants convergent across all three phenotypes showed strong genetic correlations with risk-taking, executive function, and several mental health conditions. Our results suggest that both horizontal pleiotropy and causal mechanisms may play a role in the relationship between CanUD, Smk, and Scz, but longitudinal, prospective studies are needed to confirm a causal relationship.

Attention-Deficit/Hyperactivity Disorder and Major Depressive Disorder: Evidence From Multiple Genetically Informed Designs.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) and major depressive disorder (MDD) are two highly prevalent disorders that frequently co-occur. Prior evidence from genetic and cohort studies supports an association between ADHD and MDD. However, the direction and mechanisms underlying their association remain unclear. As onset of ADHD occurs in early life, it has been hypothesized that ADHD may cause MDD. METHODS: We examined the association of ADHD with MDD using 3 different genetically informed methods to disentangle causality from confounding: 1) a nationwide longitudinal register-based full sibling comparison (N = 1,018,489) adjusting for shared familial confounding; 2) a prospective co-twin control study comprising 16,477 twins (5084 monozygotic and 11,393 dizygotic); and 3) a two-sample Mendelian randomization analysis using the largest available ADHD (N = 225,534) and MDD (N = 500,199) genome-wide association study summary statistics, adjusting for correlated and uncorrelated horizontal pleiotropy. RESULTS: Sibling and twin comparisons indicated that individuals with ADHD have an increased risk for subsequent development of MDD (hazard ratio = 4.12 [95% CI 3.62-4.69]) after adjusting for shared genetic and familial factors and that ADHD scores endorsed by parents are positively associated with subsequent MDD scores at ages 15 and 18 years (b = 0.07 [95% CI 0.05-0.08] and b = 0.09 [95% CI 0.08-0.11], respectively). Mendelian randomization analyses showed that genetic liability for ADHD is causally related to MDD (odds ratio = 1.15 [95% CI 1.08-1.23]). CONCLUSIONS: Our study provides consistent results across 3 different genetically informative approaches, strengthening the hypothesis that ADHD is causally related to MDD.

Multi-polygenic scores in psychiatry: From disorder specific to transdiagnostic perspectives.

The dense co-occurrence of psychiatric disorders questions the categorical classification tradition and motivates efforts to establish dimensional constructs with neurobiological foundations that transcend diagnostic boundaries. In this study, we examined the genetic liability for eight major psychiatric disorder phenotypes under both a disorder-specific and a transdiagnostic framework. The study sample (n = 513) was deeply phenotyped, consisting of 452 patients from tertiary care with mood disorders, anxiety disorders (ANX), attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders, and/or substance use disorders (SUD) and 61 unaffected comparison individuals. We computed subject-specific polygenic risk score (PRS) profiles and assessed their associations with psychiatric diagnoses, comorbidity status, as well as cross-disorder behavioral dimensions derived from a rich battery of psychopathology assessments. High PRSs for depression were unselectively associated with the diagnosis of SUD, ADHD, ANX, and mood disorders (p < 1e-4). In the dimensional approach, four distinct functional domains were uncovered, namely the negative valence, social, cognitive, and regulatory systems, closely matching the major functional domains proposed by the Research Domain Criteria (RDoC) framework. Critically, the genetic predisposition for depression was selectively reflected in the functional aspect of negative valence systems (R2 = 0.041, p = 5e-4) but not others. This study adds evidence to the ongoing discussion about the misalignment between current psychiatric nosology and the underlying psychiatric genetic etiology and underscores the effectiveness of the dimensional approach in both the functional characterization of psychiatric patients and the delineation of the genetic liability for psychiatric disorders.

Is there evidence of a causal link between childhood maltreatment and attention deficit/hyperactivity disorder? A systematic review of prospective longitudinal studies using the Bradford-Hill criteria.

Background: Studies report an elevated risk of maltreatment in children with attention deficit/hyperactivity disorder (ADHD), and elevated levels of ADHD in people who suffered childhood maltreatment (CM). However, the direction(s) of causality between CM and ADHD remain unclear-does ADHD create a context for CM, does CM cause ADHD, or both? Objective: This study systematically reviews and qualitatively synthesizes the research evidence relating to this question using Bradford-Hill criteria for establishing causality-strength, temporality, dose-response and plausibility. Methods: We conducted a systematic review, following PRISMA guidelines, of prospective longitudinal studies examining both CM and ADHD. We then used Bradford-Hill criteria to assess the quality of evidence for a causal link between CM and ADHD. Results: All 11 included studies demonstrated an association between CM and ADHD. Seven included evidence for temporality: five suggesting that CM precedes ADHD in the lifespan; two suggesting ADHD precedes CM. Four studies demonstrated a dose response relationship in which greater CM exposure was associated with elevated risk of ADHD. Studies presented a range of plausible mechanisms, including CM causing ADHD through biological programming, versus ADHD causing CM through parental stress. Conclusions: The high quality prospective longitudinal studies reviewed confirm the association between ADHD and CM, but present conflicting evidence about the direction of causality and mechanisms underpinning this association. To better understand the complex interplay between CM and ADHD, more studies using new research designs will be required that can partition effects by type of CM and account for bidirectional effects and other complexities.

Polygenic Risk of Mental Disorders and Subject-Specific School Grades.

BACKGROUND: Education is essential for socioeconomic security and long-term mental health; however, mental disorders are often detrimental to the educational trajectory. Genetic correlations between mental disorders and educational attainment do not always align with corresponding phenotypic associations, implying heterogeneity in the genetic overlap. METHODS: We unraveled this heterogeneity by investigating associations between polygenic risk scores for 6 mental disorders and fine-grained school outcomes: school grades in language and mathematics in ninth grade and high school, as well as educational attainment by age 25, using nationwide-representative data from established cohorts (N = 79,489). RESULTS: High polygenic liability of attention-deficit/hyperactivity disorder was associated with lower grades in language and mathematics, whereas high polygenic risk of anorexia nervosa or bipolar disorder was associated with higher grades in language and mathematics. Associations between polygenic risk and school grades were mixed for schizophrenia and major depressive disorder and neutral for autism spectrum disorder. CONCLUSIONS: Polygenic risk scores for mental disorders are differentially associated with language and mathematics school grades.

Multi-ancestry study of the genetics of problematic alcohol use in over 1 million individuals.

Problematic alcohol use (PAU), a trait that combines alcohol use disorder and alcohol-related problems assessed with a questionnaire, is a leading cause of death and morbidity worldwide. Here we conducted a large cross-ancestry meta-analysis of PAU in 1,079,947 individuals (European, N = 903,147; African, N = 122,571; Latin American, N = 38,962; East Asian, N = 13,551; and South Asian, N = 1,716 ancestries). We observed a high degree of cross-ancestral similarity in the genetic architecture of PAU and identified 110 independent risk variants in within- and cross-ancestry analyses. Cross-ancestry fine mapping improved the identification of likely causal variants. Prioritizing genes through gene expression and chromatin interaction in brain tissues identified multiple genes associated with PAU. We identified existing medications for potential pharmacological studies by a computational drug repurposing analysis. Cross-ancestry polygenic risk scores showed better performance of association in independent samples than single-ancestry polygenic risk scores. Genetic correlations between PAU and other traits were observed in multiple ancestries, with other substance use traits having the highest correlations. This study advances our knowledge of the genetic etiology of PAU, and these findings may bring possible clinical applicability of genetics insights-together with neuroscience, biology and data science-closer.

Predicting ADHD in alcohol dependence using polygenic risk scores for ADHD.

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with a high degree of comorbidity, including substance misuse. We aimed to assess whether ADHD polygenic risk scores (PRS) could predict ADHD diagnosis in alcohol dependence (AD). ADHD PRS were generated for 1223 AD subjects with ADHD diagnosis information and 1818 healthy controls. ADHD PRS distributions were compared to evaluate the differences between healthy controls and AD cases with and without ADHD. We found increased ADHD PRS means in the AD cohort with ADHD (mean 0.30, standard deviation (SD) 0.92; p = 3.9 × 10-6 ); and without ADHD (mean - 0.00, SD 1.00; p = 5.2 × 10-5 ) compared to the healthy control subjects (mean - 0.17, SD 0.99). The ADHD PRS means differed within the AD group with a higher ADHD PRS mean in those with ADHD, odds ratio (OR) 1.34, confidence interval (CI) 1.10 to 1.65; p = 0.002. This study showed a positive relationship between ADHD PRS and risk of ADHD in individuals with co-occurring AD indicating that ADHD PRS may have utility in identifying individuals that are at a higher or lower risk of ADHD. Further larger studies need to be conducted to confirm the reliability of the results before ADHD PRS can be considered as a robust biomarker for diagnosis.

Multi-ancestry genome-wide association study of cannabis use disorder yields insight into disease biology and public health implications.

As recreational use of cannabis is being decriminalized in many places and medical use widely sanctioned, there are growing concerns about increases in cannabis use disorder (CanUD), which is associated with numerous medical comorbidities. Here we performed a genome-wide association study of CanUD in the Million Veteran Program (MVP), followed by meta-analysis in 1,054,365 individuals (ncases = 64,314) from four broad ancestries designated by the reference panel used for assignment (European n = 886,025, African n = 123,208, admixed American n = 38,289 and East Asian n = 6,843). Population-specific methods were applied to calculate single nucleotide polymorphism-based heritability within each ancestry. Statistically significant single nucleotide polymorphism-based heritability for CanUD was observed in all but the smallest population (East Asian). We discovered genome-wide significant loci unique to each ancestry: 22 in European, 2 each in African and East Asian, and 1 in admixed American ancestries. A genetically informed causal relationship analysis indicated a possible effect of genetic liability for CanUD on lung cancer risk, suggesting potential unanticipated future medical and psychiatric public health consequences that require further study to disentangle from other known risk factors such as cigarette smoking.

Transcriptomic risk scores for attention deficit/hyperactivity disorder.

Attention deficit/hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder. We performed a transcriptome-wide association study (TWAS) using the latest genome-wide association study (GWAS) meta-analysis, in 38,691 individuals with ADHD and 186,843 controls, and 14 gene-expression reference panels across multiple brain tissues and whole blood. Based on TWAS results, we selected subsets of genes and constructed transcriptomic risk scores (TRSs) for the disorder in peripheral blood mononuclear cells of individuals with ADHD and controls. We found evidence of association between ADHD and TRSs constructed using expression profiles from multiple brain areas, with individuals with ADHD carrying a higher burden of TRSs than controls. TRSs were uncorrelated with the polygenic risk score (PRS) for ADHD and, in combination with PRS, improved significantly the proportion of variance explained over the PRS-only model. These results support the complementary predictive potential of genetic and transcriptomic profiles in blood and underscore the potential utility of gene expression for risk prediction and deeper insight in molecular mechanisms underlying ADHD.

Depression pathophysiology, risk prediction of recurrence and comorbid psychiatric disorders using genome-wide analyses.

Depression is a common psychiatric disorder and a leading cause of disability worldwide. Here we conducted a genome-wide association study meta-analysis of six datasets, including >1.3 million individuals (371,184 with depression) and identified 243 risk loci. Overall, 64 loci were new, including genes encoding glutamate and GABA receptors, which are targets for antidepressant drugs. Intersection with functional genomics data prioritized likely causal genes and revealed new enrichment of prenatal GABAergic neurons, astrocytes and oligodendrocyte lineages. We found depression to be highly polygenic, with ~11,700 variants explaining 90% of the single-nucleotide polymorphism heritability, estimating that >95% of risk variants for other psychiatric disorders (anxiety, schizophrenia, bipolar disorder and attention deficit hyperactivity disorder) were influencing depression risk when both concordant and discordant variants were considered, and nearly all depression risk variants influenced educational attainment. Additionally, depression genetic risk was associated with impaired complex cognition domains. We dissected the genetic and clinical heterogeneity, revealing distinct polygenic architectures across subgroups of depression and demonstrating significantly increased absolute risks for recurrence and psychiatric comorbidity among cases of depression with the highest polygenic burden, with considerable sex differences. The risks were up to 5- and 32-fold higher than cases with the lowest polygenic burden and the background population, respectively. These results deepen the understanding of the biology underlying depression, its disease progression and inform precision medicine approaches to treatment.

Multi-ancestry study of the genetics of problematic alcohol use in >1 million individuals.

Problematic alcohol use (PAU) is a leading cause of death and disability worldwide. To improve our understanding of the genetics of PAU, we conducted a large cross-ancestry meta-analysis of PAU in 1,079,947 individuals. We observed a high degree of cross-ancestral similarity in the genetic architecture of PAU and identified 110 independent risk variants in within- and cross-ancestry analyses. Cross-ancestry fine-mapping improved the identification of likely causal variants. Prioritizing genes through gene expression and/or chromatin interaction in brain tissues identified multiple genes associated with PAU. We identified existing medications for potential pharmacological studies by drug repurposing analysis. Cross-ancestry polygenic risk scores (PRS) showed better performance in independent sample than single-ancestry PRS. Genetic correlations between PAU and other traits were observed in multiple ancestries, with other substance use traits having the highest correlations. The analysis of diverse ancestries contributed significantly to the findings, and fills an important gap in the literature.

Genome-wide association study of school grades identifies genetic overlap between language ability, psychopathology and creativity.

Cognitive functions of individuals with psychiatric disorders differ from that of the general population. Such cognitive differences often manifest early in life as differential school performance and have a strong genetic basis. Here we measured genetic predictors of school performance in 30,982 individuals in English, Danish and mathematics via a genome-wide association study (GWAS) and studied their relationship with risk for six major psychiatric disorders. When decomposing the school performance into math and language-specific performances, we observed phenotypically and genetically a strong negative correlation between math performance and risk for most psychiatric disorders. But language performance correlated positively with risk for certain disorders, especially schizophrenia, which we replicate in an independent sample (n = 4547). We also found that the genetic variants relating to increased risk for schizophrenia and better language performance are overrepresented in individuals involved in creative professions (n = 2953) compared to the general population (n = 164,622). The findings together suggest that language ability, creativity and psychopathology might stem from overlapping genetic roots.

Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains.

Attention-deficit hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder with a major genetic component. Here, we present a genome-wide association study meta-analysis of ADHD comprising 38,691 individuals with ADHD and 186,843 controls. We identified 27 genome-wide significant loci, highlighting 76 potential risk genes enriched among genes expressed particularly in early brain development. Overall, ADHD genetic risk was associated with several brain-specific neuronal subtypes and midbrain dopaminergic neurons. In exome-sequencing data from 17,896 individuals, we identified an increased load of rare protein-truncating variants in ADHD for a set of risk genes enriched with probable causal common variants, potentially implicating SORCS3 in ADHD by both common and rare variants. Bivariate Gaussian mixture modeling estimated that 84-98% of ADHD-influencing variants are shared with other psychiatric disorders. In addition, common-variant ADHD risk was associated with impaired complex cognition such as verbal reasoning and a range of executive functions, including attention.

Interplay of ADHD Polygenic Liability With Birth-Related, Somatic, and Psychosocial Factors in ADHD: A Nationwide Study.

OBJECTIVE: Attention deficit hyperactivity disorder (ADHD) is a multifactorial neurodevelopmental disorder, yet the interplay between ADHD polygenic risk scores (PRSs) and other risk factors remains relatively unexplored. The authors investigated associations, confounding, and interactions of ADHD PRS with birth-related, somatic, and psychosocial factors previously associated with ADHD. METHODS: Participants included a random general population sample (N=21,578) and individuals diagnosed with ADHD (N=13,697) from the genotyped Danish iPSYCH2012 case cohort, born between 1981 and 2005. The authors derived ADHD PRSs and identified 24 factors previously associated with ADHD using national registers. Logistic regression was used to estimate associations of ADHD PRS with each risk factor in the general population. Cox models were used to evaluate confounding of risk factor associations with ADHD diagnosis by ADHD PRS and parental psychiatric history, and interactions between ADHD PRS and each risk factor. RESULTS: ADHD PRS was associated with 12 of 24 risk factors (odds ratio range, 1.03-1.30), namely, small gestational age, infections, traumatic brain injury, and most psychosocial risk factors. Nineteen risk factors were associated with ADHD diagnosis (odds ratio range, 1.20-3.68), and adjusting for ADHD PRS and parental psychiatric history led to only minor attenuations. Only the interaction between ADHD PRS and maternal autoimmune disease survived correction for multiple testing. CONCLUSIONS: Higher ADHD PRS in the general population is associated with small increases in risk for certain birth-related and somatic ADHD risk factors, and broadly to psychosocial adversity. Evidence of gene-environment interaction was limited, as was confounding by ADHD PRS and family psychiatric history on ADHD risk factor associations. This suggests that the majority of the investigated ADHD risk factors act largely independently of current ADHD PRS to increase risk of ADHD.

Uncovering the genetic architecture of broad antisocial behavior through a genome-wide association study meta-analysis.

Despite the substantial heritability of antisocial behavior (ASB), specific genetic variants robustly associated with the trait have not been identified. The present study by the Broad Antisocial Behavior Consortium (BroadABC) meta-analyzed data from 28 discovery samples (N = 85,359) and five independent replication samples (N = 8058) with genotypic data and broad measures of ASB. We identified the first significant genetic associations with broad ASB, involving common intronic variants in the forkhead box protein P2 (FOXP2) gene (lead SNP rs12536335, p = 6.32 × 10-10). Furthermore, we observed intronic variation in Foxp2 and one of its targets (Cntnap2) distinguishing a mouse model of pathological aggression (BALB/cJ strain) from controls (BALB/cByJ strain). Polygenic risk score (PRS) analyses in independent samples revealed that the genetic risk for ASB was associated with several antisocial outcomes across the lifespan, including diagnosis of conduct disorder, official criminal convictions, and trajectories of antisocial development. We found substantial genetic correlations of ASB with mental health (depression rg = 0.63, insomnia rg = 0.47), physical health (overweight rg = 0.19, waist-to-hip ratio rg = 0.32), smoking (rg = 0.54), cognitive ability (intelligence rg = -0.40), educational attainment (years of schooling rg = -0.46) and reproductive traits (age at first birth rg = -0.58, father's age at death rg = -0.54). Our findings provide a starting point toward identifying critical biosocial risk mechanisms for the development of ASB.