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Background Childbirth may be a traumatic experience and vulnerability to posttraumatic stress disorder (PTSD) may increase the risk of postpartum depression (PPD). We investigated whether genetic vulnerability to PTSD as measured by polygenic score (PGS) increases the risk of PPD and whether a predisposition to PTSD in PPD cases exceeds that of major depressive disorder (MDD) outside the postpartum period. Methods This case-control study included participants from the iPSYCH2015, a case-cohort of all singletons born in Denmark between 1981 and 2008. Restricting to women born between 1981 and 1997 and excluding women with a first diagnosis other than depression (N = 22 613), 333 were identified with PPD. For each PPD case, 999 representing the background population and 993 with MDD outside the postpartum were matched by calendar year at birth, cohort selection, and age. PTSD PGS was calculated from summary statistics from the Psychiatric Genomics Consortium with LDpred2-auto. Odds ratios (ORs) were estimated using conditional logistic regression adjusted for parental psychiatric history and country of origin, PGS for MDD and age at first birth, and the first 10 principal components. Results The PTSD PGS was significantly associated with PPD (OR 1.42, 95% CI 1.20–1.68 per standard deviation increase in PTSD PGS) compared to healthy female controls. Genetic PTSD vulnerability in PPD cases did not exceed that of matched female depression cases outside the postpartum period (OR 1.10, 95% CI 0.94–1.30 per standard deviation increase). Conclusions Genetic vulnerability to PTSD increased the risk of PPD but did not differ between PPD cases and women with depression at other times.

Poor school performance is linked to higher risks of self-harm. The association might be explained through genetic liabilities for depression or educational attainment. We investigated the association between school performance and self-harm in a population-based sample while assessing the potential influence of polygenic risk scores (PRSs) for depression (PRSMDD) and for educational attainment (PRSEDU). We conducted a follow-up study of individuals born 1987–98 and followed from age 18 until 2016. The total sample consisted of a case group (23,779 diagnosed with mental disorders; schizophrenia, bipolar disorder, depression, autism, and attention deficit hyperactivity disorder (ADHD) and a randomly sampled comparison group (n = 10,925). Genome-wide data were obtained from the Neonatal Screening Biobank and information on school performance, family psychiatric history, and socioeconomic status from national administrative registers. Individuals in the top PRSMDD decile were at higher self-harm risk in the case group (IRR: 1.30; 95% CI 1.15–1.46), whereas individuals in the top PRSEDU decile were at lower self-harm risk (IRR: 0.63; 95% CI: 0.55–0.74). Poorer school performance was associated with higher self-harm risk in persons diagnosed with any mental disorder (IRR: 1.69; 95% CI: 1.44–1.99) and among the comparison group (IRR: 7.93; 95% CI: 4.47–15.18). Observed effects of PRSMDD and PRSEDU on self-harm risk were strongest for individuals with poor school performance. Associations between PRSMDD and self-harm risk and between PRSEDU and self-harm risk were found. Nevertheless, these polygenic scores seem currently of limited clinical utility for identifying individuals at high self-harm risk.

Febrile seizures represent the most common type of pathological brain activity in young children and are influenced by genetic, environmental and developmental factors. In a minority of cases, febrile seizures precede later development of epilepsy. We conducted a genome-wide association study of febrile seizures in 7635 cases and 83 966 controls identifying and replicating seven new loci, all with P < 5 × 10−10. Variants at two loci were functionally related to altered expression of the fever response genes PTGER3 and IL10, and four other loci harboured genes (BSN, ERC2, GABRG2, HERC1) influencing neuronal excitability by regulating neurotransmitter release and binding, vesicular transport or membrane trafficking at the synapse. Four previously reported loci (SCN1A, SCN2A, ANO3 and 12q21.33) were all confirmed. Collectively, the seven novel and four previously reported loci explained 2.8% of the variance in liability to febrile seizures, and the single nucleotide polymorphism heritability based on all common autosomal single nucleotide polymorphisms was 10.8%. GABRG2, SCN1A and SCN2A are well-established epilepsy genes and, overall, we found positive genetic correlations with epilepsies (rg = 0.39, P = 1.68 × 10−4). Further, we found that higher polygenic risk scores for febrile seizures were associated with epilepsy and with history of hospital admission for febrile seizures. Finally, we found that polygenic risk of febrile seizures was lower in febrile seizure patients with neuropsychiatric disease compared to febrile seizure patients in a general population sample. In conclusion, this largest genetic investigation of febrile seizures to date implicates central fever response genes as well as genes affecting neuronal excitability, including several known epilepsy genes. Further functional and genetic studies based on these findings will provide important insights into the complex pathophysiological processes of seizures with and without fever.

Hydrocephalus is one of the most common congenital disorders of the central nervous system and often displays psychiatric co-morbidities, in particular autism spectrum disorder. The disease mechanisms behind hydrocephalus are complex and not well understood, but some association with dysfunctional cilia in the brain ventricles and subarachnoid space has been indicated. A better understanding of the genetic aetiology of hydrocephalus, including the role of ciliopathies, may bring insights into a potentially shared genetic aetiology. In this population-based case-cohort study, we, for the first time, investigated variants of postulated hydrocephalus candidate genes. Using these data, we aimed to investigate potential involvement of the ciliome in hydrocephalus and describe genotype–phenotype associations with an autism spectrum disorder. One-hundred and twenty-one hydrocephalus candidate genes were screened in a whole-exome-sequenced sub-cohort of the Lundbeck Foundation Initiative for Integrative Psychiatric Research study, comprising 72 hydrocephalus patients and 4181 background population controls. Candidate genes containing high-impact variants of interest were systematically evaluated for their involvement in ciliary function and an autism spectrum disorder. The median age at diagnosis for the hydrocephalus patients was 0 years (range 0–27 years), the median age at analysis was 22 years (11–35 years), and 70.5% were males. The median age for controls was 18 years (range 11–26 years) and 53.3% were males. Fifty-two putative hydrocephalus-associated variants in 34 genes were identified in 42 patients (58.3%). In hydrocephalus cases, we found increased, but not significant, enrichment of high-impact protein altering variants (odds ratio 1.51, 95% confidence interval 0.92–2.51, P = 0.096), which was driven by a significant enrichment of rare protein truncating variants (odds ratio 2.71, 95% confidence interval 1.17–5.58, P = 0.011). Fourteen of the genes with high-impact variants are part of the ciliome, whereas another six genes affect cilia-dependent processes during neurogenesis. Furthermore, 15 of the 34 genes with high-impact variants and three of eight genes with protein truncating variants were associated with an autism spectrum disorder. Because symptoms of other diseases may be neglected or masked by the hydrocephalus-associated symptoms, we suggest that patients with congenital hydrocephalus undergo clinical genetic assessment with respect to ciliopathies and an autism spectrum disorder. Our results point to the significance of hydrocephalus as a ciliary disease in some cases. Future studies in brain ciliopathies may not only reveal new insights into hydrocephalus but also, brain disease in the broadest sense, given the essential role of cilia in neurodevelopment. Munch et al. report 121 hydrocephalus candidate genes were screened in a whole-exome-sequenced cohort comprising 72 hydrocephalus patients and 4181 background population controls. The results 11 point to the significance of hydrocephalus as a ciliary disease in many cases, which may explain the frequent co-occurrence of other brain disease.Hydrocephalus is one of the most common congenital disorders of the central nervous system and often displays psychiatric co-morbidities, in particular autism spectrum disorder. The disease mechanisms behind hydrocephalus are complex and not well understood, but some association with dysfunctional cilia in the brain ventricles and subarachnoid space has been indicated. A better understanding of the genetic aetiology of hydrocephalus, including the role of ciliopathies, may bring insights into a potentially shared genetic aetiology. In this population-based case-cohort study, we, for the first time, investigated variants of postulated hydrocephalus candidate genes. Using these data, we aimed to investigate potential involvement of the ciliome in hydrocephalus and describe genotype-phenotype associations with an autism spectrum disorder. One-hundred and twenty-one hydrocephalus candidate genes were screened in a whole-exome-sequenced sub-cohort of the Lundbeck Foundation Initiative for Integrative Psychiatric Research study, comprising 72 hydrocephalus patients and 4181 background population controls. Candidate genes containing high-impact variants of interest were systematically evaluated for their involvement in ciliary function and an autism spectrum disorder. The median age at diagnosis for the hydrocephalus patients was 0 years (range 0-27 years), the median age at analysis was 22 years (11-35 years), and 70.5% were males. The median age for controls was 18 years (range 11-26 years) and 53.3% were males. Fifty-two putative hydrocephalus-associated variants in 34 genes were identified in 42 patients (58.3%). In hydrocephalus cases, we found increased, but not significant, enrichment of high-impact protein altering variants (odds ratio 1.51, 95% confidence interval 0.92-2.51, P = 0.096), which was driven by a significant enrichment of rare protein truncating variants (odds ratio 2.71, 95% confidence interval 1.17-5.58, P = 0.011). Fourteen of the genes with high-impact variants are part of the ciliome, whereas another six genes affect cilia-dependent processes during neurogenesis. Furthermore, 15 of the 34 genes with high-impact variants and three of eight genes with protein truncating variants were associated with an autism spectrum disorder. Because symptoms of other diseases may be neglected or masked by the hydrocephalus-associated symptoms, we suggest that patients with congenital hydrocephalus undergo clinical genetic assessment with respect to ciliopathies and an autism spectrum disorder. Our results point to the significance of hydrocephalus as a ciliary disease in some cases. Future studies in brain ciliopathies may not only reveal new insights into hydrocephalus but also, brain disease in the broadest sense, given the essential role of cilia in neurodevelopment.

BackgroundIn this study, we examined the relationship between polygenic liability for depression and number of stressful life events (SLEs) as risk factors for early-onset depression treated in inpatient, outpatient or emergency room settings at psychiatric hospitals in Denmark.MethodsData were drawn from the iPSYCH2012 case-cohort sample, a population-based sample of individuals born in Denmark between 1981 and 2005. The sample included 18 532 individuals who were diagnosed with depression by a psychiatrist by age 31 years, and a comparison group of 20 184 individuals. Information on SLEs was obtained from nationwide registers and operationalized as a time-varying count variable. Hazard ratios and cumulative incidence rates were estimated using Cox regressions.ResultsRisk for depression increased by 35% with each standard deviation increase in polygenic liability (p < 0.0001), and 36% (p < 0.0001) with each additional SLE. There was a small interaction between polygenic liability and SLEs (β = −0.04, p = 0.0009). The probability of being diagnosed with depression in a hospital-based setting between ages 15 and 31 years ranged from 1.5% among males in the lowest quartile of polygenic liability with 0 events by age 15, to 18.8% among females in the highest quartile of polygenic liability with 4+ events by age 15.ConclusionsThese findings suggest that although there is minimal interaction between polygenic liability and SLEs as risk factors for hospital-treated depression, combining information on these two important risk factors could potentially be useful for identifying high-risk individuals.

The complement system, including complement components 3 and 4 (C3, C4), traditionally has been linked to innate immunity. More recently, complement components have also been implicated in brain development and the risk of schizophrenia. Based on a large, population-based case-cohort study, we measured the blood concentrations of C3 and C4 in 68,768 neonates. We found a strong correlation between the concentrations of C3 and C4 (phenotypic correlation = 0.65,P-value < 1.0×10−100, genetic correlation = 0.38,P-value = 1.9×10−35). A genome-wide association study (GWAS) for C4 protein concentration identified 36 independent loci, 30 of which were in or near the major histocompatibility complex on chromosome 6 (which includes theC4gene), while six loci were found on six other chromosomes. A GWAS for C3 identified 15 independent loci, seven of which were located in theC3gene on chromosome 19, and eight loci on five other chromosomes. We found no association between (a) measured neonatal C3 and C4 concentrations, imputed C4 haplotypes, or predictedC4gene expression, with (b) schizophrenia (SCZ), bipolar disorder (BIP), depression (DEP), autism spectrum disorder, attention deficit hyperactivity disorder or anorexia nervosa diagnosed in later life. Mendelian randomisation (MR) suggested a small positive association between higher C4 protein concentration and an increased risk of SCZ, BIP, and DEP, but these findings did not persist in more stringent analyses. Evidence from MR supported causal relationships between C4 concentration and several autoimmune disorders: systemic lupus erythematosus (SLE, OR and 95% confidence interval, 0.37, 0.34 – 0.42); type-1 diabetes (T1D, 0.54, 0.50 - 0.58); multiple sclerosis (MS, 0.68, 0.63 - 0.74); rheumatoid arthritis (0.85, 0.80 - 0.91); and Crohn’s disease (1.26, 1.19 - 1.34). A phenome-wide association study (PheWAS) in UK Biobank confirmed that the genetic correlates of C4 concentration were associated a range of autoimmune disorders including coeliac disease, thyrotoxicosis, hypothyroidism, T1D, sarcoidosis, psoriasis, SLE and ankylosing spondylitis. We found no evidence of associations between C3 versus mental or autoimmune disorders based on either MR or PheWAS. In general, our results do not support the hypothesis that C4 is causally associated with the risk of SCZ (nor several other mental disorders). We provide new evidence to support the hypothesis that higher C4 concentration is associated with lower risks of autoimmune disorders.

Despite the large toll of opioid use disorder (OUD), genome-wide association studies (GWAS) of OUD to date have yielded few susceptibility loci. We performed a large-scale GWAS of OUD in individuals of European (EUR) and African (AFR) ancestry, optimizing genetic informativeness by performing MTAG (Multi-trait analysis of GWAS) with genetically correlated substance use disorders (SUDs). Meta-analysis included seven cohorts: the Million Veteran Program, Psychiatric Genomics Consortium, iPSYCH, FinnGen, Partners Biobank, BioVU, and Yale-Penn 3, resulting in a total N = 639,063 (Ncases = 20,686;Neffective = 77,026) across ancestries. OUD cases were defined as having a lifetime OUD diagnosis, and controls as anyone not known to meet OUD criteria. We estimated SNP-heritability (h2SNP) and genetic correlations (rg). Based on genetic correlation, we performed MTAG on OUD, alcohol use disorder (AUD), and cannabis use disorder (CanUD). A leave-one-out polygenic risk score (PRS) analysis was performed to compare OUD and OUD-MTAG PRS as predictors of OUD case status in Yale-Penn 3. The EUR meta-analysis identified three genome-wide significant (GWS; p ≤ 5 × 10−8) lead SNPs—one at FURIN (rs11372849; p = 9.54 × 10−10) and two OPRM1 variants (rs1799971, p = 4.92 × 10−09; rs79704991, p = 1.11 × 10−08; r2 = 0.02). Rs1799971 (p = 4.91 × 10−08) and another OPRM1 variant (rs9478500; p = 1.95 × 10−08; r2 = 0.03) were identified in the cross-ancestry meta-analysis. Estimated h2SNP was 12.75%, with strong rg with CanUD (rg = 0.82; p = 1.14 × 10−47) and AUD (rg = 0.77; p = 6.36 × 10−78). The OUD-MTAG resulted in a GWAS Nequivalent = 128,748 and 18 independent GWS loci, some mapping to genes or gene regions that have previously been associated with psychiatric or addiction phenotypes. The OUD-MTAG PRS accounted for 3.81% of OUD variance (beta = 0.61;s.e. = 0.066; p = 2.00 × 10−16) compared to 2.41% (beta = 0.45; s.e. = 0.058; p = 2.90 × 10−13) explained by the OUD PRS. The current study identified OUD variant associations at OPRM1, single variant associations with FURIN, and 18 GWS associations in the OUD-MTAG. The genetic architecture of OUD is likely influenced by both OUD-specific loci and loci shared across SUDs.

The predictive performance of polygenic scores (PGS) is largely dependent on the number of samples available to train the PGS. Increasing the sample size for a specific phenotype is expensive and takes time, but this sample size can be effectively increased by using genetically correlated phenotypes. We propose a framework to generate multi-PGS from thousands of publicly available genome-wide association studies (GWAS) with no need to individually select the most relevant ones. In this study, the multi-PGS framework increased prediction accuracy over single PGS for all included psychiatric disorders and other available outcomes, with prediction R2 increases of up to 9-fold for attention-deficit/hyperactivity disorder (ADHD) compared to a single PGS. We also generate multi-PGS for phenotypes without an existing GWAS and for case-case predictions, with up to 15-fold increases in prediction accuracy. We benchmark the multi-PGS framework against other methods and highlight its potential application to new emerging biobanks.

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.

Background: Asthma with severe exacerbation is one of the most common causes of hospitalization among young children. Exacerbations are typically triggered by respiratory infections, but the host factors causing recurrent infections and exacerbations in some children are poorly understood. As a result, current treatment options and preventive measures are inadequate. Objective: To identify genetic interaction associated with the development of childhood asthma. Methods: We performed an exhaustive search for pairwise interaction between genetic variants, single nucleotide polymorphisms (SNPs), using 1204 cases with a specific phenotype of early childhood asthma with severe exacerbations (age 2-6 years) combined with 5328 non-asthmatic controls. Replication was attempted in 3 independent populations, and potential underlying immune mechanisms were investigated in the COPSAC2010 and COPSAC2000 birth cohorts. Results: We found evidence of interaction, including replication in independent populations, between the known childhood asthma loci, CDHR3 and GSDMB. The effect of CDHR3 was dependent on the GSDMB genotype and this interaction was more pronounced for severe and early onset of disease. Blood immune analyses suggested a mechanism related to increased IL-17A production after viral stimulation. Conclusions: We found evidence of interaction between CDHR3 and GSDMB in development of early childhood asthma, possibly related to increased IL-17A response to viral infections. This study demonstrates the importance of focusing on specific disease subtypes for understanding the genetic mechanisms of asthma.

Proportional hazards models have previously been proposed to analyse time-to-event phenotypes in genome-wide association studies(GWAS). While proportional hazards models have many useful applications, their ability to identify genetic associations under different generative models where ascertainment is present in the analysed data is poorly understood. This includes widely used study designs such as case-control and case-cohort designs (e.g. the iPSYCH study design) where cases are commonly ascertained.Here we examine how recently proposed and computationally efficient Cox regression for GWAS perform under different generative models with and without ascertainment. We also propose the age-dependent liability threshold model (ADuLT), first introduced as the underlying model for the LT-FH++ method, as an alternative approach for time-to-event GWAS. We then benchmark ADuLT with SPACox and standard case-control GWAS using simulated data with varying degrees of ascertainment. We find Cox regression GWAS to underperform when cases are strongly ascertained (cases are oversampled by a factor larger than 5), regardless of the generative model used. In contrast, we found ADuLT to be robust to case-control ascertainment, while being much faster to run. We then used the methods to conduct GWAS for four psychiatric disorders, ADHD, Autism, Depression, and Schizophrenia in the iPSYCH case-cohort sample, which has a strong case-ascertainment. Summarising across all four mental disorders, ADuLT found 20 independent genome-wide significant associations, while case-control GWAS found 17 and SPACox found 8, consistent with our simulation results.As more genetic data are being linked to electronic health records, robust GWAS methods that can make use of age-of-onset information have the opportunity to increase power in analyses. We find that ADuLT to be a robust time-to-event GWAS method that performs on par with or better than Cox-regression GWAS, both in simulations and real data analyses of four psychiatric disorders. ADuLT has been implemented in an R package called LTFHPlus, and is available on GitHub.

Analyses of the polygenic architecture of childhood, persistent and late-diagnosed attention-deficit hyperactivity disorder (ADHD) in a Danish population-based case-cohort sample identify differences among ADHD subgroups with respect to common and rare variants. Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with onset in childhood (childhood ADHD); two-thirds of affected individuals continue to have ADHD in adulthood (persistent ADHD), and sometimes ADHD is diagnosed in adulthood (late-diagnosed ADHD). We evaluated genetic differences among childhood (n = 14,878), persistent (n = 1,473) and late-diagnosed (n = 6,961) ADHD cases alongside 38,303 controls, and rare variant differences in 7,650 ADHD cases and 8,649 controls. We identified four genome-wide significant loci for childhood ADHD and one for late-diagnosed ADHD. We found increased polygenic scores for ADHD in persistent ADHD compared with the other two groups. Childhood ADHD had higher genetic overlap with hyperactivity and autism compared with late-diagnosed ADHD and the highest burden of rare protein-truncating variants in evolutionarily constrained genes. Late-diagnosed ADHD had a larger genetic overlap with depression than childhood ADHD and no increased burden in rare protein-truncating variants. Overall, these results suggest a genetic influence on age at first ADHD diagnosis, persistence of ADHD and the different comorbidity patterns among the groups.

Currently, psychiatric diagnoses are, in contrast to most other medical fields, based on subjective symptoms and observable signs and call for new and improved diagnostics to provide the most optimal care. On the basis of a deep learning approach, we performed unsupervised patient stratification of 19,636 patients with depression [major depressive disorder (MDD)] and/or schizophrenia (SCZ) and 22,467 population controls from the iPSYCH2012 case cohort. We integrated data of disorder severity, history of mental disorders and disease comorbidities, genetics, and medical birth data. From this, we stratified the individuals in six and seven unique clusters for MDD and SCZ, respectively. When censoring data until diagnosis, we could predict MDD clusters with areas under the curve (AUCs) of 0.54 to 0.80 and SCZ clusters with AUCs of 0.71 to 0.86. Overall cases and controls could be predicted with an AUC of 0.81, illustrating the utility of data-driven subgrouping in psychiatry.

The vitamin D binding protein (DBP), encoded by the group-specific component (GC) gene, is a much-studied component of the vitamin D system. In a genome-wide association study of DBP concentration in 65,589 neonates, we identified 26 independent loci, 17 of which were in or close to the GC gene, with fine-mapping identifying 2 loci on chromosomes 12 and 17 (missense variants within SH2B3 and GSDMA, respectively). When adjusted for key GC haplotypes, we found 15 independent loci distributed over 10 chromosomes. Mendelian randomization analyses found evidence consistent with a unidirectional, causal effect of higher DBP concentration and (a) higher 25 hydroxyvitamin D (25OHD) concentration, and (b) a reduced risk of multiple sclerosis and rheumatoid arthritis. A phenome-wide association study in an external dataset confirmed that higher DBP concentration was associated with higher 25OHD concentration and a reduced risk of vitamin D deficiency. Our study provides new insights into the influence of DBP on vitamin D status and a range of health outcomes.

Genetic studies have repeatedly shown that the Bromodomain containing 1 gene, BRD1, is involved in determining mental health, and the importance of the BRD1 protein for normal brain function has been studied in both cell models and constitutive haploinsufficient Brd1+/− mice. Homozygosity for inactivated Brd1 alleles is lethal during embryonic development in mice. In order to further characterize the molecular functions of BRD1 in the brain, we have developed a novel Brd1 knockout mouse model (Brd1−/−) with bi-allelic conditional inactivation of Brd1 in the central nervous system. Brd1−/− mice were viable but smaller and with reduced muscle strength. They showed reduced exploratory behavior and increased sensitivity to pentylenetetrazole-induced seizures supporting the previously described GABAergic dysfunction in constitutive Brd1+/− mice. Because BRD1 takes part in protein complexes with histone binding and modifying functions, we investigated the effect of BRD1 depletion on the global histone modification pattern in mouse brain by mass spectrometry. We found decreased levels of histone H3 acetylation (H3K9ac, H3K14ac, and H3K18ac) and increased N-tail clipping in consequence of BRD1 depletion. Collectively, the presented results support that BRD1 controls gene expression at the epigenetic level by regulating histone H3 proteoforms in the brain.

Objective: Febrile seizure is a common childhood disorder that affects 2–5% of all children, and is associated with later development of epilepsy and psychiatric disorders. This study determines how the incidence of febrile seizures correlates with birth characteristics, age, sex and brain development. Methods: This is a cohort study of all children born Denmark between 1977 and 2011 who were alive at 3 months of age (N = 2,103,232). The Danish National Patient Register was used to identify children with febrile seizures up to 5 years of age. Follow-up ended on 31 December 2016 when all cohort members had potentially reached 5 years of age. Results: In total, 75,593 (3.59%, 95% CI: 3.57–3.62%) were diagnosed with febrile seizures. Incidence peaked at 16.7 months of age (median: 16.7 months, interquartile range: 12.5–24.0). The 5-year cumulative incidence of febrile seizures increased with decreasing birth weight (

Background: Nocturnal enuresis (bedwetting) is a common disorder affecting 10–16% of 7-year-old children globally. Nocturnal enuresis is highly heritable, but its genetic determinants remain unknown. We aimed to identify genetic variants associated with nocturnal enuresis and explore its genetic architecture and underlying biology. Methods: We did a genome-wide association study (GWAS) of nocturnal enuresis. Nocturnal enuresis cases were identified in iPSYCH2012, a large Danish population-based case cohort established to investigate mental disorders, on the basis of 10th revision of the International Statistical Classification of Diseases (ICD-10) diagnoses and redeemed desmopressin prescriptions in Danish registers. The GWAS was done in a genetically homogeneous sample of unrelated individuals using logistic regression with relevant covariates. All genome-wide significant variants were analysed for their association with nocturnal enuresis in an independent Icelandic sample from deCODE genetics. Standardised polygenic risk scores for attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder were constructed from summary statistics of large GWASs and analysed for association with nocturnal enuresis. Findings: The GWAS included 3882 nocturnal enuresis cases and 31 073 controls. We found two loci at chromosome 6 and chromosome 13 significantly associated with nocturnal enuresis. Six genetic variants at the two loci (five variants at chromosome 6q16.2 and one variant at chromosome 13q22.3) surpassed the threshold for genome-wide significance (p−8). There were two lead variants: rs9376454 (chromosome 6q16.2), with an odds ratio (OR) of 1·199 (95% CI 1·135–1·267; p=9·91 × 10−11), and rs60721117 (chromosome 13q22.3), with an OR of 1·149 (1·095–1·205; p=1·21 × 10−8). All associated variants in the chromosome 6 locus were replicated (p−3) in the independent Icelandic cohort of 5475 nocturnal enuresis cases and 303 996 controls, whereas the associated variant in the chromosome 13 locus showed nominal significant association (p=0·031). The percentage of nocturnal enuresis phenotypic variance explained by the common genetic variants was 23·9–30·4%. Polygenic risk for ADHD was associated with nocturnal enuresis (OR 1·06, 95% CI, 1·01–1·10; p=0·011). Among the potential nocturnal enuresis risk genes mapped, PRDM13 and EDNRB have biological functions associated with known pathophysiological mechanisms in nocturnal enuresis, and SIM1 regulates the formation of the hypothalamic neuroendocrine lineage that produces arginine vasopressin, a well known nocturnal enuresis drug target. Interpretation: This study shows that common genetic variants contribute considerably to nocturnal enuresis, and it identifies potential nocturnal enuresis risk genes with roles in sleep, urine production, and bladder function. Given that available treatments target these mechanisms, any of the identified genes and their functional gene networks are potential drug targets. Funding: The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Stanley Foundation.

BACKGROUND: Tourette syndrome (TS) is often found comorbid with other neurodevelopmental disorders across the impulsivity-compulsivity spectrum, with attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD) as most prevalent. This points to the possibility of a common etiological thread along an impulsivity-compulsivity continuum.METHODS: Investigating the shared genetic basis across TS, ADHD, ASD, and OCD, we undertook an evaluation of cross-disorder genetic architecture and systematic meta-analysis, integrating summary statistics from the latest genome-wide association studies (93,294 individuals, 6,788,510 markers).RESULTS: As previously identified, a common unifying factor connects TS, ADHD, and ASD, while TS and OCD show the highest genetic correlation in pairwise testing among these disorders. Thanks to a more homogeneous set of disorders and a targeted approach that is guided by genetic correlations, we were able to identify multiple novel hits and regions that seem to play a pleiotropic role for the specific disorders analyzed here and could not be identified through previous studies. In the TS-ADHD-ASD genome-wide association study single nucleotide polymorphism-based and gene-based meta-analysis, we uncovered 13 genome-wide significant regions that host single nucleotide polymorphisms with a high posterior probability for association with all three studied disorders (m-value > 0.9), 11 of which were not identified in previous cross-disorder analysis. In contrast, we also identified two additional pleiotropic regions in the TS-OCD meta-analysis. Through conditional analysis, we highlighted genes and genetic regions that play a specific role in a TS-ADHD-ASD genetic factor versus TS-OCD. Cross-disorder tissue specificity analysis implicated the hypothalamus-pituitary-adrenal gland axis in TS-ADHD-ASD.CONCLUSIONS: Our work underlines the value of redefining the framework for research across traditional diagnostic categories.

Endophenotypes are heritable and quantifiable traits indexing genetic liability for a disorder. Here, we examined three potential endophenotypes, working memory function, response inhibition, and reaction time variability, for attention-deficit hyperactivity disorder (ADHD) measured as a dimensional latent trait in a large general population sample derived from the Adolescent Brain Cognitive DevelopmentSM Study. The genetic risk for ADHD was estimated using polygenic risk scores (PRS) whereas ADHD traits were quantified as a dimensional continuum using Bartlett factor score estimates, derived from Attention Problems items from the Child Behaviour Checklist and Effortful Control items from the Early Adolescent Temperament Questionnaire-Revised. The three candidate cognitive endophenotypes were quantified using task-based performance measures. Higher ADHD PRSs were associated with higher ADHD traits, as well as poorer working memory performance and increased reaction time variability. Lower working memory performance, poorer response inhibition, and increased reaction time variability were associated with more pronounced ADHD traits. Working memory and reaction time variability partially statistically mediated the relationship between ADHD PRS and ADHD traits, explaining 14% and 16% of the association, respectively. The mediation effect was specific to the genetic risk for ADHD and did not generalise to genetic risk for four other major psychiatric disorders. Together, these findings provide robust evidence from a large general population sample that working memory and reaction time variability can be considered endophenotypes for ADHD that mediate the relationship between ADHD PRS and ADHD traits.

While over a hundred genes are significantly associated with autism, little is known about the prevalence of variants affecting them in the general population. Nor do we fully appreciate the phenotypic diversity beyond the formal autism diagnosis. Using data from more than 13,000 autistic individuals and 210,000 undiagnosed individuals, we provide a gene-level map of the odds ratio for autism associated to rare loss-of-function (LoF) variants in 185 genes robustly associated with autism, alongside 2,492 genes displaying intolerance to LoF variants. In contrast to autism-centric approaches, we investigated the phenotype of undiagnosed individuals heterozygous for such variants and show that they exhibit a decrease in fluid intelligence, qualification level and income, and an increase in material deprivation. These effects were larger for LoFs in autism-associated genes than in other LoF-intolerant genes and appeared largely independent of sex and polygenic scores for autism. Using brain imaging data from 21,049 UK-Biobank individuals, we provide evidence for smaller cortical surface area and volume among carriers of LoFs in genes with high odds ratios for autism. Our gene-level map is a key resource to distinguish genes with high and low odds ratio for autism, and highlights the importance of including quantitative data on both diagnosed and undiagnosed individuals to better delineate the effect of genetic variants beyond the categorical diagnosis. Data are available at https://genetrek.pasteur.fr/.