Publications by authors named "Anders D Børglum"

162 Publications

Genetic, Clinical, and Sociodemographic Factors Associated With Stimulant Treatment Outcomes in ADHD.

Am J Psychiatry 2021 Jun 22:appiajp202020121686. Epub 2021 Jun 22.

Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Copenhagen and Aarhus, Denmark (Brikell, Wimberley, Albiñana, Pedersen, Vilhjálmsson, Agerbo, Demontis, Børglum, Schork, LaBianca, Werge, Mors, Hougaard, Mortensen, Dalsgaard); National Center for Register-Based Research, Department of Economics and Business Economics, Aarhus University, Aarhus, Denmark (Brikell, Wimberley, Albiñana, Pedersen, Vilhjálmsson, Agerbo, Mortensen, Dalsgaard); Center for Integrated Register-Based Research (CIRRAU), Aarhus University, Aarhus, Denmark (Wimberley, Agerbo, Mortensen, Dalsgaard); Department of Biomedicine and Center for Integrative Sequencing, Aarhus University, Aarhus, Denmark (Demontis, Børglum); Center for Genomics and Personalized Medicine, Central Region Denmark and Aarhus University, Aarhus, Denmark (Demontis, Børglum); Neurogenomics Division, Translational Genomics Research Institute, Phoenix (Schork); Institute of Biological Psychiatry, Mental Health Services, Copenhagen University Hospital, Copenhagen (Schork, LaBianca, Werge); Department of Clinical Medicine and Center for GeoGenetics, GLOBE Institute, University of Copenhagen, Copenhagen (Werge); Psychosis Research Unit, Aarhus University Hospital, Psychiatry, Aarhus, Denmark (Mors); Department for Congenital Disorders, Statens Serum Institut, Copenhagen (Hougaard); Division of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Child and Adolescent Psychiatry, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff, U.K. (Thapar).

Objective: Stimulant medications are effective for treating attention deficit hyperactivity disorder (ADHD), yet discontinuation and switch to nonstimulant ADHD medications are common. This study aimed to identify genetic, clinical, and sociodemographic factors influencing stimulant treatment initiation, discontinuation, and switch to nonstimulants in individuals with ADHD.

Methods: The authors obtained genetic and national register data for 9,133 individuals with ADHD from the Danish iPSYCH2012 sample and defined stimulant treatment initiation, discontinuation, and switch from prescriptions. For each stimulant treatment outcome, they examined associations with polygenic risk scores (PRSs) for psychiatric disorders and clinical and sociodemographic factors using survival analyses, and conducted genome-wide association studies (GWASs) and estimated single-nucleotide polymorphism heritability (h).

Results: Eighty-one percent of the sample initiated stimulant treatment. Within 2 years, 45% discontinued stimulants and 15% switched to nonstimulants. Bipolar disorder PRS (hazard ratio=1.05, 95% CI=1.02, 1.09) and schizophrenia PRS (hazard ratio=1.07, 95% CI=1.03, 1.11) were associated with discontinuation. Depression, bipolar disorder, and schizophrenia PRSs were marginally but not significantly associated with switch (hazard ratio range, 1.05-1.07). No associations were observed for ADHD and autism PRSs. Individuals diagnosed with ADHD at age 13 or older had higher rates of stimulant initiation, discontinuation, and switch (hazard ratio range, 1.27-2.01). Psychiatric comorbidities generally reduced rates of initiation (hazard ratio range, 0.84-0.88) and increased rates of discontinuation (hazard ratio range, 1.19-1.45) and switch (hazard ratio range, 1.40-2.08). h estimates were not significantly different from zero. No GWAS hits were identified for stimulant initiation or discontinuation. A locus on chromosome 16q23.3 reached genome-wide significance for switch.

Conclusions: The study findings suggest that individuals with ADHD with higher polygenic liability for mood and/or psychotic disorders, delayed ADHD diagnosis, and psychiatric comorbidities have a higher risk for stimulant treatment discontinuation and switch to nonstimulants. Despite the study's limited sample size, one putative GWAS hit for switch was identified, illustrating the potential of utilizing genomics linked to prescription databases to advance ADHD pharmacogenomics.
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http://dx.doi.org/10.1176/appi.ajp.2020.20121686DOI Listing
June 2021

Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders.

Biol Psychiatry 2021 Mar 23. Epub 2021 Mar 23.

Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, Illinois; Department of Psychiatry and Behavioral Sciences, North Shore University Health System, Evanston, Illinois.

Background: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk.

Methods: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH.

Results: Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10; rs73033497, p = 8.8 × 10; rs7914279, p = 6.4 × 10), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05).

Conclusions: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.
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http://dx.doi.org/10.1016/j.biopsych.2021.02.972DOI Listing
March 2021

Corrigendum to "Genetic factors underlying the bidirectional relationship between autoimmune and mental disorders - Findings from a Danish population-based study" [Brain Behav. Immun. 91 (2021) 10-23].

Brain Behav Immun 2021 Aug 27;96:307-308. Epub 2021 May 27.

CORE-Copenhagen Research Centre for Mental Health, Mental Health Centre Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark; Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address:

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http://dx.doi.org/10.1016/j.bbi.2021.05.019DOI Listing
August 2021

Pharmacogenetic genotype and phenotype frequencies in a large Danish population-based case-cohort sample.

Transl Psychiatry 2021 05 18;11(1):294. Epub 2021 May 18.

Department of Affective Disorders, Aarhus University Hospital Psychiatry, Aarhus, Denmark.

Pharmacogenetics aims to improve clinical care by studying the relationship between genetic variation and variable drug response. Large population-based datasets could improve our current understanding of pharmacogenetics from selected study populations. We provide real-world pharmacogenetic frequencies of genotypes and (combined) phenotypes of a large Danish population-based case-cohort sample (iPSYCH2012; data of the Integrative Psychiatric Research consortium). The genotyped sample consists of 77,684 individuals, of which 51,464 individuals had diagnoses of severe mental disorders (SMD case-cohort) and 26,220 were individuals randomly selected from the Danish population (population cohort). Array-based genotype data imputed to 8.4 million genetic variants was searched for a selected pharmacogenetic panel of 42 clinically relevant variants and a CYP2D6 gene deletion and duplication. We identified 19 of 42 variants. Minor allele frequencies (MAFs) were consistent with previously reported MAFs, and did not differ between SMD cases and population cohorts. Almost all individuals carried at least one genetic variant (> 99.9%) and 87% carried three or more genetic variants. When genotypes were translated into phenotypes, also > 99.9% of individuals had at least one divergent phenotype (i.e. divergent from the common phenotypes considered normal, e.g. extensive metabolizer). The high number of identified individuals with at least one pharmacogenetic variant or divergent phenotype indicates the importance of pharmacogenetic panel-based genotyping. Combined CYP2C19-CYP2D6 phenotypes revealed that 72.7% of individuals had divergent phenotypes for one or both enzymes. As CYP2D6 and CYP2C19 have an important role in the metabolism of psychotropic drugs, this indicates the relevance of pharmacogenetic testing specifically in individuals using psychotropic drugs.
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http://dx.doi.org/10.1038/s41398-021-01417-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131614PMC
May 2021

Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology.

Nat Genet 2021 06 17;53(6):817-829. Epub 2021 May 17.

Department of Neuroscience, Istituto Di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.

Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.
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http://dx.doi.org/10.1038/s41588-021-00857-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192451PMC
June 2021

Leveraging both individual-level genetic data and GWAS summary statistics increases polygenic prediction.

Am J Hum Genet 2021 06 7;108(6):1001-1011. Epub 2021 May 7.

The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, 8210 Aarhus V, Denmark; National Centre for Register-Based Research, Aarhus University, 8210 Aarhus V, Denmark; Bioinformatics Research Centre, Aarhus University, 8000 Aarhus C, Denmark. Electronic address:

The accuracy of polygenic risk scores (PRSs) to predict complex diseases increases with the training sample size. PRSs are generally derived based on summary statistics from large meta-analyses of multiple genome-wide association studies (GWASs). However, it is now common for researchers to have access to large individual-level data as well, such as the UK Biobank data. To the best of our knowledge, it has not yet been explored how best to combine both types of data (summary statistics and individual-level data) to optimize polygenic prediction. The most widely used approach to combine data is the meta-analysis of GWAS summary statistics (meta-GWAS), but we show that it does not always provide the most accurate PRS. Through simulations and using 12 real case-control and quantitative traits from both iPSYCH and UK Biobank along with external GWAS summary statistics, we compare meta-GWAS with two alternative data-combining approaches, stacked clumping and thresholding (SCT) and meta-PRS. We find that, when large individual-level data are available, the linear combination of PRSs (meta-PRS) is both a simple alternative to meta-GWAS and often more accurate.
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http://dx.doi.org/10.1016/j.ajhg.2021.04.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206385PMC
June 2021

Polygenic liability, stressful life events and risk for secondary-treated depression in early life: a nationwide register-based case-cohort study.

Psychol Med 2021 May 5:1-10. Epub 2021 May 5.

The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus, Denmark.

Background: In 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.

Methods: Data 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.

Results: Risk 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.

Conclusions: These 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.
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http://dx.doi.org/10.1017/S0033291721001410DOI Listing
May 2021

Exploring associations between constipation, severity of neurofibromatosis type 1 and NF1 mutational spectrum.

Sci Rep 2021 Apr 28;11(1):9179. Epub 2021 Apr 28.

Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.

Neurofibromatosis type 1 (NF1) is inherited in an autosomal dominant manner and is a rather common rare disease. Until recently, studies on gastrointestinal symptoms in patients with NF1 have been few and mostly described as case reports. In three previously published studies, the frequency of constipation in patients with NF1 has been found to be as high as 30%. In this study, associations between the frequency of constipation and NF1 disease severity and NF1 mutational spectrum were investigated. Among 277 patients with NF1, 49 had constipation. The highest rate of constipation was found among patients with a high perception of NF1 illness burden, and patients with constipation had a significantly higher NF1 illness burden when comparing the "not bothered" and the "very bothered" (p = 0.013). We found no significant association between constipation and the remaining measures on severity of NF1, nor between constipation and genetic variants. When observing the NF1 mutational spectrum, one variant (c.1013A>G (p.Asp338Gly/p.?) was identified in three patients with constipation of which two patients were related. The variant c.2970_2972delAAT (p.Met992del) associated with a mild NF1 phenotype was identified in two related patients with constipation. This study is the first to explore the association between symptoms of constipation, NF1 severity, and NF1 mutational spectrum. The results suggest an association between constipation and a high degree of illness burden. Awareness of this association among physicians could lead to more patients with NF1 being diagnosed with constipation. Constipation impacts on quality of life, hence a timely diagnosis and treatment will improve quality of life.
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http://dx.doi.org/10.1038/s41598-021-87686-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080678PMC
April 2021

Genetic analyses identify widespread sex-differential participation bias.

Nat Genet 2021 05 22;53(5):663-671. Epub 2021 Apr 22.

Faculty of Behavioural and Movement Sciences, Biological Psychology, Vrije Universiteit, Amsterdam, the Netherlands.

Genetic association results are often interpreted with the assumption that study participation does not affect downstream analyses. Understanding the genetic basis of participation bias is challenging since it requires the genotypes of unseen individuals. Here we demonstrate that it is possible to estimate comparative biases by performing a genome-wide association study contrasting one subgroup versus another. For example, we showed that sex exhibits artifactual autosomal heritability in the presence of sex-differential participation bias. By performing a genome-wide association study of sex in approximately 3.3 million males and females, we identified over 158 autosomal loci spuriously associated with sex and highlighted complex traits underpinning differences in study participation between the sexes. For example, the body mass index-increasing allele at FTO was observed at higher frequency in males compared to females (odds ratio = 1.02, P = 4.4 × 10). Finally, we demonstrated how these biases can potentially lead to incorrect inferences in downstream analyses and propose a conceptual framework for addressing such biases. Our findings highlight a new challenge that genetic studies may face as sample sizes continue to grow.
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http://dx.doi.org/10.1038/s41588-021-00846-7DOI Listing
May 2021

Investigating Shared Genetic Basis Across Tourette Syndrome and Comorbid Neurodevelopmental Disorders Along the Impulsivity-Compulsivity Spectrum.

Biol Psychiatry 2021 Jan 8. Epub 2021 Jan 8.

Department of Biological Sciences, Purdue University, West Lafayette, Indiana. Electronic address:

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.
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http://dx.doi.org/10.1016/j.biopsych.2020.12.028DOI Listing
January 2021

Examining Sex-Differentiated Genetic Effects Across Neuropsychiatric and Behavioral Traits.

Biol Psychiatry 2021 06 9;89(12):1127-1137. Epub 2021 Jan 9.

Psychiatric & Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

Background: The origin of sex differences in prevalence and presentation of neuropsychiatric and behavioral traits is largely unknown. Given established genetic contributions and correlations, we tested for a sex-differentiated genetic architecture within and between traits.

Methods: Using European ancestry genome-wide association summary statistics for 20 neuropsychiatric and behavioral traits, we tested for sex differences in single nucleotide polymorphism (SNP)-based heritability and genetic correlation (r < 1). For each trait, we computed per-SNP z scores from sex-stratified regression coefficients and identified genes with sex-differentiated effects using a gene-based approach. We calculated correlation coefficients between z scores to test for shared sex-differentiated effects. Finally, we tested for sex differences in across-trait genetic correlations.

Results: We observed no consistent sex differences in SNP-based heritability. Between-sex, within-trait genetic correlations were high, although <1 for educational attainment and risk-taking behavior. We identified 4 genes with significant sex-differentiated effects across 3 traits. Several trait pairs shared sex-differentiated effects. The top genes with sex-differentiated effects were enriched for multiple gene sets, including neuron- and synapse-related sets. Most between-trait genetic correlation estimates were not significantly different between sexes, with exceptions (educational attainment and risk-taking behavior).

Conclusions: Sex differences in the common autosomal genetic architecture of neuropsychiatric and behavioral phenotypes are small and polygenic and unlikely to fully account for observed sex-differentiated attributes. Larger sample sizes are needed to identify sex-differentiated effects for most traits. For well-powered studies, we identified genes with sex-differentiated effects that were enriched for neuron-related and other biological functions. This work motivates further investigation of genetic and environmental influences on sex differences.
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http://dx.doi.org/10.1016/j.biopsych.2020.12.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163257PMC
June 2021

Risk variants and polygenic architecture of disruptive behavior disorders in the context of attention-deficit/hyperactivity disorder.

Nat Commun 2021 01 25;12(1):576. Epub 2021 Jan 25.

The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark.

Attention-Deficit/Hyperactivity Disorder (ADHD) is a childhood psychiatric disorder often comorbid with disruptive behavior disorders (DBDs). Here, we report a GWAS meta-analysis of ADHD comorbid with DBDs (ADHD + DBDs) including 3802 cases and 31,305 controls. We identify three genome-wide significant loci on chromosomes 1, 7, and 11. A meta-analysis including a Chinese cohort supports that the locus on chromosome 11 is a strong risk locus for ADHD + DBDs across European and Chinese ancestries (rs7118422, P = 3.15×10, OR = 1.17). We find a higher SNP heritability for ADHD + DBDs (h = 0.34) when compared to ADHD without DBDs (h = 0.20), high genetic correlations between ADHD + DBDs and aggressive (r = 0.81) and anti-social behaviors (r = 0.82), and an increased burden (polygenic score) of variants associated with ADHD and aggression in ADHD + DBDs compared to ADHD without DBDs. Our results suggest an increased load of common risk variants in ADHD + DBDs compared to ADHD without DBDs, which in part can be explained by variants associated with aggressive behavior.
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http://dx.doi.org/10.1038/s41467-020-20443-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835232PMC
January 2021

Identification of genetic loci associated with nocturnal enuresis: a genome-wide association study.

Lancet Child Adolesc Health 2021 03 15;5(3):201-209. Epub 2021 Jan 15.

The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Denmark; Department of Biomedicine, Aarhus University, Aarhus, Denmark; Centre for Integrative Sequencing (iSEQ), Aarhus University, Aarhus, Denmark; Centre for Genomics and Personalized Medicine (CGPM), Aarhus University, Aarhus, Denmark. Electronic address:

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<5 × 10). 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), and rs60721117 (chromosome 13q22.3), with an OR of 1·149 (1·095-1·205; p=1·21 × 10). All associated variants in the chromosome 6 locus were replicated (p<8 × 10) 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.
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http://dx.doi.org/10.1016/S2352-4642(20)30350-3DOI Listing
March 2021

Risk of Early-Onset Depression Associated With Polygenic Liability, Parental Psychiatric History, and Socioeconomic Status.

JAMA Psychiatry 2021 Apr;78(4):387-397

Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus, Denmark.

Importance: Combining information on polygenic risk scores (PRSs) with other known risk factors could potentially improve the identification of risk of depression in the general population. However, to our knowledge, no study has estimated the association of PRS with the absolute risk of depression, and few have examined combinations of the PRS and other important risk factors, including parental history of psychiatric disorders and socioeconomic status (SES), in the identification of depression risk.

Objective: To assess the individual and joint associations of PRS, parental history, and SES with relative and absolute risk of early-onset depression.

Design, Setting, And Participants: This case-cohort study included participants from the iPSYCH2012 sample, a case-cohort sample of all singletons born in Denmark between May 1, 1981, and December 31, 2005. Hazard ratios (HRs) and absolute risks were estimated using Cox proportional hazards regression for case-cohort designs.

Exposures: The PRS for depression; SES measured using maternal educational level, maternal marital status, and paternal employment; and parental history of psychiatric disorders (major depression, bipolar disorder, other mood or psychotic disorders, and other psychiatric diagnoses).

Main Outcomes And Measures: Hospital-based diagnosis of depression from inpatient, outpatient, or emergency settings.

Results: Participants included 17 098 patients with depression (11 748 [68.7%] female) and 18 582 (9429 [50.7%] male) individuals randomly selected from the base population. The PRS, parental history, and lower SES were all significantly associated with increased risk of depression, with HRs ranging from 1.32 (95% CI, 1.29-1.35) per 1-SD increase in PRS to 2.23 (95% CI, 1.81-2.64) for maternal history of mood or psychotic disorders. Fully adjusted models had similar effect sizes, suggesting that these risk factors do not confound one another. Absolute risk of depression by the age of 30 years differed substantially, depending on an individual's combination of risk factors, ranging from 1.0% (95% CI, 0.1%-2.0%) among men with high SES in the bottom 2% of the PRS distribution to 23.7% (95% CI, 16.6%-30.2%) among women in the top 2% of PRS distribution with a parental history of psychiatric disorders.

Conclusions And Relevance: This study suggests that current PRSs for depression are not more likely to be associated with major depressive disorder than are other known risk factors; however, they may be useful for the identification of risk in conjunction with other risk factors.
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http://dx.doi.org/10.1001/jamapsychiatry.2020.4172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7807393PMC
April 2021

FUT2-ABO epistasis increases the risk of early childhood asthma and Streptococcus pneumoniae respiratory illnesses.

Nat Commun 2020 12 16;11(1):6398. Epub 2020 Dec 16.

Department of Human Genetics, University of Chicago, Chicago, IL, USA.

Asthma with severe exacerbation is the most common cause of hospitalization among young children. We aim to increase the understanding of this clinically important disease entity through a genome-wide association study. The discovery analysis comprises 2866 children experiencing severe asthma exacerbation between ages 2 and 6 years, and 65,415 non-asthmatic controls, and we replicate findings in 918 children from the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC) birth cohorts. We identify rs281379 near FUT2/MAMSTR on chromosome 19 as a novel risk locus (OR = 1.18 (95% CI = 1.11-1.25), P = 2.6 × 10) as well as a biologically plausible interaction between functional variants in FUT2 and ABO. We further discover and replicate a potential causal mechanism behind this interaction related to S. pneumoniae respiratory illnesses. These results suggest a novel mechanism of early childhood asthma and demonstrates the importance of phenotype-specificity for discovery of asthma genes and epistasis.
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http://dx.doi.org/10.1038/s41467-020-19814-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744576PMC
December 2020

The genetic architecture of sporadic and multiple consecutive miscarriage.

Nat Commun 2020 11 25;11(1):5980. Epub 2020 Nov 25.

University of Queensland, St Lucia, QLD, Australia.

Miscarriage is a common, complex trait affecting ~15% of clinically confirmed pregnancies. Here we present the results of large-scale genetic association analyses with 69,054 cases from five different ancestries for sporadic miscarriage, 750 cases of European ancestry for multiple (≥3) consecutive miscarriage, and up to 359,469 female controls. We identify one genome-wide significant association (rs146350366, minor allele frequency (MAF) 1.2%, P = 3.2 × 10, odds ratio (OR) = 1.4) for sporadic miscarriage in our European ancestry meta-analysis and three genome-wide significant associations for multiple consecutive miscarriage (rs7859844, MAF = 6.4%, P = 1.3 × 10, OR = 1.7; rs143445068, MAF = 0.8%, P = 5.2 × 10, OR = 3.4; rs183453668, MAF = 0.5%, P = 2.8 × 10, OR = 3.8). We further investigate the genetic architecture of miscarriage with biobank-scale Mendelian randomization, heritability, and genetic correlation analyses. Our results show that miscarriage etiopathogenesis is partly driven by genetic variation potentially related to placental biology, and illustrate the utility of large-scale biobank data for understanding this pregnancy complication.
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http://dx.doi.org/10.1038/s41467-020-19742-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689465PMC
November 2020

Genome-wide association study across pediatric central nervous system tumors implicates shared predisposition and points to 1q25.2 (PAPPA2) and 11p12 (LRRC4C) as novel candidate susceptibility loci.

Childs Nerv Syst 2021 03 23;37(3):819-830. Epub 2020 Nov 23.

Danish Center for Neonatal Screening, Department of Congenital Diseases, Statens Serum Institut, Copenhagen, Denmark.

Introduction: Central nervous system (CNS) tumors constitute the most common form of solid neoplasms in children, but knowledge on genetic predisposition is sparse. In particular, whether susceptibility attributable to common variants is shared across CNS tumor types in children has not been investigated. The purpose of this study was to explore potential common genetic risk variants exhibiting pleiotropic effects across pediatric CNS tumors. We also investigated whether such susceptibility differs between early and late onset of disease.

Method: A Danish nationwide genome-wide association study (GWAS) of 1,097 consecutive patients (< 15 years of age) with CNS tumors and a cohort of 4,745 population-based controls.

Results: For both the overall cohort and patients diagnosed after the age of four, the strongest association was rs12064625 which maps to PAPPA2 at 1q25.2 (p = 3.400 × 10 and 9.668 × 10, respectively). PAPPA2 regulates local bioavailability of insulin-like growth factor I (IGF-I). IGF-I is fundamental to CNS development and is involved in tumorigenesis across a wide range of different cancers. For the younger children, the strongest association was provided by rs11036373 mapping to LRRC4C at 11p12 (p = 7.620 × 10), which encoded protein acts as an axon guidance molecule during CNS development and has not formerly been associated with brain tumors.

Discussion: This GWAS indicates shared susceptibility attributable to common variants across pediatric CNS tumor types. Variations in genetic loci with roles in CNS development appear to be involved, possibly via altered IGF-I related pathways.
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http://dx.doi.org/10.1007/s00381-020-04946-3DOI Listing
March 2021

Genetic predictors of educational attainment and intelligence test performance predict voter turnout.

Nat Hum Behav 2021 02 9;5(2):281-291. Epub 2020 Nov 9.

Department of Political Science, Aarhus University, Aarhus, Denmark.

Although the genetic influence on voter turnout is substantial (typically 40-50%), the underlying mechanisms remain unclear. Across the social sciences, research suggests that 'resources for politics' (as indexed notably by educational attainment and intelligence test performance) constitute a central cluster of factors that predict electoral participation. Educational attainment and intelligence test performance are heritable. This suggests that the genotypes that enhance these phenotypes could positively predict turnout. To test this, we conduct a genome-wide complex trait analysis of individual-level turnout. We use two samples from the Danish iPSYCH case-cohort study, including a nationally representative sample as well as a sample of individuals who are particularly vulnerable to political alienation due to psychiatric conditions (n = 13,884 and n = 33,062, respectively). Using validated individual-level turnout data from the administrative records at the polling station, genetic correlations and Mendelian randomization, we show that there is a substantial genetic overlap between voter turnout and both educational attainment and intelligence test performance.
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http://dx.doi.org/10.1038/s41562-020-00952-2DOI Listing
February 2021

Common schizophrenia risk variants are enriched in open chromatin regions of human glutamatergic neurons.

Nat Commun 2020 11 4;11(1):5581. Epub 2020 Nov 4.

Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.

The chromatin landscape of human brain cells encompasses key information to understanding brain function. Here we use ATAC-seq to profile the chromatin structure in four distinct populations of cells (glutamatergic neurons, GABAergic neurons, oligodendrocytes, and microglia/astrocytes) from three different brain regions (anterior cingulate cortex, dorsolateral prefrontal cortex, and primary visual cortex) in human postmortem brain samples. We find that chromatin accessibility varies greatly by cell type and, more moderately, by brain region, with glutamatergic neurons showing the largest regional variability. Transcription factor footprinting implicates cell-specific transcriptional regulators and infers cell-specific regulation of protein-coding genes, long intergenic noncoding RNAs and microRNAs. In vivo transgenic mouse experiments validate the cell type specificity of several of these human-derived regulatory sequences. We find that open chromatin regions in glutamatergic neurons are enriched for neuropsychiatric risk variants, particularly those associated with schizophrenia. Integration of cell-specific chromatin data with a bulk tissue study of schizophrenia brains increases statistical power and confirms that glutamatergic neurons are most affected. These findings illustrate the utility of studying the cell-type-specific epigenome in complex tissues like the human brain, and the potential of such approaches to better understand the genetic basis of human brain function.
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http://dx.doi.org/10.1038/s41467-020-19319-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643171PMC
November 2020

Subdividing Y-chromosome haplogroup R1a1 reveals Norse Viking dispersal lineages in Britain.

Eur J Hum Genet 2021 Mar 2;29(3):512-523. Epub 2020 Nov 2.

Department of Genetics & Genome Biology, University of Leicester, Leicester, UK.

The influence of Viking-Age migrants to the British Isles is obvious in archaeological and place-names evidence, but their demographic impact has been unclear. Autosomal genetic analyses support Norse Viking contributions to parts of Britain, but show no signal corresponding to the Danelaw, the region under Scandinavian administrative control from the ninth to eleventh centuries. Y-chromosome haplogroup R1a1 has been considered as a possible marker for Viking migrations because of its high frequency in peninsular Scandinavia (Norway and Sweden). Here we select ten Y-SNPs to discriminate informatively among hg R1a1 sub-haplogroups in Europe, analyse these in 619 hg R1a1 Y chromosomes including 163 from the British Isles, and also type 23 short-tandem repeats (Y-STRs) to assess internal diversity. We find three specifically Western-European sub-haplogroups, two of which predominate in Norway and Sweden, and are also found in Britain; star-like features in the STR networks of these lineages indicate histories of expansion. We ask whether geographical distributions of hg R1a1 overall, and of the two sub-lineages in particular, correlate with regions of Scandinavian influence within Britain. Neither shows any frequency difference between regions that have higher (≥10%) or lower autosomal contributions from Norway and Sweden, but both are significantly overrepresented in the region corresponding to the Danelaw. These differences between autosomal and Y-chromosomal histories suggest either male-specific contribution, or the influence of patrilocality. Comparison of modern DNA with recently available ancient DNA data supports the interpretation that two sub-lineages of hg R1a1 spread with the Vikings from peninsular Scandinavia.
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http://dx.doi.org/10.1038/s41431-020-00747-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940619PMC
March 2021

A large-scale genome-wide association study meta-analysis of cannabis use disorder.

Lancet Psychiatry 2020 12 20;7(12):1032-1045. Epub 2020 Oct 20.

Stanford University Graduate School of Education, Stanford University, Stanford, CA, USA.

Background: Variation in liability to cannabis use disorder has a strong genetic component (estimated twin and family heritability about 50-70%) and is associated with negative outcomes, including increased risk of psychopathology. The aim of the study was to conduct a large genome-wide association study (GWAS) to identify novel genetic variants associated with cannabis use disorder.

Methods: To conduct this GWAS meta-analysis of cannabis use disorder and identify associations with genetic loci, we used samples from the Psychiatric Genomics Consortium Substance Use Disorders working group, iPSYCH, and deCODE (20 916 case samples, 363 116 control samples in total), contrasting cannabis use disorder cases with controls. To examine the genetic overlap between cannabis use disorder and 22 traits of interest (chosen because of previously published phenotypic correlations [eg, psychiatric disorders] or hypothesised associations [eg, chronotype] with cannabis use disorder), we used linkage disequilibrium score regression to calculate genetic correlations.

Findings: We identified two genome-wide significant loci: a novel chromosome 7 locus (FOXP2, lead single-nucleotide polymorphism [SNP] rs7783012; odds ratio [OR] 1·11, 95% CI 1·07-1·15, p=1·84 × 10) and the previously identified chromosome 8 locus (near CHRNA2 and EPHX2, lead SNP rs4732724; OR 0·89, 95% CI 0·86-0·93, p=6·46 × 10). Cannabis use disorder and cannabis use were genetically correlated (r 0·50, p=1·50 × 10), but they showed significantly different genetic correlations with 12 of the 22 traits we tested, suggesting at least partially different genetic underpinnings of cannabis use and cannabis use disorder. Cannabis use disorder was positively genetically correlated with other psychopathology, including ADHD, major depression, and schizophrenia.

Interpretation: These findings support the theory that cannabis use disorder has shared genetic liability with other psychopathology, and there is a distinction between genetic liability to cannabis use and cannabis use disorder.

Funding: National Institute of Mental Health; National Institute on Alcohol Abuse and Alcoholism; National Institute on Drug Abuse; Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing; The European Commission, Horizon 2020; National Institute of Child Health and Human Development; Health Research Council of New Zealand; National Institute on Aging; Wellcome Trust Case Control Consortium; UK Research and Innovation Medical Research Council (UKRI MRC); The Brain & Behavior Research Foundation; National Institute on Deafness and Other Communication Disorders; Substance Abuse and Mental Health Services Administration (SAMHSA); National Institute of Biomedical Imaging and Bioengineering; National Health and Medical Research Council (NHMRC) Australia; Tobacco-Related Disease Research Program of the University of California; Families for Borderline Personality Disorder Research (Beth and Rob Elliott) 2018 NARSAD Young Investigator Grant; The National Child Health Research Foundation (Cure Kids); The Canterbury Medical Research Foundation; The New Zealand Lottery Grants Board; The University of Otago; The Carney Centre for Pharmacogenomics; The James Hume Bequest Fund; National Institutes of Health: Genes, Environment and Health Initiative; National Institutes of Health; National Cancer Institute; The William T Grant Foundation; Australian Research Council; The Virginia Tobacco Settlement Foundation; The VISN 1 and VISN 4 Mental Illness Research, Education, and Clinical Centers of the US Department of Veterans Affairs; The 5th Framework Programme (FP-5) GenomEUtwin Project; The Lundbeck Foundation; NIH-funded Shared Instrumentation Grant S10RR025141; Clinical Translational Sciences Award grants; National Institute of Neurological Disorders and Stroke; National Heart, Lung, and Blood Institute; National Institute of General Medical Sciences.
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http://dx.doi.org/10.1016/S2215-0366(20)30339-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674631PMC
December 2020

Polygenic risk score, psychosocial environment and the risk of attention-deficit/hyperactivity disorder.

Transl Psychiatry 2020 10 2;10(1):335. Epub 2020 Oct 2.

The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus, Denmark.

The objective of the present study was to investigate whether the polygenic liability for attention-deficit/hyperactivity disorder (ADHD) and the psychosocial environment impact the risk of ADHD in interaction or independently of each other. We conducted a register- and biobank-based cohort study of 13,725 individuals with ADHD and 20,147 randomly drawn population-based controls. These 33,872 cohort members were genotyped on the Infinium PsychChip v1.0 array (Illumina). Subsequently, we calculated the polygenic risk score (PRS) for ADHD and extracted register data regarding the following risk factors pertaining to the psychosocial environment for each cohort member at the time of birth: maternal/paternal history of mental disorders, maternal/paternal education, maternal/paternal work status, and maternal/paternal income. We used logistic regression analyses to assess the main effects of the PRS for ADHD and the psychosocial environment on the risk of ADHD. Subsequently, we evaluated whether the effect of the PRS and the psychosocial environment act independently or in interaction upon the risk of ADHD. We found that ADHD was strongly associated with the PRS (odds ratio: 6.03, 95%CI: 4.74-7.70 for highest vs. lowest 2% liability). All risk factors pertaining to the psychosocial environment were associated with an increased risk of ADHD. These associations were only slightly attenuated after mutual adjustments. We found no statistically significant interaction between the polygenic liability and the psychosocial environment upon the risk of ADHD. In conclusion, we found main effects of both polygenic liability and risk factors pertaining to the psychosocial environment on the risk of ADHD-in the expected direction.
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http://dx.doi.org/10.1038/s41398-020-01019-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532146PMC
October 2020

Genetic liability to major depression and risk of childhood asthma.

Brain Behav Immun 2020 10 28;89:433-439. Epub 2020 Jul 28.

NCRR-The National Centre for Register-based Research, Aarhus University, Aarhus, Denmark; iPSYCH-Lundbeck Foundation Initiative for Integrative Psychiatric Research, Denmark; CIRRAU-Centre for Integrated Register-based Research, Aarhus University, Aarhus, Denmark.

Objective: Major depression and asthma frequently co-occur, suggesting shared genetic vulnerability between these two disorders. We aimed to determine whether a higher genetic liability to major depression was associated with increased childhood asthma risk, and if so, whether such an association differed by sex of the child.

Methods: We conducted a population-based cohort study comprising 16,687 singletons born between 1991 and 2005 in Denmark. We calculated the polygenic risk score (PRS) for major depression as a measure of genetic liability based on the summary statistics from the Major Depressive Disorder Psychiatric Genomics Consortium collaboration. The outcome was incident asthma from age 5 to 15 years, identified from the Danish National Patient Registry and the Danish National Prescription Registry. Stratified Cox regression was used to analyze the data.

Results: Greater genetic liability to major depression was associated with an increased asthma risk with a hazard ratio (HR) of 1.06 (95% CI: 1.01-1.10) per standard deviation increase in PRS. Children in the highest major depression PRS quartile had a HR for asthma of 1.20 (95% CI: 1.06-1.36), compared with children in the lowest quartile. However, major depression PRS explained only 0.03% of asthma variance (Pseudo-R). The HRs of asthma by major depression PRS did not differ between boys and girls.

Conclusion: Our results suggest a shared genetic contribution to major depression and childhood asthma, and there is no evidence of a sex-specific difference in the association.
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http://dx.doi.org/10.1016/j.bbi.2020.07.030DOI Listing
October 2020

Reduced Brd1 expression leads to reversible depression-like behaviors and gene-expression changes in female mice.

Transl Psychiatry 2020 07 17;10(1):239. Epub 2020 Jul 17.

IPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark.

The schizophrenia-associated gene, BRD1, encodes an epigenetic regulator in which chromatin interactome is enriched with genes implicated in mental health. Alterations in histone modifications and epigenetic regulation contribute to brain transcriptomic changes in affective disorders and preclinical data supports a role for BRD1 in psychopathology. However, the implication of BRD1 on affective pathology remains poorly understood. In this study, we assess affective behaviors and associated neurobiology in Brd1 mice along with their responses to Fluoxetine and Imipramine. This involves behavioral, neurostructural, and neurochemical characterizations along with regional cerebral gene expression profiling combined with integrative functional genomic analyses. We report behavioral changes in female Brd1 mice with translational value to depressive symptomatology that can be alleviated by the administration of antidepressant medications. Behavioral changes are accompanied by altered brain morphometry and imbalances in monoaminergic systems. In accordance, gene expression changes across brain tissues reveal altered neurotransmitter signaling and cluster in functional pathways associated with depression including 'Adrenergic-, GPCR-, cAMP-, and CREB/CREM-signaling'. Integrative gene expression analysis specifically links changes in amygdaloid intracellular signaling activity to the behavioral treatment response in Brd1 mice. Collectively, our study highlights the importance of BRD1 as a modulator of affective pathology and adds to our understanding of the molecular mechanisms underlying affective disorders and their treatment response.
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http://dx.doi.org/10.1038/s41398-020-00914-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367888PMC
July 2020

Polygenic Risk and Progression to Bipolar or Psychotic Disorders Among Individuals Diagnosed With Unipolar Depression in Early Life.

Am J Psychiatry 2020 10 14;177(10):936-943. Epub 2020 Jul 14.

Department of Economics and Business Economics, National Center for Register-Based Research, Aarhus University, Aarhus, Denmark (Musliner, Albiñana, Vilhjalmsson, Agerbo, Mortensen); Lundbeck Foundation Initiative for Integrative Psychiatric Research, Denmark (Musliner, Krebs, Albiñana, Hougaard, Vilhjalmsson, Agerbo, Nordentoft, Børglum, Werge, Mortensen, Østergaard); Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Mental Health Services, Roskilde, Denmark (Krebs, Werge); Center for Integrated Register-Based Research, Aarhus University, Aarhus (Agerbo, Mortensen); Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore (Zandi); Department for Congenital Disorders, Danish Center for Neonatal Screening, Statens Serum Institut, Copenhagen (Hougaard); Department of Clinical Medicine, Copenhagen Research Center for Mental Health, Copenhagen University Hospital, Copenhagen (Nordentoft); Center for Genomics and Personalized Medicine, Aarhus (Børglum); Department of Biomedicine and the Center for Integrative Sequencing (Børglum), and Department of Clinical Medicine (Østergaard), Aarhus University, Aarhus; and Department of Affective Disorders, Aarhus University Hospital-Psychiatry, Aarhus (Østergaard).

Objective: The authors investigated the associations between polygenic liability and progression to bipolar disorder or psychotic disorders among individuals diagnosed with unipolar depression in early life.

Methods: A cohort comprising 16,949 individuals (69% female, 10-35 years old at the first depression diagnosis) from the iPSYCH Danish case-cohort study (iPSYCH2012) who were diagnosed with depression in Danish psychiatric hospitals from 1994 to 2016 was examined. Polygenic risk scores (PRSs) for major depression, bipolar disorder, and schizophrenia were generated using the most recent results from the Psychiatric Genomics Consortium. Hazard ratios for each disorder-specific PRS were estimated using Cox regressions with adjustment for the other two PRSs. Absolute risk of progression was estimated using the cumulative hazard.

Results: Patients were followed for up to 21 years (median=7 years, interquartile range, 5-10 years). The absolute risks of progression to bipolar disorder and psychotic disorders were 7.3% and 13.8%, respectively. After mutual adjustment for the other PRSs, only the PRS for bipolar disorder predicted progression to bipolar disorder (adjusted hazard ratio for a one-standard-deviation increase in PRS=1.11, 95% CI=1.03, 1.21), and only the PRS for schizophrenia predicted progression to psychotic disorders (adjusted hazard ratio=1.10, 95% CI=1.04, 1.16). After adjusting for PRSs, parental history still strongly predicted progression to bipolar disorder (adjusted hazard ratio=5.02, 95% CI=3.53, 7.14) and psychotic disorders (adjusted hazard ratio=1.63, 95% CI=1.30, 2.06).

Conclusions: PRSs for bipolar disorder and schizophrenia are associated with risk for progression to bipolar disorder or psychotic disorders, respectively, among individuals diagnosed with depression; however, the effects are small compared with parental history, particularly for bipolar disorder.
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http://dx.doi.org/10.1176/appi.ajp.2020.19111195DOI Listing
October 2020

Genetic factors underlying the bidirectional relationship between autoimmune and mental disorders - Findings from a Danish population-based study.

Brain Behav Immun 2021 01 11;91:10-23. Epub 2020 Jun 11.

CORE-Copenhagen Research Centre for Mental Health, Mental Health Centre Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark; Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address:

Background: Previous studies have indicated the bidirectionality between autoimmune and mental disorders. However, genetic studies underpinning the co-occurrence of the two disorders have been lacking. In this study, we examined the potential genetic contribution to the association between autoimmune and mental disorders and investigated the genetic basis of overall autoimmune disease.

Methods: We used diagnostic information from patients with seven autoimmune diseases and six mental disorders from the Danish population-based case-cohort sample (iPSYCH2012). We explored the epidemiological association using survival analysis and modelled the effect of polygenic risk scores (PRSs) on autoimmune and mental diseases. Genetic factors were investigated using GWAS and imputed HLA alleles in the iPSYCH cohort.

Results: Of 64,039 individuals, a total of 43,902 (68.6%) were diagnosed with mental disorders and 1383 (2.2%) with autoimmune diseases. There was a significant comorbidity between the two disease classes (P = 2.67 × 10, OR = 1.38, 95%CI = 1.22-1.56), with an overall bidirectional association, wherein individuals with autoimmune diseases had an increased risk of subsequent mental disorders (HR = 1.13, 95%CI: 1.07-1.21, P = 7.95 × 10) and vice versa (HR = 1.27, 95%CI = 1.16-1.39, P = 8.77 × 10). Adding PRSs to these adjustment models did not have an impact on the associations. PRSs for autoimmune diseases were only slightly associated with increased risk of mental disorders (HR = 1.01, 95%CI: 1.00-1.02, p = 0.038), whereas PRSs for mental disorders were not associated with autoimmune diseases overall. Our GWAS highlighted 12 loci on chromosome 6 (minimum P = 2.74 × 10, OR = 1.80, 95% CI: 1.64-1.96), which were implicated in gene regulation through bioinformatic functional analyses, thereby identifying new candidate genes for overall autoimmune disease. Moreover, we observed 20 human leukocyte antigen (HLA) alleles strongly associated, either positively or negatively, with overall autoimmune disease, but we did not find significant evidence of their associations with overall mental disorders. A GWAS of a comorbid diagnosis of an autoimmune disease and a mental disorder identified a genome-wide significant locus on chromosome 7 as well (P = 1.43 × 10, OR = 10.65, 95%CI = 3.21-35.36).

Conclusions: Our findings confirm the overall comorbidity and bidirectionality between autoimmune diseases and mental disorders and identify HLA genes which are significantly associated with overall autoimmune disease. Additionally, we identified several new candidate genes for overall autoimmune disease and ranked them based on their association with the investigated diseases.
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http://dx.doi.org/10.1016/j.bbi.2020.06.014DOI Listing
January 2021

Genome-wide meta-analysis of problematic alcohol use in 435,563 individuals yields insights into biology and relationships with other traits.

Nat Neurosci 2020 07 25;23(7):809-818. Epub 2020 May 25.

Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA.

Problematic alcohol use (PAU) is a leading cause of death and disability worldwide. Although genome-wide association studies have identified PAU risk genes, the genetic architecture of this trait is not fully understood. We conducted a proxy-phenotype meta-analysis of PAU, combining alcohol use disorder and problematic drinking, in 435,563 European-ancestry individuals. We identified 29 independent risk variants, 19 of them novel. PAU was genetically correlated with 138 phenotypes, including substance use and psychiatric traits. Phenome-wide polygenic risk score analysis in an independent biobank sample (BioVU, n = 67,589) confirmed the genetic correlations between PAU and substance use and psychiatric disorders. Genetic heritability of PAU was enriched in brain and in conserved and regulatory genomic regions. Mendelian randomization suggested causal effects on liability to PAU of substance use, psychiatric status, risk-taking behavior and cognitive performance. In summary, this large PAU meta-analysis identified novel risk loci and revealed genetic relationships with numerous other traits.
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http://dx.doi.org/10.1038/s41593-020-0643-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7485556PMC
July 2020
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