There is a limited understanding about the impact of rare protein-truncating variants across multiple phenotypes. We explore the impact of this class of variants on 13 quantitative traits and 10 ...diseases using whole-exome sequencing data from 100,296 individuals. Protein-truncating variants in genes intolerant to this class of mutations increased risk of autism, schizophrenia, bipolar disorder, intellectual disability, and ADHD. In individuals without these disorders, there was an association with shorter height, lower education, increased hospitalization, and reduced age at enrollment. Gene sets implicated from GWASs did not show a significant protein-truncating variants burden beyond what was captured by established Mendelian genes. In conclusion, we provide a thorough investigation of the impact of rare deleterious coding variants on complex traits, suggesting widespread pleiotropic risk.
OBJECTIVE: Individuals with schizophrenia and their relatives tend to have either higher or lower than expected prevalences of autoimmune disorders, especially rheumatoid arthritis, celiac disease, ...autoimmune thyroid diseases, and type 1 diabetes. The purpose of the study was to estimate the association of schizophrenia with these disorders as well as a range of other autoimmune diseases in a single large epidemiologic study. METHOD: The Danish Psychiatric Register, the National Patient Register, and a register with socioeconomic information were linked to form a data file that included all 7,704 persons in Denmark diagnosed with schizophrenia from 1981 to 1998 and their parents along with a sample of matched comparison subjects and their parents. The data linkage required that the autoimmune disease occur before the diagnosis of schizophrenia. RESULTS: A history of any autoimmune disease was associated with a 45% increase in risk for schizophrenia. Nine autoimmune disorders had higher prevalence rates among patients with schizophrenia than among comparison subjects (crude incidence rate ratios ranging from 1.9 to 12.5), and 12 autoimmune diseases had higher prevalence rates among parents of schizophrenia patients than among parents of comparison subjects (adjusted incidence rate ratios ranging from 1.3 to 3.8). Thyrotoxicosis, celiac disease, acquired hemolytic anemia, interstitial cystitis, and Sjögren's syndrome had higher prevalence rates among patients with schizophrenia than among comparison subjects and also among family members of schizophrenia patients than among family members of comparison subjects. CONCLUSIONS: Schizophrenia is associated with a larger range of autoimmune diseases than heretofore suspected. Future research on comorbidity has the potential to advance understanding of pathogenesis of both psychiatric and autoimmune disorders.
Human leukocyte antigen (HLA) genes encode proteins with important roles in the regulation of the immune system. Many studies have also implicated HLA genes in psychiatric and neurodevelopmental ...disorders. However, these studies usually focus on one disorder and/or on one HLA candidate gene, often with small samples. Here, we access a large dataset of 65,534 genotyped individuals consisting of controls (N = 19,645) and cases having one or more of autism spectrum disorder (N = 12,331), attention deficit hyperactivity disorder (N = 14,397), schizophrenia (N = 2401), bipolar disorder (N = 1391), depression (N = 18,511), anorexia (N = 2551) or intellectual disability (N = 3175). We imputed participants' HLA alleles to investigate the involvement of HLA genes in these disorders using regression models. We found a pronounced protective effect of DPB1*1501 on susceptibility to autism (p = 0.0094, OR = 0.72) and intellectual disability (p = 0.00099, OR = 0.41), with an increased protective effect on a comorbid diagnosis of both disorders (p = 0.003, OR = 0.29). We also identified a risk allele for intellectual disability, B*5701 (p = 0.00016, OR = 1.33). Associations with both alleles survived FDR correction and a permutation procedure. We did not find significant evidence for replication of previously-reported associations for autism or schizophrenia. Our results support an implication of HLA genes in autism and intellectual disability, which requires replication by other studies. Our study also highlights the importance of large sample sizes in HLA association studies.
Attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are highly heritable neurodevelopmental conditions, with considerable overlap in their genetic etiology. We ...dissected their shared and distinct genetic etiology by cross-disorder analyses of large datasets. We identified seven loci shared by the disorders and five loci differentiating them. All five differentiating loci showed opposite allelic directions in the two disorders and significant associations with other traits, including educational attainment, neuroticism and regional brain volume. Integration with brain transcriptome data enabled us to identify and prioritize several significantly associated genes. The shared genomic fraction contributing to both disorders was strongly correlated with other psychiatric phenotypes, whereas the differentiating portion was correlated most strongly with cognitive traits. Additional analyses revealed that individuals diagnosed with both ASD and ADHD were double-loaded with genetic predispositions for both disorders and showed distinctive patterns of genetic association with other traits compared with the ASD-only and ADHD-only subgroups. These results provide insights into the biological foundation of the development of one or both conditions and of the factors driving psychopathology discriminatively toward either ADHD or ASD.
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.
Predicting antidepressant response has been a clinical challenge for mood disorder. Although several genome-wide association studies have suggested a number of genetic variants to be associated with ...antidepressant response, the sample sizes are small and the results are difficult to replicate. Previous animal studies have shown that knockout of the serotonin receptor 7 gene (HTR7) resulted in an antidepressant-like phenotype, suggesting it was important to antidepressant action. In this report, in the first stage, we used a cost-effective pooled-sequencing strategy to sequence the entire HTR7 gene and its regulatory regions to investigate the association of common variants in HTR7 and clinical response to four selective serotonin reuptake inhibitors (SSRIs: citalopram, paroxetine, fluoxetine and sertraline) in a retrospective cohort mainly consisting of subjects with bipolar disorder (n = 359). We found 80 single-nucleotide polymorphisms (SNPs) with false discovery rate < 0.05 associated with response to paroxetine. Among the significant SNPs, rs7905446 (T/G), which is located at the promoter region, also showed nominal significance (P < 0.05) in fluoxetine group. GG/TG genotypes for rs7905446 and female gender were associated with better response to two SSRIs (paroxetine and fluoxetine). In the second stage, we replicated this association in two independent prospective samples of SSRI-treated patients with major depressive disorder: the MARS (n = 253, P = 0.0169) and GENDEP studies (n = 432, P = 0.008). The GG/TG genotypes were consistently associated with response in all three samples. Functional study of rs7905446 showed greater activity of the G allele in regulating expression of HTR7. The G allele displayed higher luciferase activity in two neuronal-related cell lines, and estrogen treatment decreased the activity of only the G allele. Electrophoretic mobility shift assay suggested that the G allele interacted with CCAAT/enhancer-binding protein beta transcription factor (TF), while the T allele did not show any interaction with any TFs. Our results provided novel pharmacogenomic evidence to support the role of HTR7 in association with antidepressant response.
Objective
Information on mental disorders over time is critical for documenting changes in population burden, and aiding understanding of potential causal and non‐causal factors. The aim of this ...study was to provide temporal changes in the sex‐ and age‐specific incidence rates (IR) of mental disorders diagnosed in Danish hospitals during five decades and investigate whether such changes may be attributable to changes in administrative reporting practice.
Methods
This population‐based cohort study included all people living in Denmark between 1970 and 2016. Mental disorders diagnoses were obtained from the Danish Psychiatric Central Research Register. We estimated the IR of each mental disorder (all persons, and sex‐ and age‐specific IRs) and examined the impact of two administrative changes.
Results
Our study included 9 107 157 people, followed for 233.0 million person‐years. During follow‐up, 9.5% were diagnosed with at least one mental disorder. The IR for any mental disorder was 39.0 per 10,000 person‐years. Despite fluctuations, this increased between 1970–84 and 2005–2016, from 28.9 to 63.0 per 10,000 person‐years. Increases were most pronounced for younger age groups. Administrative changes did appear to influence incidence rates.
Conclusion
Mental disorder IRs have increased in Denmark since 1970, with age of diagnosis shifting downwards. Both trends were likely impacted by administrative changes, while the latter is likely to be (partly) attributable to earlier detection and increased reporting of child‐onset conditions. Our findings may provide valuable context of the epidemiology of mental disorders across age groups for comparison with other studies and populations.
There is great interest in the role epigenetic variation induced by non-genetic exposures may play in the context of health and disease. In particular, DNA methylation has previously been shown to be ...highly dynamic during the earliest stages of development and is influenced by in utero exposures such as maternal smoking and medication. In this study we sought to identify the specific DNA methylation differences in blood associated with prenatal and birth factors, including birth weight, gestational age and maternal smoking. We quantified neonatal methylomic variation in 1263 infants using DNA isolated from a unique collection of archived blood spots taken shortly after birth (mean = 6.08 days; s.d. = 3.24 days). An epigenome-wide association study (EWAS) of gestational age and birth weight identified 4299 and 18 differentially methylated positions (DMPs) respectively, at an experiment-wide significance threshold of p < 1 × 10
. Our EWAS of maternal smoking during pregnancy identified 110 DMPs in neonatal blood, replicating previously reported genomic loci, including AHRR. Finally, we tested the hypothesis that DNA methylation mediates the relationship between maternal smoking and lower birth weight, finding evidence that methylomic variation at three DMPs may link exposure to outcome. These findings complement an expanding literature on the epigenomic consequences of prenatal exposures and obstetric factors, confirming a link between the maternal environment and gene regulation in neonates. This article is part of the theme issue 'Developing differences: early-life effects and evolutionary medicine'.
Depression and anxiety disorders are highly comorbid conditions and a worldwide disease burden; however, large-scale studies delineating their association are scarce. In this retrospective study, we ...aimed to assess the effect of severe anxiety disorders on the risk and course of depression.
We did a population-based cohort study with prospectively gathered data in Denmark using data from three Danish population registers: The Danish Civil Registration System, the Danish Psychiatric Central Register, and the Danish National Hospital Registry. We selected the cohort from people born in Denmark between Jan 1, 1955, and Dec 31, 2002, who we followed up from Jan 1, 1994, to Dec 31, 2012. The cohort was restricted to individuals with known parents. First, we investigated the effect of specific anxiety diagnoses on risk of single depressive episodes and recurrent depressive disorder. Second, we investigated the effect of comorbid anxiety on risk of readmission for depression, adjusting for sex, age, calendar year, parental age, place at residence at time of birth, and the interaction of age with sex.
We included 3,380,059 individuals in our study cohort. The adjusted incidence rate ratio (IRR) for single depressive episodes was 3·0 (95% CI 2·8-3·1, p<0·0001) and for recurrent depressive disorder was 5·0 (4·8-5·2) in patients with severe anxiety disorders compared with the general population. Compared with control individuals, the offspring of parents with anxiety disorders were more likely to be diagnosed with single depressive episodes (1·9, 1·8-2·0) or recurrent depressive disorder (2·1, 1·9-2·2). Comorbid anxiety increased the readmission rates in both patients with single depressive episodes and patients with recurrent depressive disorder.
Severe anxiety constitutes a significant risk factor for depression. Focusing on specific anxiety disorders might help to identify individuals at risk of depression, thereby providing new insights for prevention and treatment.
The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH).
Many antidepressants, atomoxetine, and several antipsychotics are metabolized by the cytochrome P450 enzymes CYP2D6 and CYP2C19, and guidelines for prescribers based on genetic variants exist. ...Although some laboratories offer such testing, there is no consensus regarding validated methodology for clinical genotyping of CYP2D6 and CYP2C19. The aim of this paper was to cross-validate multiple technologies for genotyping CYP2D6 and CYP2C19 against each other, and to contribute to feasibility for clinical implementation by providing an enhanced range of assay options, customizable automated translation of data into haplotypes, and a workflow algorithm. AmpliChip CYP450 and some TaqMan single nucleotide variant (SNV) and copy number variant (CNV) data in the Genome-based therapeutic drugs for depression (GENDEP) study were used to select 95 samples (out of 853) to represent as broad a range of CYP2D6 and CYP2C19 genotypes as possible. These 95 included a larger range of CYP2D6 hybrid configurations than have previously been reported using inter-technology data. Genotyping techniques employed were: further TaqMan CNV and SNV assays, xTAGv3 Luminex CYP2D6 and CYP2C19, PharmacoScan, the Ion AmpliSeq Pharmacogenomics Panel, and, for samples with CYP2D6 hybrid configurations, long-range polymerase chain reactions (L-PCRs) with Sanger sequencing and Luminex. Agena MassARRAY was also used for CYP2C19. This study has led to the development of a broader range of TaqMan SNV assays, haplotype phasing methodology with TaqMan adaptable for other technologies, a multiplex genotyping method for efficient identification of some hybrid haplotypes, a customizable automated translation of SNV and CNV data into haplotypes, and a clinical workflow algorithm.
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