Search

For more than half a century, Denmark has maintained population-wide demographic, health care, and socioeconomic registers that provide detailed information on the interaction between all residents and the extensive national social services system. We leverage this resource to reconstruct the genealogy of the entire nation based on all individuals legally residing in Denmark since 1968. We cross-reference 6,691,426 individuals with nationwide health care registers to estimate heritability and genetic correlations of 10 broad diagnostic categories involving all major organs and systems. Heritability estimates for mental disorders were consistently the highest across demographic cohorts (average h² = 0.406, 95% CI = [0.403, 0.408]), whereas estimates for cancers were the lowest (average h² = 0.130, 95% CI = [0.125, 0.134]). The average genetic correlation of each of the 10 diagnostic categories with the other nine was highest for gastrointestinal conditions (average rg = 0.567, 95% CI = [0.566, 0.567]) and lowest for urogenital conditions (average rg = 0.386,95% CI = [0.385, 0.388]). Mental, pulmonary, gastrointestinal, and neurological conditions had similar genetic correlation profiles. [ABSTRACT FROM AUTHOR]

Eating disorders (ED) are mental disorders associated with high levels of morbidity, mortality, and social, psychological and physical impairment. Currently, eating disorders are more prevalent in women, yet they affect people from all sectors of society (i.e., sex, ancestry, sexual orientation, age etc). Lifetime prevalence estimates of ED vary dramatically between studies. This high level of variability is likely due to sample size variations, differences in diagnostic practices, and ascertainment biases (e.g., clinical vs population wide sampling). These biases influence downstream estimates of the genetic contribution to the liability of EDs. Consequently, while family, twin, and adoption studies have shown that genetic factors contribute to the risk of developing an eating disorder, the variability in estimates is substantial. This highlights the need for large population representative studies. Here, we estimated the heritability of three eating disorders (anorexia, bulimia, and ED NOS) and the genetic correlations between them and seven other mental disorders using information from nationally collected civil- and medical registers in Denmark (>6 million) and Sweden (>13 million). These registers contain information about all individuals in the two Nordic countries during roughly the last 100 years, their extended genealogy, and all hospital records. Both datasets reflect a total population, uniformly diagnosed across the country in a nationally run public healthcare system. Therefore, the effect of different kinds of biases associated with cohorts ascertained from (psychiatric) clinics or voluntary participants is reduced. Using Danish data, we showed that all eating disorders were heritable (h2: 0.28–0.35) and presented substantial positive genetic correlations with other mental disorders (rG: 0.23–0.63 (anorexia); 0.24–0.46 (bulimia); 0.42–0.73 (ED NOS)). While there is some variation, all genetic correlations presented overlapping confidence intervals. OCD showed the largest genetic correlation with both Anorexia and ED NOS. A similar association was observed using genotype-based estimates of genetic correlations. Eating disorders, especially anorexia, are commonly observed comorbid with OCD and anxiety phenotypes. The observed large genetic correlations with eating disorders point to a substantial relevance of shared genetic effects as a partial explanation for those clinical observations. The same pattern of results was observed using the larger Swedish data, indicating a high degree of similarity between countries. From the sex-stratified analyses, we observed that the female estimates were nearly identical to the main results, while the male estimates could not be considered reliable. These results suggest that due to the substantial difference in ED prevalence between males and females, and despite using the complete data of two Nordic countries, the estimations we observed by using males and females together are driven by the female samples and that we are underpowered to estimate heritability and genetic correlations in males. Here, using unascertained population-wide register data of two Nordic countries representing 20 million people, we have shown that eating disorders are complex heritable outcomes with substantial evidence for partially shared genetic risk across many mental disorders. [ABSTRACT FROM AUTHOR]

Importance: Recurrent copy number variants (rCNVs) have been associated with increased risk of psychiatric disorders in case-control studies, but their population-level impact is unknown., Objective: To provide unbiased population-based estimates of prevalence and risk associated with psychiatric disorders for rCNVs and to compare risks across outcomes, rCNV dosage type (deletions or duplications), and locus features., Design, Setting, and Participants: This genetic association study is an analysis of data from the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH) case-cohort sample of individuals born in Denmark in 1981-2008 and followed up until 2015, including (1) all individuals (n = 92 531) with a hospital discharge diagnosis of attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder, major depressive disorder (MDD), or schizophrenia spectrum disorder (SSD) and (2) a subcohort (n = 50 625) randomly drawn from the source population. Data were analyzed from January 2021 to August 2023., Exposures: Carrier status of deletions and duplications at 27 autosomal rCNV loci was determined from neonatal blood samples genotyped on single-nucleotide variant microarrays., Main Outcomes and Measures: Population-based rCNV prevalence was estimated with a survey model using finite population correction to account for oversampling of cases. Hazard ratio (HR) estimates and 95% CIs for psychiatric disorders were derived using weighted Cox proportional hazard models. Risks were compared across outcomes, dosage type, and locus features using generalized estimating equation models., Results: A total of 3547 rCNVs were identified in 64 735 individuals assigned male at birth (53.8%) and 55 512 individuals assigned female at birth (46.2%) whose age at the end of follow-up ranged from 7.0 to 34.7 years (mean, 21.8 years). Most observed increases in rCNV-associated risk for ADHD, ASD, or SSD were moderate, and risk estimates were highly correlated across these disorders. Notable exceptions included high ASD-associated risk observed for Prader-Willi/Angelman syndrome duplications (HR, 20.8; 95% CI, 7.9-55). No rCNV was associated with increased MDD risk. Also, rCNV-associated risk was positively correlated with locus size and gene constraint but not with dosage type. Comparison with published case-control and community-based studies revealed a higher prevalence of deletions and lower associated increase in risk for several rCNVs in iPSYCH2015., Conclusions and Relevance: This study found that several rCNVs were more prevalent and conferred less risk of psychiatric disorders than estimated previously. Most case-control studies overestimate rCNV-associated risk of psychiatric disorders, likely because of selection bias. In an era where genetics is increasingly being clinically applied, these results highlight the importance of population-based risk estimates for genetics-based predictions.

Mental disorders are leading causes of disability and premature death worldwide, partly due to high comorbidity with cardiometabolic disorders. Reasons for this comorbidity are still poorly understood. We leverage nation-wide health records and near-complete genealogies of Denmark and Sweden (n = 17 million) to reveal the genetic and environmental contributions underlying the observed comorbidity between six mental disorders and 15 cardiometabolic disorders. Genetic factors contributed about 50% to the comorbidity of schizophrenia, affective disorders, and autism spectrum disorder with cardiometabolic disorders, whereas the comorbidity of attention-deficit/hyperactivity disorder and anorexia with cardiometabolic disorders was mainly or fully driven by environmental factors. In this work we provide causal insight to guide clinical and scientific initiatives directed at achieving mechanistic understanding as well as preventing and alleviating the consequences of these disorders., (© 2024. The Author(s).)

Background: Increased prevalence of mental illness has been reported in clinical studies of sex chromosome aneuploidies, but accurate population-based estimates of the prevalence and clinical detection rate of sex chromosome aneuploidies and the associated risks of psychiatric disorders are needed. In this study, we provide such estimates, valid for children and young adults of the contemporary Danish population., Methods: We used the iPSYCH2015 case-cohort dataset, which is based on a source population of single-born individuals born in Denmark between May 1, 1981, and Dec 31, 2008. The case sample comprises all individuals from the source population with a diagnosis of any index psychiatric disorder (schizophrenia spectrum disorder, bipolar disorder, major depressive disorder, autism spectrum disorder, or ADHD) by the end of follow-up (Dec 31, 2015), registered in the hospital-based Danish Psychiatric Central Research Register. The cohort consists of individuals randomly selected from the source population, and overlaps with the case sample. Biobanked blood samples for individuals in the case and cohort samples underwent genotyping and quality-control filtering, after which we analysed microarray data to detect sex chromosome aneuploidy karyotypes (45,X, 47,XXX, 47,XXY, and 47,XYY). We estimated the population-valid prevalence of these karyotypes from the cohort sample. Weighted Cox proportional hazards models were used to estimate the risks of each index psychiatric disorder associated with each sex chromosome aneuploidy karyotype, by use of date of first hospitalisation with the index disorder in the respective case group and the cohort as outcome. The clinical detection rate was determined by comparing records of clinical diagnoses of genetic conditions from the Danish National Patient Register with sex chromosome aneuploidy karyotype determined by our study., Findings: The assessed sample comprised 119 481 individuals (78 726 in the case sample and 43 326 in the cohort) who had genotyped and quality-control-filtered blood samples, including 64 533 (54%) people of gonadal male sex and 54 948 (46%) of gonadal female sex. Age during follow-up ranged from 0 to 34·7 years (mean 10·9 years [SD 3·5 years]). Information on ethnicity was not available. We identified 387 (0·3%) individuals as carriers of sex chromosome aneuploidies. The overall prevalence of sex chromosome aneuploidies was 1·5 per 1000 individuals. Each sex chromosome aneuploidy karyotype was associated with an increased risk of at least one index psychiatric disorder, with hazard ratios (HRs) of 2·20 (95% CI 1·42-3·39) for 47,XXY; 2·73 (1·25-6·00) for 47,XXX; 3·56 (1·01-12·53) for 45,X; and 4·30 (2·48-7·55) for 47,XYY. All karyotypes were associated with an increased risk of ADHD (HRs ranging from 1·99 [1·24-3·19] to 6·15 [1·63-23·19]), autism spectrum disorder (2·72 [1·72-4·32] to 8·45 [2·49-28·61]), and schizophrenia spectrum disorder (1·80 [1·15-2·80] to 4·60 [1·57-13·51]). Increased risk of major depressive disorder was found for individuals with 47,XXY (1·88 [1·07-3·33]) and 47,XYY (2·65 [1·12-5·90]), and of bipolar disorder for those with 47,XXX (4·32 [1·12-16·62]). The proportion of sex chromosome aneuploidy carriers who had been clinically diagnosed was 93% for 45,X, but lower for 47,XXY (22%), 47,XXX (15%), and 47,XYY (15%). Among carriers, the risk of diagnosis of at least one index psychiatric disorder did not significantly differ between those who had and had not been clinically diagnosed with sex chromosome aneuploidies (p=0·65)., Interpretation: Increased risks of psychiatric disorders associated with sex chromosome aneuploidies, combined with low rates of clinical diagnosis of sex chromosome aneuploidies, compromise the adequate provision of necessary health care and counselling to affected individuals and their families, which might be helped by increased application of genetic testing in clinical settings., Funding: Lundbeck Foundation and National Institutes of Health., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

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 -7 , 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 -5 ) and vice versa (HR = 1.27, 95%CI = 1.16-1.39, P = 8.77 × 10 -15 ). 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 -36 , 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 -8 , 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., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) are highly heritable neurodevelopmental disorders that frequently co-occur. Both rare and common genetic variants are important for ASD and ADHD risk but their combined contribution to clinical heterogeneity is unclear. In a sample of 39 ASD and/or ADHD families we estimated the overall variance explained by known rare copy number variants (CNVs) and polygenic risk score (PRS) from common variants to be 10% in comorbid ASD/ADHD, 4% in ASD and 2% in ADHD. We show that burden of large, rare CNVs and PRS is significantly higher in adult ASD and/or ADHD patients with sustained need for specialist care compared to their unaffected relatives, while affected relatives fall in-between the two.

Circulating inflammatory markers are essential to human health and disease, and they are often dysregulated or malfunctioning in cancers as well as in cardiovascular, metabolic, immunologic and neuropsychiatric disorders. However, the genetic contribution to the physiological variation of levels of circulating inflammatory markers is largely unknown. Here we report the results of a genome-wide genetic study of blood concentration of ten cytokines, including the hitherto unexplored calcium-binding protein (S100B). The study leverages a unique sample of neonatal blood spots from 9,459 Danish subjects from the iPSYCH initiative. We estimate the SNP-heritability of marker levels as ranging from essentially zero for Erythropoietin (EPO) up to 73% for S100B. We identify and replicate 16 associated genomic regions (p < 5 x 10-9), of which four are novel. We show that the associated variants map to enhancer elements, suggesting a possible transcriptional effect of genomic variants on the cytokine levels. The identification of the genetic architecture underlying the basic levels of cytokines is likely to prompt studies investigating the relationship between cytokines and complex disease. Our results also suggest that the genetic architecture of cytokines is stable from neonatal to adult life., Competing Interests: The authors have declared that no competing interests exist.

Gastrointestinal infections can be life threatening, but not much is known about the host's genetic contribution to susceptibility to gastrointestinal infections or the latter's association with psychiatric disorders. We utilized iPSYCH, a genotyped population-based sample of individuals born between 1981 and 2005 comprising 65,534 unrelated Danish individuals (45,889 diagnosed with mental disorders and 19,645 controls from a random population sample) in which all individuals were linked utilizing nationwide population-based registers to estimate the genetic contribution to susceptibility to gastrointestinal infections, identify genetic variants associated with gastrointestinal infections, and examine the link between gastrointestinal infections and psychiatric and neurodevelopmental disorders. The SNP heritability of susceptibility to gastrointestinal infections ranged from 3.7% to 6.4% on the liability scale. Significant correlations were found between gastrointestinal infections and the combined group of mental disorders (OR = 2.09; 95% CI: 1.82-2.4, P = 1.87 × 10 -25 ). Correlations with autism spectrum disorder, attention deficit hyperactivity disorder, and depression were also significant. We identified a genome-wide significant locus associated with susceptibility to gastrointestinal infections (OR = 1.13; 95% CI: 1.08-1.18, P = 2.9 × 10 -8 ), where the top SNP was an eQTL for the ABO gene. The risk allele was associated with reduced ABO expression, providing, for the first time, genetic evidence to support previous studies linking the O blood group to gastrointestinal infections. This study also highlights the importance of integrative work in genetics, psychiatry, infection, and epidemiology on the road to translational medicine.

Infections and mental disorders are two of the major global disease burdens. While correlations between mental disorders and infections have been reported, the possible genetic links between them have not been assessed in large-scale studies. Moreover, the genetic basis of susceptibility to infection is largely unknown, as large-scale genome-wide association studies of susceptibility to infection have been lacking. We utilized a large Danish population-based sample (N = 65,534) linked to nationwide population-based registers to investigate the genetic architecture of susceptibility to infection (heritability estimation, polygenic risk analysis, and a genome-wide association study (GWAS)) and examined its association with mental disorders (comorbidity analysis and genetic correlation). We found strong links between having at least one psychiatric diagnosis and the occurrence of infection (P = 2.16 × 10 -208 , OR = 1.72). The SNP heritability of susceptibility to infection ranged from ~2 to ~7% in samples of differing psychiatric diagnosis statuses (suggesting the environment as a major contributor to susceptibility), and polygenic risk scores moderately but significantly explained infection status in an independent sample. We observed a genetic correlation of 0.496 (P = 2.17 × 10 -17 ) between a diagnosis of infection and a psychiatric diagnosis. While our GWAS did not identify genome-wide significant associations, we found 90 suggestive (P ≤ 10 -5 ) associations for susceptibility to infection. Our findings suggest a genetic component in susceptibility to infection and indicate that the occurrence of infections in individuals with mental illness may be in part genetically driven.

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.

Spatial mapping is a promising strategy to investigate the mechanisms underlying the incidence of psychosis. We analyzed a case-cohort study (n = 24,028), drawn from the 1.47 million Danish persons born between 1981 and 2005, using a novel framework for decomposing the geospatial risk for schizophrenia based on locale of upbringing and polygenic scores. Upbringing in a high environmental risk locale increases the risk for schizophrenia by 122%. Individuals living in a high gene-by-environmental risk locale have a 78% increased risk compared to those who have the same genetic liability but live in a low-risk locale. Effects of specific locales vary substantially within the most densely populated city of Denmark, with hazard ratios ranging from 0.26 to 9.26 for environment and from 0.20 to 5.95 for gene-by-environment. These findings indicate the critical synergism of gene and environment on the etiology of schizophrenia and demonstrate the potential of incorporating geolocation in genetic studies.