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Nordentoft, M.

Publications and source records attributed to Nordentoft, M..

18 recordsLinked to original sources
bioRxiv2024

Circadian Coupling Orchestrates Cell Growth

Single-cell circadian oscillators exchange extracellular information to sustain coherent circadian rhythms at the tissue level. Within cells, the circadian clock and the cell cycle couple, yet the mechanisms governing this interplay remain poorly elucidated. Here, we study the role of extracellular circadian communication in the intracellular coordination between the circadian clock and the cell cycle. We demonstrate that the loss of extracellular circadian synchronization disrupts circadian and cell cycle coordination within individual cells, impeding collective tissue growth. Coherent circadian rhythms yield oscillatory growth patterns, unveiling a global timing regulator of tissue dynamics. Knocking down core circadian elements abolishes observed effects, highlighting the central role of circadian clock regulation. Our research underscores the significance of tissue-level circadian disruption in regulating proliferation, thereby linking disrupted circadian clocks with oncogenic processes. These findings illuminate the intricate interplay between circadian rhythms, cellular signaling, and tissue physiology, enhancing our understanding of tissue homeostasis and growth regulation in both health and disease contexts.

cell biology↗
bioRxiv2022

Accuracy of haplotype estimation and whole genome imputation affects complex trait analyses in complex biobanks

Sample recruitment for research consortia, hospitals, biobanks, and personal genomics companies span years, necessitating genotyping in batches, using different technologies. As marker content on genotyping arrays varies systematically, integrating such datasets is non-trivial and its impact on haplotype estimation (phasing) and whole genome imputation, necessary steps for complex trait analysis, remains under-evaluated. Using the iPSYCH consortium dataset, comprising 130,438 individuals, genotyped in two stages, on different arrays, we evaluated phasing and imputation performance across multiple phasing methods and data integration protocols. While phasing accuracy varied both by choice of method and data integration protocol, imputation accuracy varied mostly between data integration protocols. We demonstrate an attenuation in imputation accuracy within samples of non-European origin, highlighting challenges to studying complex traits in diverse populations. Finally, imputation errors can modestly bias association tests and reduce predictive utility of polygenic scores. This is the largest, most comprehensive comparison of data integration approaches in the context of a large psychiatric biobank.

bioinformatics↗
bioRxiv2021

Accounting for age-of-onset and family history improves power in genome-wide association studies

Genome-wide association studies (GWAS) have revolutionized human genetics, allowing researchers to identify thousands of disease-related genes and possible drug targets. However, case-control status does not account for the fact that not all controls may have lived through their period of risk for the disorder of interest. This can be quantified by examining the age-of-onset distribution and the age of the controls or the age-of-onset for cases. The age-of-onset distribution may also depend on information such as sex and birth year. In addition, family history is not routinely included in the assessment of control status. Here we present LT-FH++, an extension of the liability threshold model conditioned on family history (LT-FH), that jointly accounts for age-of-onset and sex, as well as family history. Using simulations, we show that, when family history and the age-of-onset distribution are available, the proposed approach yields large power gains over both LT-FH and genome-wide association study by proxy (GWAX). We applied our method to four psychiatric disorders available in the iPSYCH data, and to mortality in the UK Biobank, finding 20 genome-wide significant associations with LT-FH++, compared to 10 for LT-FH and 8 for a standard case-control GWAS. As more genetic data with linked electronic health records become available to researchers, we expect methods that account for additional health information, such as LT-FH++, to become even more beneficial.

bioinformatics↗
bioRxiv2020

Association of educational attainment polygenic score with school grades in individuals with and without psychiatric disorders.

Suboptimal school performance is often seen in children with psychiatric disorders and is influenced by both genetics and the environment. Educational attainment polygenic score (EA-PGS) has been shown to significantly predict school performance in the general population. Here we analyze the association of EA-PGS with school performance in 18,495 children with and 12,487, without one or more of six psychiatric disorders and show that variance explained in the school performance by the EA-PGS is substantially lower in children with attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Accounting for parents socioeconomic status obliterated the variance difference between ADHD-but not ASD-and controls. Given that a large proportion of the prediction performance of EA-PGS originate from family environment, our findings hint that family environmental influences on school performance might differ between ADHD and controls; studying the same further will open new avenues to improve the school performance of children with ADHD.

genetics↗
bioRxiv2020

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

Individuals with psychiatric disorders perform differently in school compared to the general population. Genetic factors contribute substantially to such differences. It is however unclear if differential performance is seen across all cognitive domains such as math and language. Here we report a genome-wide association study (GWAS) of school grades in 30,982 individuals (18,495 with and 12,487 without one or more of six major psychiatric disorders) and a replication study in 4,547 individuals. GWAS of overall school performance yielded results that were highly similar to the results of a previous GWAS of educational attainment. Analyzing subject specific grades, we observed that math performance was severely affected whereas language performance (Danish and English) was relatively unaffected or enhanced in those with psychiatric disorders compared to controls. We found that the genetic variants associated with poor math performance, but better language performance were also associated with increased risk for multiple psychiatric disorders. The same variants were also associated with creativity, which we show through a polygenic score analysis of 2953 creative professionals and 164,622 controls. The results overall suggest that risk for psychiatric disorders, language ability and creativity might have overlapping genetic roots.

genomics↗
bioRxiv2019

Meta-analysis of Scandinavian Schizophrenia Exomes

Rare genetic variants may play a prominent role in schizophrenia. We report on the to date largest whole exome sequencing study of schizophrenia case-control samples from related populations and combine with other available sequence data, analysing in total 34,084 individuals (14,302 cases). Three genes showed significant association at FDR < 0.10 (SETD1A, TAF13 and MKI67) and gene-set analyses highlighted the involvement of the synaptome and excitatory neurons, and demonstrated shared architecture with high-functioning autism.

genetics↗
bioRxiv2019

Identification of risk variants and characterization of the polygenic architecture of disruptive behavior disorders in the context of ADHD

Attention-Deficit/Hyperactivity Disorder (ADHD) is a childhood psychiatric disorder often comorbid with disruptive behavior disorders (DBDs). ADHD comorbid with DBDs (ADHD+DBDs) is a complex phenotype with a risk component that can be attributed to common genetic variants. Here we report a large GWAS meta-analysis of ADHD+DBDs based on seven cohorts in total including 3,802 cases and 31,305 controls. Three genome-wide significant loci were identified on chromosomes 1, 7, and 11. A GWAS meta-analysis including a Chinese cohort supported the locus on chromosome 11 to be a strong risk locus for ADHD+DBDs across European and Chinese ancestries (rs7118422, P=3.15x10-10, OR=1.17). This locus was not associated with ADHD without DBDs in a secondary GWAS of 13,583 ADHD cases and 22,314 controls, suggesting that the locus is a specific risk locus for the comorbid phenotype.\n\nWe found a higher SNP heritability for ADHD+DBDs (h2SNP =0.34) when compared to ADHD without DBDs (h2SNP =0.20). Genetic correlations of ADHD+DBDs with aggressive (rg =0.81) and anti-social behaviors (rg=0.82) were high, and polygenic risk score analyses revealed a significant increased burden of variants associated with ADHD and aggression in individuals with ADHD+DBDs compared to ADHD without DBDs. Our results suggests that ADHD+DBDs represent a more severe phenotype with respect to the genetic risk load than ADHD without DBDs, in line with previous studies, and that the risk load to some extent can be explained by variants associated with aggressive behavior.

genomics↗
bioRxiv2019

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

BackgroundPrevious 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.\n\nMethodsWe used diagnostic information for 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 two diseases. The genetic factors were investigated using GWAS and HLA imputation data based on iPSYCH cohort.\n\nResultsAmong 64,039 individuals, a total of 43,902 (68.6%) were diagnosed with mental disorders and 1,383 (2.2%) with autoimmune diseases. There was a significant comorbidity between the two diseases (P=2.67x10-7, 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=7.95x10-5) and vice versa (HR=1.27, 95%CI=1.16-1.39, P=8.77x10-15). Though PRSs were significantly correlated with both types of diagnosis, PRSs had little effect on the bidirectional relationship. Importantly, we for the first time observed 12 human leukocyte antigen (HLA) loci and 20 HLA alleles strongly associated with overall autoimmune diseases, but we did not find significant evidence of their associations with overall mental disorders.\n\nConclusionsOur findings confirm the overall comorbidity and bidirectionality between autoimmune and mental disorders and discover HLA genes which are significantly associated with overall autoimmune diseases, but not with overall mental disorders.

bioinformatics↗
bioRxiv2018

Genome-wide Association Study of Anxiety and Stress-related Disorders in the iPSYCH Cohort

Anxiety and stress-related disorders (ASRD) are among the most common mental disorders with the majority of patients suffering from additional disorders. Family and twin studies indicate that genetic and environmental factors are underlying their etiology. As ASRD are likely to configure various expressions of abnormalities in the basic stress-response system, we conducted a genome-wide association study including 12,655 cases with various anxiety and stress-related diagnoses and 19,225 controls. Standard association analyses were performed supplemented by a framework of sensitivity analyses. Variants in PDE4B showed consistent association with ASRD across a wide range of our analyses. In mice models, alternations in PDE4B expression were observed in those mice displaying anxious behavior after exposure to chronic stress. We also showed that 28% of the variance in ASRD was accounted for by common variants and that the genetic signature of ASRD overlapped with psychiatric traits, educational outcomes, obesity-related phenotypes, smoking, and reproductive success.

genetics↗
bioRxiv2017

A genome-wide association study for shared risk across major psychiatric disorders in a nation-wide birth cohort implicates fetal neurodevelopment as a key mediator

There is mounting evidence that seemingly diverse psychiatric disorders share genetic etiology, but the biological substrates mediating this overlap are not well characterized. Here, we leverage the unique iPSYCH study, a nationally representative cohort ascertained through clinical psychiatric diagnoses indicated in Danish national health registers. We confirm previous reports of individual and cross-disorder SNP-heritability for major psychiatric disorders and perform a cross-disorder genome-wide association study. We identify four novel genome-wide significant loci encompassing variants predicted to regulate genes expressed in radial glia and interneurons in the developing neocortex during midgestation. This epoch is supported by partitioning cross-disorder SNP-heritability which is enriched at regulatory chromatin active during fetal neurodevelopment. These findings indicate that dysregulation of genes that direct neurodevelopment by common genetic variants results in general liability for many later psychiatric outcomes.

genetics↗
bioRxiv2017

Genome-wide association study implicates CHRNA2 in cannabis use disorder

Introductory paragraphCannabis is the most frequently used illicit psychoactive substance worldwide1. Life time use has been reported among 35-40% of adults in Denmark2 and the United States3. Cannabis use is increasing in the population4-6 and among users around 9% become dependent7. The genetic risk component is high with heritability estimates of 518-70%9. Here we report the first genome-wide significant risk locus for cannabis use disorder (CUD, P=9.31x10-12) that replicates in an independent population (Preplication=3.27x10-3, Pmetaanalysis=9.09x10-12). The finding is based on a genome-wide association study (GWAS) of 2,387 cases and 48,985 controls followed by replication in 5,501 cases and 301,041 controls. The index SNP (rs56372821) is a strong eQTL for CHRNA2 and analyses of the genetic regulated gene expressions identified significant association of CHRNA2 expression in cerebellum with CUD. This indicates a potential therapeutic use in CUD of compounds with agonistic effect on the neuronal acetylcholine receptor alpha-2 subunit encoded by CHRNA2. At the polygenic level analyses revealed a significant decrease in the risk of CUD with increased load of variants associated with cognitive performance.

genomics↗
bioRxiv2017

Elevated polygenic burden for autism is associated with differential DNA methylation at birth.

BackgroundAutism spectrum disorder (ASD) is a severe neurodevelopmental disorder characterized by deficits in social communication and restricted, repetitive behaviors, interests, or activities. The etiology of ASD involves both inherited and environmental risk factors, with epigenetic processes hypothesized as one mechanism by which both genetic and non-genetic variation influence gene regulation and pathogenesis.\n\nMethodsWe quantified neonatal methylomic variation in 1,263 infants - of whom ~50% went on to subsequently develop ASD - using DNA isolated from a unique collection of archived blood spots taken shortly after birth. We used matched genetic data from the same individuals to examine the molecular consequences of ASD genetic risk variants, identifying methylomic variation associated with elevated polygenic burden for ASD. In addition, we performed DNA methylation quantitative trait loci (mQTL) mapping to prioritize target genes from ASD GWAS findings.\n\nResultsAlthough we did not identify specific loci showing consistent changes in neonatal DNA methylation associated with later ASD, we found a significant association between increased polygenic burden for autism and methylomic variation at two CpG sites located proximal to a robust GWAS signal for ASD on chromosome 8.\n\nConclusionsThis study is the largest analysis of DNA methylation in ASD yet undertaken and the first to integrate both genetic and epigenetic variation at birth in ASD. We demonstrate the utility of using a polygenic risk score to identify molecular variation associated with disease, and of using mQTL to refine the functional and regulatory variation associated with ASD risk variants.

genetics↗
bioRxiv2017

A genetic investigation of sex bias in the prevalence of attention deficit hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) shows substantial heritability and is 2-7 times more common in males than females. We examined two putative genetic mechanisms underlying this sex bias: sex-specific heterogeneity and higher burden of risk in female cases. We analyzed genome-wide common variants from the Psychiatric Genomics Consortium and iPSYCH Project (20,183 cases, 35,191 controls) and Swedish population-registry data (N=77,905 cases, N=1,874,637 population controls). We find strong genetic correlation for ADHD across sex and no mean difference in polygenic burden across sex. In contrast, siblings of female probands are at an increased risk of ADHD, compared to siblings of male probands. The results also suggest that females with ADHD are at especially high risk of comorbid developmental conditions. Overall, this study supports a greater familial burden of risk in females with ADHD and some clinical and etiological heterogeneity. However, autosomal common variants largely do not explain the sex bias in ADHD prevalence.

genetics↗
bioRxiv2017

Mitochondrial DNA SNPs associated with Schizophrenia exhibit Highly Variable Inter-allelic Haplogroup Affiliation and Nuclear Genogeographic Affinity: Bi-Genomic Linkage Disequilibrium raises Major Concerns for Link to Disease

Mitochondria play a significant role in human diseases. However, disease associations with mitochondrial DNA (mtDNA) SNPs have proven difficult to replicate. A reanalysis of eight schizophrenia-associated mtDNA SNPs, in 23,743 normal Danes and 2,538 schizophrenia patients, revealed marked inter-allelic differences in haplogroup affiliation and nuclear ancestry, genogeophraphic affinity (GGA). This bi-genomic linkage disequilibrium (2GLD) could entail population stratification. Only two mitochondrial SNPs, m. 15043A and m. 15218G, were significantly associated with schizophrenia. However, these associations disappeared when corrected for haplogroup affiliation. The extensive 2GLD documented is a major concern when interpreting historic as well as designing future mtDNA association studies.

genomics↗
bioRxiv2017

Complex spatio-temporal distribution and genogeographic affinity of mitochondrial DNA haplogroups in 24,216 Danes

Mitochondrial DNA (mtDNA) haplogroups (hgs) are evolutionarily conserved sets of mtDNA SNP-haplotypes with characteristic geographical distribution. Associations of hgs with disease and physiological characteristics have been reported, but have frequently not been reproducible. Using 418 mtDNA SNPs on the PsychChip (Illumina), we assessed the spatio-temporal distribution of mtDNA hgs in Denmark in DNA isolated from 24,642 geographically un-biased dried blood spots (DBS), collected from 1981 to 2005 through the Danish National Neonatal Screening program. Geno-geographic affinity (ancestry background) was established with ADMIXTURE using a reference of 100K+ autosomal SNPs in 2,248 individuals from nine populations. The hg distribution was typically Northern European, and hgs were highly variable based on median-joining analysis, suggesting multiple founder events. Considerable heterogeneity and variation in autosomal geno-geographic affinity was observed. Thus, individuals with hg H exhibited 95 %, and U hgs 38.2 % - 92.5 %, Danish ancestry. Significant clines between geographical regions and rural and metropolitan populations were found. Over 25 years, macro-hg L increased from 0.2 % to 1.2 % (p = 1.1*E-10), and M from 1 % to 2.4 % (p = 3.7*E-8). Hg U increased among the R macro-hg from 14.1 % to 16.5 % (p = 1.9*E-3). Geno-geographic affinity, geographical skewedness, and sub-hg distribution suggested that the L, M and U increases are due to immigration. The complex spatio-temporal dynamics and geno-geographic heterogeneity of mtDNA in the Danish population reflect repeated migratory events and, in later years, net immigration. Such complexity may explain the often contradictory and population-specific reports of mito-genomic association with disease.

genomics↗
bioRxiv2017

Quantifying the impact of rare and ultra-rare coding variation across the phenotypic spectrum

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, ADHD. In individuals without these disorders, there was an association with shorter height, lower education, increased hospitalization and reduced age. Gene sets implicated from GWAS did not show a significant protein truncating variants-burden beyond what captured by established Mendelian genes. In conclusion, we provide the most thorough investigation to date of the impact of rare deleterious coding variants on complex traits, suggesting widespread pleiotropic risk.\n\nMain abbreviations

genetics↗
bioRxiv2017

The iPSYCH2012 case-cohort sample: New directions for unravelling genetic and environmental architectures of severe mental disorders

The iPSYCH consortium has established a large Danish population-based Case-Cohort sample (iPSYCH2012) aimed at unravelling the genetic and environmental architecture of severe mental disorders. The iPSYCH2012 sample is nested within the entire Danish population born 1981-2005 including 1,472,762 persons. This paper introduces the iPSYCH2012 sample and outlines key future research directions. Cases were identified as persons with schizophrenia (N=3,540), autism (N=16,146), ADHD (N=18,726), and affective disorder (N=26,380), of which 1928 had bipolar affective disorder. Controls were randomly sampled individuals (N=30,000). Within the sample of 86,189 individuals, a total of 57,377 individuals had at least one major mental disorder. DNA was extracted from the neonatal dried blood spot samples obtained from the Danish Neonatal Screening Biobank and genotyped using the Illumina PsychChip. Genotyping was successful for 90% of the sample. The assessments of exome sequencing, methylation profiling, metabolome profiling, vitamin-D, inflammatory and neurotrophic factors are in progress. For each individual, the iPSYCH2012 sample also includes longitudinal information on health, prescribed medicine, social and socioeconomic information and analogous information among relatives. To the best of our knowledge, the iPSYCH2012 sample is the largest and most comprehensive data source for the combined study of genetic and environmental aetiologies of severe mental disorders.

genetics↗