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

Background Although recent sequencing studies have revealed that 10% of childhood gliomas are caused by rare germline mutations, the role of common variants is undetermined and no genome-wide significant risk loci for pediatric central nervous system tumors have been identified to date. Methods Meta-analysis of 3 population-based genome-wide association studies comprising 4069 children with glioma and 8778 controls of multiple genetic ancestries. Replication was performed in a separate case–control cohort. Quantitative trait loci analyses and a transcriptome-wide association study were conducted to assess possible links with brain tissue expression across 18 628 genes. Results Common variants in CDKN2B-AS1 at 9p21.3 were significantly associated with astrocytoma, the most common subtype of glioma in children (rs573687, P-value of 6.974e-10, OR 1.273, 95% CI 1.179–1.374). The association was driven by low-grade astrocytoma (P-value of 3.815e-9) and exhibited unidirectional effects across all 6 genetic ancestries. For glioma overall, the association approached genome-wide significance (rs3731239, P-value of 5.411e-8), while no significant association was observed for high-grade tumors. Predicted decreased brain tissue expression of CDKN2B was significantly associated with astrocytoma (P-value of 8.090e-8). Conclusions In this population-based genome-wide association study meta-analysis, we identify and replicate 9p21.3 (CDKN2B-AS1) as a risk locus for childhood astrocytoma, thereby establishing the first genome-wide significant evidence of common variant predisposition in pediatric neuro-oncology. We furthermore provide a functional basis for the association by showing a possible link to decreased brain tissue CDKN2B expression and substantiate that genetic susceptibility differs between low- and high-grade astrocytoma.

Intake of fish-oil and fatty fish during pregnancy has been shown to reduce the risk of childhood asthma but biomarkers of such intake are lacking.To establish biomarkers of prenatal fish-oil exposure from newborn dry blood spot metabolomics profiles and assess their relevance for childhood asthma risk stratification.The Danish COPSACThe newborn metabolomics profiles differed between children in the fish-oil vs. placebo group in COPSACNewborn children's blood levels of the furan fatty acid metabolite CMPF reflect fish-oil and fatty fish intake during pregnancy and are associated with a lower risk of asthma across two cohorts, which could aid newborn screening for childhood asthma.

Next-generation sequencing (NGS) based population screening holds great promise for disease prevention and earlier diagnosis, but associated sequencing costs remain prohibitive. We developed double batched sequencing (DoBSeq) and tested it on neonatal blood spot DNA in an explorative (n = 100) and a validation (n = 100) cohort selected from a nation-wide childhood cancer whole genome sequencing (WGS) study. Each cohort was enriched for loss-of-function/pathogenic variants in cancer predisposition syndrome genes. Using a commercial 113-gene panel benchmarked against individual WGS data, we demonstrated replicable detection of deleterious and pathogenic variants, with positive and negative predictive values of 100% (95%CI 0.91-1.00 & 95%CI 0.98-1.00, respectively). Pathogenic variants were detected in RB1, TP53, BRCA2, APC, and 19 other genes. Analyses of larger batches (n = 24, 48, 72 & 96) indicate that DoBSeq is highly scalable and thus a promising, cost-effective method for realizing the potential of population-scale NGS-based screening.

Newborn screening is a public health programme for early diagnosis of treatable diseases.The subjects included were newborns born 2002-2019. Expanded newborn screening (eNBS) for metabolic diseases was introduced as a pilot project from 2002 to 2009, followed by routine screening with informed dissent. A total of 967,780 newborns were screened; 82,930 were unscreened. Furthermore, a historic cohort of clinically diagnosed children born in the 1992-2001 period was included. Children in the unscreened and historic cohorts were evaluated for the same diseases as were the screened children. Dried blood spot samples were collected locally and sent for screening analyses. We recorded newborns with true and false positive results as well as false negative results and their clinical signs at screening and at the last follow-up.A total of 603 samples were screen positive: 354 false positives and 249 true positives (222 newborns and 27 mothers). The positive predictive value (PPV) was 41% for the entire screening period; 62% for 2018. The false positive rate (FPR) was 0.036% overall; 0.024% for 2018. The overall prevalence of diseases was 1:3,900; in the historic cohort, the prevalence of the same diseases was 1:8,300; 7.3% had symptoms at the time of screening. At follow-up, 93% of the children had no clinically significant sequelae. Among 82,930 unscreened newborns, 27 (1:3,000) had eNBS panel diseases, some with severe manifestations.This update of eNBS in Denmark confirms that eNBS is a successful preventive public health programme. Early treatment in a latent phase of disease is effective and screening should be extended to other diseases not currently in the programme.The work was supported by grants from The Ronald McDonald Børnefond, Danmarks Sundhedsfond, Direktør Ib Henriksens Fond, Ragnhild Ibsens Legat til Medicinsk Forskning, Gerda og Aage Haenschs Fond, Dronning Louises Børnehospitals Forskningsfond, Læge Sofus Carl Emil Friis og Hustru Olga Doris Friis's Legat, Aase and Ejnar Danielsens Fond, Oda og Hans Svenningsens Fond, Fonden af 1870, Vanførefonden, Fonden til Lægevidenskabens Fremme and Danish Medical Research Council.not relevant.

Vitamin D deficiency and elevated high sensitivity C-reactive protein (hs-CRP) have been associated with several health outcomes, but knowledge on early life trajectories and association between 25 hydroxyvitamin D (25(OH)D) and hs-CRP is lacking. We investigated the association between longitudinal measurements of 25(OH)D and hs-CRP, respectively, from pregnancy to childhood and throughout childhood in two Danish mother–child cohorts—the COPSAC2010 and COPSAC2000. In COPSAC2010, there was an association between 25(OH)D concentrations at week 24 in pregnancy and at age 6 months in childhood (n = 633): estimate (95% CI); 0.114 (0.041;0.187), p = 0.002, and between 25(OH)D at age 6 months and 6 years (n = 475): 0.155 (0.083;0.228), p < 0.001. This was also demonstrated in the COPSAC2000 cohort between 25(OH)D concentrations in cord blood and at age 4 years (n = 188): 0.294 (0.127;0.461), p < 0.001 and at age 6 months and 4 years (n = 264): 0.260 (0.133;0.388), p < 0.001. In COPSAC2000, we also found an association between hs-CRP at age 6 months and 12 years in childhood (n = 232): 0.183 (0.076;0.289), p < 0.001. Finally, we found a negative association between the cross-sectional measurements of 25(OH)D and hs-CRP at age 6 months (n = 613) in COPSAC2010: −0.004 (−0.008;−0.0004), p = 0.030, but this was not replicated in COPSAC2000. In this study, we found evidence of associations across timepoints of 25(OH)D concentrations from mid-pregnancy to infancy and through childhood and associations between hs-CRP levels during childhood, although with weak correlations. We also found a negative cross-sectional association between 25(OH)D and hs-CRP concentrations in COPSAC2010 proposing a role of vitamin D in systemic low-grade inflammation, though this association was not present in COPSAC2000.

Background Cannabis is the most widely used illicit drug in the world. Cannabis Use Disorder (CUD) is associated with adverse consequences, including psychiatric symptoms, cognitive decline, anxiety disorder and poor quality of life. 35–40% of adults in Denmark and the United States are reported with life-time use of cannabis. The prevalence of diagnosed CUD in Europeans and Americans is estimated to 1–1.5% and the heritability of CUD is estimated to 51–70%. With respect to the amount of risk explained by common variants, the SNP heritability has been estimated to 0.06–0.2. The difference between total heritability and SNP heritability suggests that rare variants might contribute to the risk of CUD, which require sequencing to find them. Methods We performed whole-exome sequencing of ~7,366 Danish individuals identified in the Danish Newborn Screening Biobank (DNSB), including 1,236 affected with CUD, and ~6,100 unaffected controls. We aligned exome sequence data against GRCh37 human genome reference with bwa and identified variants using GATK. We performed quality control of variants and individuals (including principal component analysis for exclusion of non-Europeans), annotated variants with respect to gene, functional impact and presence in the ExAC non-psych database using Hail. Subsequently various burden tests were performed. Results Here we will present results from analysis of the impact of Ultra-Rare Variants (URVs) in CUD. We will especially focus on the burden of these variants in CUD cases compared to controls in highly evolutionary constrained genes as well as specific gene-sets relevant to CUD. Furthermore, we will assess whether CUD risk genes identified based on the common variant analysis also carry an increased burden of URVs. In addition, we will conduct gene-based association analysis to identify top-ranking genes most frequently hit by rare deleterious variants in CUD cases compared with controls. Discussion We will discuss our comprehensive analyses of the role of URVs in CUD, which will further contribute to the understanding of the genetic architecture underlying the disorder, and help elucidating relevant biological mechanism contributing to disease risk.

Peptide antibodies are particularly useful for immunocytochemistry (ICC) and immunohistochemistry (IHC), where antigens may denature due to fixation of tissues and cells. Peptide antibodies can be made to any defined sequence, including unknown putative proteins and posttranslationally modified sequences. Moreover, the availability of large amounts of the antigen (peptide) allows inhibition/adsorption controls, which are important in ICC/IHC, due to the many possibilities for false-positive reactions caused by immunoglobulin Fc receptors, nonspecific reactions, and cross-reactivity of primary and secondary antibodies with other antigens and endogenous immunoglobulins, respectively. Here, simple protocols for ICC and IHC are described together with recommendations for appropriate controls.

Clinical manifestations and metabolic risk factors may differ in ethnic subgroups of patients with polycystic ovary syndrome (PCOS).Retrospective trans-sectional study.One thousand and two premenopausal women with the diagnoses hirsutism or PCOS were divided according to ethnicity: Caucasian (CA, n = 784), Middle East (ME, n = 190), Asian (n = 14) and others (n = 14).Clinical evaluation (hirsutism, BMI, waist, blood pressure), hormone analyses (testosterone, sex hormone-binding globulin, prolactin, lipids, insulin, glucose) and transvaginal ultrasound were performed. Oral glucose tolerance tests (OGTT) (n = 499) and ACTH tests (n = 434) were performed in a subgroup of patients.(CA vs ME women) CA women were older [32(25-37) vs 25(18-32) years, median (quartiles)] and had increased BMI compared to ME women. After correcting for age and BMI, CA women were less hirsute, but had increased testosterone levels compared to ME women. The Rotterdam criteria were fulfilled in 56% of both populations, but PCO was diagnosed in 47% CA vs 29% ME women, P0·01. CA women had increased blood pressure and smoked at a higher frequency (40 vs 23%), whereas area under the curve for insulin during OGTT was decreased, all P0·001. Prolactin levels were significantly lower in CA women compared to ME women [7(5-10) vs 9(6-12) μg/l] and were inversely associated with smoking status.CA women had a more adverse cardiovascular profile than ME women, whereas insulin sensitivity was higher. The prevalence of the individual Rotterdam criteria differed significantly in the two study populations.

In 2004 the Danish National Board of Health (DNBH) published new guidelines for the prenatal risk assessment and diagnostic service. The new guidelines are nationally implemented. DNBH has pointed out the importance of quality control, but has not given any specific guidelines concerning this. We demonstrate the feasibility of a quality assessment of a considerable part of the screening programme.The quality assessment is conducted on a cohort from Holbaek Hospital during 12 months by merging data from one local hospital database to data from the Danish Cytogenetic Centralregistry and the Danish National Newborn Screening Registry.The study included 1796 singleton pregnancies and 47 twin pregnancies. 46 invasive procedures were carried out among the singleton pregnancies, which corresponds to an invasive rate of 2.6%. Two fetuses with Down's syndrome (DS) and one with trisomy 18 were found and the pregnancies were terminated. One fetus with Turners syndrome was diagnosed prenatally, but ended as a missed abortion. One child with DS was not diagnosed prenatally. The detection rate for DS was 2/3 (67%).We suggest that the outlined quality program is implemented as a national programme.

Background: Although the usefulness of polygenic risk scores as a measure of genetic liability for major depressive disorder (MDD) has been established, their capacity to predict who will develop depression in the general population remains relatively unexplored. Our goals were to evaluate whether polygenic risk scores for MDD, bipolar disorder (BPD) and schizophrenia (SCZ) can predict depression in the general population, and explore whether these polygenic liabilities are associated with heterogeneity in age at onset and severity at initial depression diagnosis. Methods: Data were obtained from the iPSYCH2012 sample, a case-cohort sample comprised of a subcohort of 30,000 individuals randomly sampled from the Danish population and all additional individuals diagnosed in a psychiatric hospital with five different psychiatric disorders, including depression (ICD-10 codes F32, F33). For this study we included all genotyped individuals from the subcohort with Danish ancestry (N=20,158) along with all additional genotyped depression cases with Danish ancestry (N=18,030). Severity at depression diagnosis was assessed using the ICD-10 severity specifier (mild, moderate, severe without psychotic symptoms, severe with psychotic symptoms), and treatment setting (outpatient, inpatient, emergency). Age at onset (AAO) was operationalized as each individual's age in years at first depression diagnosis. Polygenic risk scores were trained using the most recent results from the PGC as discovery datasets. Hazard of depression was estimated using Cox regressions modified to accommodate the case-cohort design. Case-only analyses were conducted using linear and multinomial regressions. All models were adjusted for sex, birth year and the first 4 principal components. Results: In this nationally-representative sample of the Danish population, a one standard deviation increase in polygenic liability for MDD was associated with a 32% increase in hazard for depression (p < .0001). The corresponding increases associated with PRS-BPD and PRS-SCZ were 10% and 12%, respectively (p < .0001 for both). Hazard of depression was 2.65 times higher among individuals in the top decile of PRS-MDD relative to individuals in the bottom decile. PRS-MDD was not associated with differences in either AAO or severity, however among depression cases, PRS-BPD and PRS-SCZ showed small associations with earlier age at diagnosis (p = .013 for both), and PRS-BPD was associated with increased odds of inpatient (OR=1.05, 95% CI= [1.01-1.09]) and emergency (1.04, [1.00-1.08]) treatment. Discussion: Polygenic liability for MDD trained using prevalent samples of MDD cases predicts depression in the general population, suggesting that these scores are tapping in to an underlying liability for developing depression, not just risk for maintaining the disorder. The fact that PRS-BPD and PRS-SCZ also predict depression, although to a lesser extent than PRS-MDD, is consistent with prior results suggesting a degree of common genetic overlap among these disorders. Variation in polygenic loading for BPD and SCZ may contribute slightly to heterogeneity in clinical presentation at first diagnosis among depression cases.

BackgroundBirth by caesarean section is linked to an increased risk of developing asthma, but the underlying mechanisms are unclear.ObjectiveTo elucidate the link between birth by caesarean section and asthma using newborn metabolomic profiles and integrating early-life gut microbiome data and cord blood immunology.MethodsWe investigated the influence of caesarean section on liquid chromatography mass spectrometry metabolomic profiles of dried blood spots from newborns of the two independent Copenhagen Prospective Studies on Asthma in Childhood cohorts, i.e. COPSAC2010 (n=677) and COPSAC2000 (n=387). We assessed the associations between the caesarean section metabolic profile, gut microbiome data and frequency of cord blood regulatory T-cells (Tregs) at 1 week of age.ResultsIn COPSAC2010, a partial least square discriminant analysis model showed that children born by caesarean section versus natural delivery had different metabolic profiles (area under the curve (AUC)=0.77, p=2.2×10−16), which was replicated in COPSAC2000 (AUC=0.66, p=1.2×10−5). The metabolic profile of caesarean section was significantly associated with an increased risk of asthma at school age in both COPSAC2010 (p=0.03) and COPSAC2000 (p=0.005). Caesarean section was associated with lower abundance of tryptophan, bile acid and phenylalanine metabolites, indicative of a perturbed gut microbiota. Furthermore, gut bacteria dominating after natural delivery, i.e. Bifidobacterium and Bacteroides were correlated with caesarean section-discriminative microbial metabolites, suggesting maternal microbial transmission during birth regulating the newborn's metabolism. Finally, the caesarean section metabolic profile was associated with frequency of cord blood Tregs.ConclusionsThese findings propose that caesarean section programmes the risk of childhood asthma through perturbed immune responses and gut microbial colonisation patterns reflected in the blood metabolome at birth.