Danish Psychiatric Central Registry Research Articles

13 - MITOCHONDRIAL DNA HAPLOGROUPS ARE ASSOCIATED WITH PSYCHIATRIC DISEASE: A NATION-WIDE STUDY OF 74,763 DANES

Background Disturbed mitochondrial function has been implicated in psychiatric disease. All mitochondria contain a small maternally inherited DNA (mtDNA) of 16.6 kb. Through evolution and genetic drift, the mtDNA sequence has become fixed into haplogroups (hgs) with a characteristic population and geographical distribution. Different hgs exhibit variable functional capacity and have been demonstrated to be susceptibility factors for various, predominantly degenerative, diseases. Associations with Parkinsons and Alzheimers diseases, as well as cardiac, metabolic and psychiatric disorders have been reported. These findings have prompted the suggestion that variations in mitochondrial function might be susceptibility factors for disease. However, reports on association between mtDNA hgs and disease have frequently been conflicting. This is partly due to population stratification in examined populations and low-powered study designs. We analysed the association between mtDNA hgs and psychiatric disease using a very large geographically unbiased cohort, iPSYCH, comprising 2% of Danes as controls and 50,000+ psychiatric patients. Methods Using DNA extracted from dried blood spots from 50,567 Danish psychiatric patients (ADHD: 13,103; ASD: 12,891; Anorexia: 2,124; BD: 1,242; SCZ: 2,438, and AD: 16,225) and 24,196 controls we examined the association between psychiatric disease and mtDNA haplogroup in the Danish population. Psychiatric patients were identified from the Danish Psychiatric Central Registry. DNA was obtained from the Danish Neonatal Screening Biobank. Haplotyping was performed using the PGC developed PsychChip v.1.0. containing 418 SNPs in mtDNA. The SNP data were manually analysed and haplotyped according to haplogroup defining SNPs in Phylotree. Results Hg M was associated with affective disorder (n = 17260) with an OR of 0.47 (cfi.95%: 0.39 – 0.58) (p = 1*10–14), ADHD (n = 13395) with an OR of 0.50 (0.40 – 0.62)(p = 2*10–11). Among patients belonging to the macro-hg N, patients with schizophrenia (n = 2589), had a high proportion of hg A (n = 45), OR: 4.52 (cfi.95%: 3.0 – 6.7)(p = 1.2*10–12). No significant associations between mtDNA hgs and BD or ASD were found. In a mitoGWAS for all six conditions, three mitoSNPs were highly associated with affective disorder (p-values ranging from 2*10E-25 – 2*10E-21), ADHD (p-values: 2*10E-11 – 1*10E-10), and anorexia (p-values: 6*10E -8 - 6*10E-7) and another mitoSNP with schizophrenia (p = 2*10–11). Discussion Psychiatric disease seems to be bigenomic diseases with contributions from both the mitochondrial and nuclear genome. Haplogroup A is a risk factor for schizophrenia and haplogroup M is a protective factor for ADHD and affective disorder. However, both hgs A and M are infrequent in the Danish population and markers of Greenlandic and Asian origin, respectively. So it will be important through studies of interaction between mtDNA and the genomic DNA to precisely define the role of each of these factors in the etiology of psychiatric disease.

Attention deficit/hyperactivity disorder and childhood autism in association with prenatal exposure to perfluoroalkyl substances: a nested case-control study in the Danish National Birth Cohort.

Background:Perfluoroalkyl substances (PFASs) are persistent pollutants found to be endocrine disruptive and neurotoxic in animals. Positive correlations between PFASs and neurobehavioral problems in children were reported in cross-sectional data, but findings from prospective studies are limited.Objectives:We investigated whether prenatal exposure to PFASs is associated with attention deficit/hyperactivity disorder (ADHD) or childhood autism in children.Methods:Among 83,389 mother–child pairs enrolled in the Danish National Birth Cohort during 1996–2002, we identified 890 ADHD cases and 301 childhood autism cases from the Danish National Hospital Registry and the Danish Psychiatric Central Registry. From this cohort, we randomly selected 220 cases each of ADHD and autism, and we also randomly selected 550 controls frequency matched by child’s sex. Sixteen PFASs were measured in maternal plasma collected in early or mid-pregnancy. We calculated risk ratios (RRs) using generalized linear models, taking into account sampling weights.Results:Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) were detected in all samples; four other PFASs were quantified in ≥ 90% of the samples. We did not find consistent evidence of associations between mother’s PFAS plasma levels and ADHD [per natural log nanograms per milliliter increase: PFOS RR = 0.87 (95% CI: 0.74, 1.02); PFOA RR = 0.98 (95% CI: 0.82, 1.16)] or autism [per natural log nanograms per milliliter increase: PFOS RR = 0.92 (95% CI: 0.69, 1.22); PFOA RR = 0.98 (95% CI: 0.73, 1.31)]. We found positive as well as negative associations between higher PFAS quartiles and ADHD in models that simultaneously adjusted for all PFASs, but these estimates were imprecise.Conclusions:In this study we found no consistent evidence to suggest that prenatal PFAS exposure increases the risk of ADHD or childhood autism in children.Citation:Liew Z, Ritz B, von Ehrenstein OS, Bech BH, Nohr EA, Fei CY, Bossi R, Henriksen TB, Bonefeld-Jørgensen EC, Olsen J. 2015. Attention deficit/hyperactivity disorder and childhood autism in association with prenatal exposure to perfluoroalkyl substances: a nested case–control study in the Danish National Birth Cohort. Environ Health Perspect 123:367–373; http://dx.doi.org/10.1289/ehp.1408412

Acetaminophen Use During Pregnancy, Behavioral Problems, and Hyperkinetic Disorders

Acetaminophen (paracetamol) is the most commonly used medication for pain and fever during pregnancy in many countries. Research data suggest that acetaminophen is a hormone disruptor, and abnormal hormonal exposures in pregnancy may influence fetal brain development. To evaluate whether prenatal exposure to acetaminophen increases the risk for developing attention-deficit/hyperactivity disorder (ADHD)-like behavioral problems or hyperkinetic disorders (HKDs) in children. We studied 64,322 live-born children and mothers enrolled in the Danish National Birth Cohort during 1996-2002. Acetaminophen use during pregnancy was assessed prospectively via 3 computer-assisted telephone interviews during pregnancy and 6 months after child birth. To ascertain outcome information we used (1) parental reports of behavioral problems in children 7 years of age using the Strengths and Difficulties Questionnaire; (2) retrieved HKD diagnoses from the Danish National Hospital Registry or the Danish Psychiatric Central Registry prior to 2011; and (3) identified ADHD prescriptions (mainly Ritalin) for children from the Danish Prescription Registry. We estimated hazard ratios for receiving an HKD diagnosis or using ADHD medications and risk ratios for behavioral problems in children after prenatal exposure to acetaminophen. More than half of all mothers reported acetaminophen use while pregnant. Children whose mothers used acetaminophen during pregnancy were at higher risk for receiving a hospital diagnosis of HKD (hazard ratio = 1.37; 95% CI, 1.19-1.59), use of ADHD medications (hazard ratio = 1.29; 95% CI, 1.15-1.44), or having ADHD-like behaviors at age 7 years (risk ratio = 1.13; 95% CI, 1.01-1.27). Stronger associations were observed with use in more than 1 trimester during pregnancy, and exposure response trends were found with increasing frequency of acetaminophen use during gestation for all outcomes (ie, HKD diagnosis, ADHD medication use, and ADHD-like behaviors; P trend < .001). Results did not appear to be confounded by maternal inflammation, infection during pregnancy, the mother's mental health problems, or other potential confounders we evaluated. Maternal acetaminophen use during pregnancy is associated with a higher risk for HKDs and ADHD-like behaviors in children. Because the exposure and outcome are frequent, these results are of public health relevance but further investigations are needed.

Prenatal Antidepressant Exposure and Risk of Spontaneous Abortion – A Population-Based Study

PurposeTo estimate the risk of spontaneous abortion after use of antidepressant medication during pregnancy.MethodsFrom the Danish Medical Birth Registry and the Danish National Hospital Registry, we identified all pregnancies leading to in- or outpatient contacts in Denmark from February 1997 to December 2008. The Danish Registry of Medicinal Product Statistics provided information on the women's prescriptions for antidepressants during pregnancy. We obtained information on women who were diagnosed with depression from the Danish Psychiatric Central Registry. Adjusted relative risks (aRR) of spontaneous abortion were estimated according to exposure to antidepressants or maternal depression using binomial regression.ResultsOf the 1,005,319 pregnancies (547,300 women) identified, 114,721 (11.4%) ended in a spontaneous abortion. We identified 22,061 pregnancies exposed to antidepressants and 1,843 with a diagnosis of depression with no antidepressant use, of which 2,637 (12.0%) and 205 (11.1%) ended in a spontaneous abortion, respectively. Antidepressant exposure was associated with an aRR of 1.14 (95% confidence interval (CI) 1.10–1.18) for spontaneous abortion compared with no exposure to antidepressants. Among women with a diagnosis of depression, the aRR for spontaneous abortion after any antidepressant exposure was 1.00 (95% CI 0.80–1.24). No individual selective serotonin reuptake inhibitor (SSRI) was associated with spontaneous abortions. In unadjusted analyses, we found that mirtazapine, venlafaxine, and duloxetine were associated with spontaneous abortions among women with depression but we had no information on potential differences in disease severity and only few pregnancies were exposed in the population.ConclusionWe identified a slightly increased risk of spontaneous abortion associated with the use of antidepressants during pregnancy. However, among women with a diagnosis of depression, antidepressants in general or individual SSRI in particular were not associated with spontaneous abortions. Further studies are warranted on the newer non-SSRI antidepressants, as we had insufficient data to adjust for important confounding factors.

Psychiatric disorders in women with fertility problems: results from a large Danish register-based cohort study

Do women who don't succeed in giving birth after an infertility evaluation have a higher risk of psychiatric disorders compared with women who do? The results indicated that being unsuccessful in giving birth after an infertility evaluation could be an important risk factor for psychiatric disorders. Several studies have investigated the association between fertility treatment and psychological distress, but the results from these studies show substantial variation and lack of homogeneity that may be due to methodological limitations. A retrospective cohort study was designed using data from a cohort of 98 320 Danish women evaluated for fertility problems during 1973-2008 and linked to several Danish population-based registries. All women were followed from the date of first infertility evaluation until date of hospitalization for the psychiatric disorder in question, date of emigration, date of death or 31 December 2008, whichever occurred first. Owing to the precise linkage between the infertility cohort and the Danish population-based registries, using the unique Danish personal identification number, virtually no women were lost to follow-up. Information on reproductive status for all women in the infertility cohort was obtained by linkage to the Danish Medical Birth Registry. A total of 53 547 (54.5%) women gave birth after the initial infertility evaluation, whereas 44 773 (45.5%) women did not gave birth after the evaluation. To determine psychiatric disorders diagnosed in the women after enrolment in the infertility cohort, the cohort was linked to the Danish Psychiatric Central Registry. A total of 4633 women were hospitalized for a psychiatric disorder. The Cox proportional hazard regression model was applied to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for the association between parity status after the initial infertility evaluation and risk of hospitalization for various groups of psychiatric disorders, including 'all mental disorders' and six main discharge subgroups labelled: 'alcohol and intoxicant abuse', 'schizophrenia and psychoses', 'affective disorders', 'anxiety, adjustment and obsessive compulsive disorders', 'eating disorder' and 'other mental disorders'. The incidence rate for all mental disorders was 393 cases per 100 000 person-years among women who did not succeed in giving birth after the infertility evaluation but only 353 cases per 100 000 person-years among women who succeeded in giving birth after the infertility evaluation. Women not giving birth after the infertility evaluation had an increased risk of hospitalization for all mental disorders (HR 1.17, 95% CI 1.11; 1.25), alcohol and intoxicant abuse (HR 2.02, 95% CI 1.69; 2.41), schizophrenia and psychoses (HR 1.46, 95% CI 1.17; 1.82) and other mental disorders (HR 1.42, 95% CI 1.27; 1.58) compared with women who gave birth after the infertility evaluation. In contrast, the risk of affective disorders (HR 0.90, 95% CI 0.81; 0.99) was decreased among women not giving birth after the infertility evaluation. Finally, the risk of anxiety, adjustment and obsessive compulsive disorders (HR 1.07, 95% CI 0.97; 1.17) as well as of eating disorders (HR 1.40, 95% CI 0.88; 2.22) was not significantly affected by parity status after the infertility evaluation. As only psychiatric conditions warranting hospitalization could be included in the present study, the true incidence of all psychiatric disorders among women with fertility problems is likely to be somewhat underestimated. Furthermore, since detailed information on fertility treatment was not available for all cohort members the association between different modalities of assisted reproductive techniques and risk of psychiatric disorders was not assessed. Clinicians and other healthcare personnel involved in diagnosis and treatment of women with fertility problems should be aware of the potential risk modification of psychiatric disorders associated with unsuccessful fertility treatment. Hence, our results may point to new aspects of follow-up of women with fertility problems who are unsuccessful in giving birth in order to prevent or identify and treat these possible psychological side effects. The study was supported by the Danish Cancer Society (award number: 96 222 54). All authors report no conflicts of interest.

Congenital Heart Defects and Developmental and Other Psychiatric Disorders

We examined the risk of psychiatric in-patient admissions and out-patient visits among Danish patients with congenital heart defects (CHD). Using the Danish National Registry of Patients, we identified CHD patients born January 1, 1977, to January 1, 2002. For each patient, we randomly selected 10 population-comparison cohort members from the Danish Civil Registration System, matched by sex and birth year. We computed cumulative risk and hazard ratios (HRs) of time to first psychiatric in-patient admission or out-patient visit identified in the Danish Psychiatric Central Registry and adjusted for parents' educational level and parents' psychiatric morbidity. We identified 6927 CHD patients. At 15 years of age, the cumulative risk of psychiatric admissions or out-patient visits was 5.9% (95% confidence interval [CI], 5.2%-6.6%) among CHD patients. The HRs for CHD patients and comparison cohort members aged 0 to 14 years were 1.8 (95% CI: 1.5-2.1) for males and 2.5 (95% CI: 2.0-3.1) for females. For patients aged 15 to 30 years, the HRs were 1.6 (95% CI: 1.2-2.0) for males and 1.0 (95% CI: 0.8-1.3) for females. Congenital heart defect patients, both with and without invasive therapeutic interventions or extracardiac defects or syndromes, had a higher risk of psychiatric in-patient admissions or out-patient visits than comparison cohort members. After restriction of the comparison cohort to patients with diabetes mellitus or asthma (n=2554), the HR was 1.41 (95% CI: 1.07-1.85) for patients aged 0 to 14 years and 0.70 (95% CI: 0.52-0.94) for patients aged 15 to 30 years. Congenital heart disease patients with or without invasive therapeutic interventions are at increased risk of developmental and other psychiatric disorders, which seem to develop earlier than in patients with diabetes mellitus or asthma.

Facial clefting and psychiatric diseases: a follow-up of the Danish 1936-1987 Facial Cleft cohort.

This study assesses whether patients with facial cleft have an increased risk of psychiatric diseases. Through the Danish Facial Cleft Database, patients with facial cleft born between 1936 and 1987 in Denmark were identified, and the admission pattern for these patients with facial cleft was available for the period 1969 through 1993 through the Danish Psychiatric Central Registry. A total of 6,462 patients with facial cleft followed up for a total of 127,068 person-years. MAIN OUTCOME MEASURES Hospitalization for psychiatric diseases. The expected number of admissions for the cleft population was calculated by multiplication of the observed person-years with admission rates for Denmark stratified for sex, 1-year age group, and 1-year calendar period. A total of 284 patients with facial cleft (4.4%) were hospitalized for psychiatric diseases. The relative risk of hospitalization was 1.65 (95% confidence interval 1.3 to 2.0) for patients with isolated cleft palate (CP) and 1.15 (95% confidence interval 0.99 to 1.29) for patients with cleft lip +/- cleft palate (CL[P]). The overall risk estimates were above unity for both CP and CL(P) in all major diagnosis groups, neurosis and autism (for CL[P]) being the only exceptions. The excess risk was not accounted for by patients with known associated anomalies/syndromes. The risk of hospitalized mental disorders in general is increased in patients with CP but not to any substantial degree in patients with CL(P). Both groups had an increased risk of mental retardation and substance abuse, but the risk for schizophrenia or bipolar illness was not statistically significantly increased, compared with the background population. Further, our data provide no evidence that the psychosocial stressors associated with CL(P) and its treatment have any substantial impact on the risk for hospitalized mental illness.