Genetic and environmental components as well as their interaction contribute to the risk of schizophrenia, making it highly relevant to include environmental factors in genetic studies of ...schizophrenia. This study comprises genome-wide association (GWA) and follow-up analyses of all individuals born in Denmark since 1981 and diagnosed with schizophrenia as well as controls from the same birth cohort. Furthermore, we present the first genome-wide interaction survey of single nucleotide polymorphisms (SNPs) and maternal cytomegalovirus (CMV) infection. The GWA analysis included 888 cases and 882 controls, and the follow-up investigation of the top GWA results was performed in independent Danish (1396 cases and 1803 controls) and German-Dutch (1169 cases, 3714 controls) samples. The SNPs most strongly associated in the single-marker analysis of the combined Danish samples were rs4757144 in ARNTL (P=3.78 × 10(-6)) and rs8057927 in CDH13 (P=1.39 × 10(-5)). Both genes have previously been linked to schizophrenia or other psychiatric disorders. The strongest associated SNP in the combined analysis, including Danish and German-Dutch samples, was rs12922317 in RUNDC2A (P=9.04 × 10(-7)). A region-based analysis summarizing independent signals in segments of 100 kb identified a new region-based genome-wide significant locus overlapping the gene ZEB1 (P=7.0 × 10(-7)). This signal was replicated in the follow-up analysis (P=2.3 × 10(-2)). Significant interaction with maternal CMV infection was found for rs7902091 (P(SNP × CMV)=7.3 × 10(-7)) in CTNNA3, a gene not previously implicated in schizophrenia, stressing the importance of including environmental factors in genetic studies.
STUDY QUESTION
What is the prevalence in a normal population of polycystic ovary syndrome (PCOS) according to the Rotterdam criteria versus revised criteria including anti-Müllerian hormone (AMH)?
...SUMMARY ANSWER
The prevalence of PCOS was 16.6% according to the Rotterdam criteria. When replacing the criterion for polycystic ovaries by antral follicle count (AFC) > 19 or AMH > 35 pmol/l, the prevalence of PCOS was 6.3 and 8.5%, respectively.
WHAT IS KNOWN ALREADY?
The Rotterdam criteria state that two out of the following three criteria should be present in the diagnosis of PCOS: oligo-anovulation, clinical and/or biochemical hyperandrogenism and polycystic ovaries (AFC ≥ 12 and/or ovarian volume >10 ml). However, with the advances in sonography, the relevance of the AFC threshold in the definition of polycystic ovaries has been challenged, and AMH has been proposed as a marker of polycystic ovaries in PCOS.
STUDY DESIGN, SIZE, DURATION
From 2008 to 2010, a prospective, cross-sectional study was performed including 863 women aged 20–40 years and employed at Copenhagen University Hospital, Rigshospitalet, Denmark.
PARTICIPANTS/MATERIAL, SETTING, METHODS
We studied a subgroup of 447 women with a mean (±SD) age of 33.5 (±4.0) years who were all non-users of hormonal contraception. Data on menstrual cycle disorder and the presence of hirsutism were obtained. On cycle Days 2–5, or on a random day in the case of oligo- or amenorrhoea, sonographic and endocrine parameters were measured.
MAIN RESULTS AND THE ROLE OF CHANCE
The prevalence of PCOS was 16.6% according to the Rotterdam criteria. PCOS prevalence significantly decreased with age from 33.3% in women < 30 years to 14.7% in women aged 30–34 years, and 10.2% in women ≥ 35 years (P < 0.001). In total, 53.5% fulfilled the criterion for polycystic ovaries with a significant age-related decrease from 69.0% in women < 30 years to 55.8% in women aged 30–34 years, and 42.8% in women ≥ 35 years (P < 0.001). AMH or age-adjusted AMH Z-score was found to be a reliable marker of polycystic ovaries in women with PCOS according to the Rotterdam criteria area under the curve (AUC) 0.994; 95% confidence interval (CI): 0.990–0.999 and AUC 0.992 (95% CI: 0.987–0.998), respectively, and an AMH cut-off value of 18 pmol/l and AMH Z-score of −0.2 showed the best compromise between sensitivity (91.8 and 90.4%, respectively) and specificity (98.1 and 97.9%, respectively). In total, AFC > 19 or AMH > 35 occurred in 17.7 and 23.0%, respectively. The occurrence of AFC > 19 or AMH > 35 in the age groups < 30, 30–34 and ≥ 35 years was 31.0 and 35.7%, 18.8 and 21.3%, and 9.6 and 18.7%, respectively. When replacing the Rotterdam criterion for polycystic ovaries by AFC > 19 or AMH > 35 pmol/l, the prevalence of PCOS was 6.3 or 8.5%, respectively, and in the age groups < 30, 30–34 and ≥ 35 years, the prevalences were 17.9 and 22.6%, 3.6 and 5.6%, and 3.6 and 4.8%, respectively.
LIMITATIONS, REASON FOR CAUTION
The participants of the study were all health-care workers, which may be a source of selection bias. Furthermore, the exclusion of hormonal contraceptive users from the study population may have biased the results, potentially excluding women with symptoms of PCOS.
WIDER IMPLICATIONS OF THE FINDINGS
AMH may be used as a marker of polycystic ovaries in PCOS. However, future studies are needed to validate AMH threshold levels, and AMH Z-score may be appropriate to adjust for the age-related decline in the AFC.
STUDY FUNDING/COMPETING INTEREST(S)
None.
TRIAL REGISTRATION NUMBER
Not applicable.
Autism affects males more than females, giving rise to the idea that the influence of steroid hormones on early fetal brain development may be one important early biological risk factor. Utilizing ...the Danish Historic Birth Cohort and Danish Psychiatric Central Register, we identified all amniotic fluid samples of males born between 1993 and 1999 who later received ICD-10 (International Classification of Diseases, 10th Revision) diagnoses of autism, Asperger syndrome or PDD-NOS (pervasive developmental disorder not otherwise specified) (n=128) compared with matched typically developing controls. Concentration levels of Δ4 sex steroids (progesterone, 17α-hydroxy-progesterone, androstenedione and testosterone) and cortisol were measured with liquid chromatography tandem mass spectrometry. All hormones were positively associated with each other and principal component analysis confirmed that one generalized latent steroidogenic factor was driving much of the variation in the data. The autism group showed elevations across all hormones on this latent generalized steroidogenic factor (Cohen's d=0.37, P=0.0009) and this elevation was uniform across ICD-10 diagnostic label. These results provide the first direct evidence of elevated fetal steroidogenic activity in autism. Such elevations may be important as epigenetic fetal programming mechanisms and may interact with other important pathophysiological factors in autism.
Objective To determine if selected pro-inflammatory and anti-inflammatory cytokines and/or mediators of inflammation reported to be related to the development of cerebral palsy (CP) predict ...neurodevelopmental outcome in extremely low birth weight infants. Study design Infants with birth weights ≤1000 g (n = 1067) had blood samples collected at birth and on days 3 ± 1, 7 ± 1, 14 ± 3, and 21 ± 3 to examine the association between cytokines and neurodevelopmental outcomes. The analyses were focused on 5 cytokines (interleukin IL 1β; IL-8; tumor necrosis factor-α; regulated upon activation, normal T-cell expressed, and secreted (RANTES); and IL-2) reported to be most predictive of CP in term and late preterm infants. Results IL-8 was higher on days 0-4 and subsequently in infants who developed CP compared with infants who did not develop CP in both unadjusted and adjusted analyses. Other cytokines (IL-12, IL-17, tumor necrosis factor-β, soluble IL rα, macrophage inflammatory protein 1β) were found to be altered on days 0-4 in infants who developed CP. Conclusions CP in former preterm infants may, in part, have a late perinatal and/or early neonatal inflammatory origin.
The Integrative Psychiatric Research (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 between 1981 and 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=3540), autism (N=16 146), attention-deficit/hyperactivity disorder (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.
Difficulties in social communication are part of the phenotypic overlap between autism spectrum disorders (ASD) and schizophrenia. Both conditions follow, however, distinct developmental patterns. ...Symptoms of ASD typically occur during early childhood, whereas most symptoms characteristic of schizophrenia do not appear before early adulthood. We investigated whether overlap in common genetic influences between these clinical conditions and impairments in social communication depends on the developmental stage of the assessed trait. Social communication difficulties were measured in typically-developing youth (Avon Longitudinal Study of Parents and Children, N⩽5553, longitudinal assessments at 8, 11, 14 and 17 years) using the Social Communication Disorder Checklist. Data on clinical ASD (PGC-ASD: 5305 cases, 5305 pseudo-controls; iPSYCH-ASD: 7783 cases, 11 359 controls) and schizophrenia (PGC-SCZ2: 34 241 cases, 45 604 controls, 1235 trios) were either obtained through the Psychiatric Genomics Consortium (PGC) or the Danish iPSYCH project. Overlap in genetic influences between ASD and social communication difficulties during development decreased with age, both in the PGC-ASD and the iPSYCH-ASD sample. Genetic overlap between schizophrenia and social communication difficulties, by contrast, persisted across age, as observed within two independent PGC-SCZ2 subsamples, and showed an increase in magnitude for traits assessed during later adolescence. ASD- and schizophrenia-related polygenic effects were unrelated to each other and changes in trait-disorder links reflect the heterogeneity of genetic factors influencing social communication difficulties during childhood versus later adolescence. Thus, both clinical ASD and schizophrenia share some genetic influences with impairments in social communication, but reveal distinct developmental profiles in their genetic links, consistent with the onset of clinical symptoms.
Objective To explore differences in blood cytokine profiles among distinct bronchopulmonary dysplasia (BPD) patterns. Study design We evaluated blood spots collected from 943 infants born at ≤1000 g ...and surviving to 28 days on postnatal days 1, 3, 7, 14, and 21 for 25 cytokines. Infants were assigned to the following lung disease patterns: (1) no lung disease (NLD); (2) respiratory distress syndrome without BPD; (3) classic BPD (persistent exposure to supplemental oxygen until 28 days of age); or (4) atypical BPD (period without supplemental oxygen before 28 days). Median cytokine levels for infants with BPD were compared with the IQR of results among infants with NLD. Results The distribution of enrolled infants by group was as follows: 69 (NLD), 73 (respiratory distress syndrome), 381 (classic BPD), and 160 (atypical BPD). The remaining 260 infants could not be classified because of missing data (104) or not fitting a predefined pattern (156). Median levels of 3 cytokines (elevated interleukin IL-8, matrix metalloproteinase-9; decreased granulocyte macrophage colony-stimulating factor) fell outside the IQR for at least 2 time points in both infants with atypical and classic BPD. Profiles of 7 cytokines (IL-6, IL-10, IL-18, macrophage inflammatory protein-1α, C-reactive protein, brain-derived neurotrophic factor, regulated on activation, normal T cell expressed and secreted) differed between infants with classic and atypical BPD. Conclusions Blood cytokine profiles may differ between infants developing classic and atypical BPD. These dissimilarities suggest the possibility that differing mechanisms could explain the varied patterns of pathophysiology of lung disease in extremely premature infants.
Genomic risk profile scores (GRPSs) have been shown to predict case-control status of schizophrenia (SCZ), albeit with varying sensitivity and specificity. The extent to which this variability in ...prediction accuracy is related to differences in sampling strategies is unknown. Danish population-based registers and Neonatal Biobanks were used to identify two independent incident data sets (denoted target and replication) comprising together 1861 cases with SCZ and 1706 controls. A third data set was a German prevalent sample with diagnoses assigned to 1773 SCZ cases and 2161 controls based on clinical interviews. GRPSs were calculated based on the genome-wide association results from the largest SCZ meta-analysis yet conducted. As measures of genetic risk prediction, Nagelkerke pseudo-R(2) and variance explained on the liability scale were calculated. GRPS for SCZ showed positive correlations with the number of psychiatric admissions across all P-value thresholds in both the incident and prevalent samples. In permutation-based test, Nagelkerke pseudo-R(2) values derived from samples enriched for frequently admitted cases were found to be significantly higher than for the full data sets (Ptarget=0.017, Preplication=0.04). Oversampling of frequently admitted cases further resulted in a higher proportion of variance explained on the liability scale (improvementtarget= 50%; improvementreplication= 162%). GRPSs are significantly correlated with chronicity of SCZ. Oversampling of cases with a high number of admissions significantly increased the amount of variance in liability explained by GRPS. This suggests that at least part of the effect of common single-nucleotide polymorphisms is on the deteriorative course of illness.
Summary Background Extracranial arterial dilatation has been hypothesised to be the cause of pain in patients who have migraine without aura. To test that hypothesis, we aimed to measure extracranial ...and intracranial arteries during attacks of migraine without aura. Methods In this cross-sectional study, we recruited patients aged 18–60 years from the Danish Headache Centre and via announcements on a Danish website. We did magnetic resonance angiography during spontaneous unilateral migraine attacks. Primary endpoints were difference in circumference of extracranial and intracranial arterial segments comparing attack and attack-free days and the pain and the non-pain side. The extracranial arterial segments measured were the external carotid (ECA), the superficial temporal (STA), the middle meningeal (MMA), and the cervical part of the internal carotid (ICAcervical ) arteries. The intracranial arterial segments were the cavernous (ICAcavernous ) and cerebral (ICAcerebral ) parts of the internal carotid, the middle cerebral (MCA), and the basilar (BA) arteries. This study is registered at Clinicaltrials.gov , number NCT01471314. Findings Between Oct 12, 2010, and Feb 8, 2012, we recruited 78 patients, of whom 19 women had a scan during migraine and were included in the final analysis. On migraine compared with non-migraine days, we detected no statistically significant dilatation of the extracranial arteries on the pain side (ECA, mean difference 1·2% 95% CI −5·7 to 8·2 p=0·985, STA 3·6% –3·7 to 11·0 p=0·532, MMA 1·7% –1·7 to 5·2 p=0·341, and ICAcervical 2·3% –0·3 to 4·9 p=0·093); the intracranial arteries were more dilated during attacks (MCA, 13·0% 6·4 to 19·6 p=0·001, ICAcerebral 11·5% 5·6 to 17·3 p=0·0004, and ICAcavernous 11·4% 5·3 to 17·5 p=0·001), except for the BA (1·6% –2·7 to 5·9 p=0·621). Compared with the non-pain side, during attacks we detected dilatation on the pain side of the intracranial arteries (MCA, mean difference 10·5% 0·7–20·3 p=0·044, ICAcerebral (14·4% 4·6–24·1 p=0·013), and ICAcavernous (9·1% 3·9–14·4 p=0·003) but not of the extracranial arteries (ECA, 2·1% –3·8 to 9·2 p=0·238, STA, 3·6% –3·7 to 10·8 p=0·525, MMA, 2·7% –1·3 to 5·6 p=0·531, and ICAcervical , 5·0% –0·5 to 10·4 p=0·119). Interpretation Migraine pain was not accompanied by extracranial arterial dilatation, and by only slight intracranial dilatation. Future migraine research should focus on the peripheral and central pain pathways rather than simple arterial dilatation. Funding University of Copenhagen, the Lundbeck Foundation, the Research Foundation of the Capital Region of Denmark, Danish Council for Independent Research-Medical Sciences, and the Novo Nordisk Foundation.
The predictive performance of polygenic scores (PGS) is largely dependent on the number of samples available to train the PGS. Increasing the sample size for a specific phenotype is expensive and ...takes time, but this sample size can be effectively increased by using genetically correlated phenotypes. We propose a framework to generate multi-PGS from thousands of publicly available genome-wide association studies (GWAS) with no need to individually select the most relevant ones. In this study, the multi-PGS framework increases prediction accuracy over single PGS for all included psychiatric disorders and other available outcomes, with prediction R
increases of up to 9-fold for attention-deficit/hyperactivity disorder compared to a single PGS. We also generate multi-PGS for phenotypes without an existing GWAS and for case-case predictions. We benchmark the multi-PGS framework against other methods and highlight its potential application to new emerging biobanks.
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