Clinically decisive (dis)agreement in multidisciplinary team assessment of esophageal squamous cell carcinoma; a prospective, national, multicenter study.

BACKGROUND: Decisions regarding tumor staging, operability, resectability, and treatment strategy in patients with esophageal cancer are made at multidisciplinary team (MDT) conferences. We aimed to assess interobserver agreement from four national MDT conferences and whether this would have a clinical impact. METHODS: A total of 20 patients with esophageal cancer were included across all four upper gastrointestinal (GI) cancer centers. Fully anonymized patient data were distributed among the MDT conferences which decided on TNM category, resectability, operability, curability, and treatment strategy blinded to each other's decisions. The interobserver agreement was expressed as both the raw observer agreement and with Krippendorff's α values. Finally, a case-by-case evaluation was performed to determine if disagreement would have had a clinical impact. RESULTS: A total of 80 MDT evaluations were available for analysis. A moderate to near-perfect observer agreement of 79.2%, 55.8%, and 82.5% for TNM category was observed, respectively. Substantial agreement for resectability and moderate agreement for curability were found. However, an only fair agreement was observed for the operability category. The treatment strategies had a slight agreement which corresponded to disagreement having a clinical impact in 12 patients. CONCLUSIONS: Esophageal cancer MDT conferences had an acceptable interobserver agreement on resectability and TM categories; however, the operability assessment had a high level of disagreement. Consequently, the agreement on treatment strategy was reduced with a potential clinical impact. In future MDT conferences, emphasis should be on prioritizing the relevant information being readily available (operability, T & M categories) to minimize the risk of disagreement in the assessments and treatment strategies, and thus, delayed or suboptimal treatment.

ASD and schizophrenia show distinct developmental profiles in common genetic overlap with population-based social communication difficulties.

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.

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

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.

The role of genetic liability in the association of urbanicity at birth and during upbringing with schizophrenia in Denmark.

BACKGROUND: Studies have indicated that the association of urbanicity at birth and during upbringing with schizophrenia may be driven by familial factors such as genetic liability. We used a population-based nested case-control study to assess whether polygenic risk score (PRS) for schizophrenia was associated with urbanicity at birth and at age 15, and to assess whether PRS and parental history of mental disorder together explained the association between urbanicity and schizophrenia. METHODS: Data were drawn from Danish population registries. Cases born since 1981 and diagnosed with schizophrenia between 1994 and 2009 were matched to controls with the same sex and birthdate (1549 pairs). Genome-wide data were obtained from the Danish Neonatal Screening Biobank and PRSs were calculated based on results of a separate, large meta-analysis. RESULTS: Those with higher PRS were more likely reside in the capital compared with rural areas at age 15 [odds ratio (OR) 1.19, 95% confidence interval (CI) 1.01-1.40], but not at birth (OR 1.09, 95% CI 0.95-1.26). Adjustment for PRS produced almost no change in relative risks of schizophrenia associated with urbanicity at birth, but slightly attenuated those for urban residence at age 15. Additional adjustment for parental history led to slight attenuation of relative risks for urbanicity at birth [incidence rate ratio (IRR) for birth in capital = 1.54, 95% CI 1.18-2.02; overall p = 0.016] and further attenuation of relative risks for urbanicity at age 15 (IRR for residence in capital = 1.32, 95% CI 0.97-1.78; overall p = 0.148). CONCLUSIONS: While results regarding urbanicity during upbringing were somewhat equivocal, genetic liability as measured here does not appear to explain the association between urbanicity at birth and schizophrenia.

Familial confounding of the association between maternal smoking during pregnancy and internalizing disorders in offspring.

BACKGROUND: Maternal smoking has consistently been associated with multiple adverse childhood outcomes including externalizing disorders. In contrast the association between maternal smoking during pregnancy (MSDP) and internalizing (anxiety and depressive) disorders in offspring has received less investigation. METHOD: We conducted a nationwide cohort study including 957635 individuals born in Denmark between 1991 and 2007. Data on MSDP and diagnoses of depression or anxiety disorders were derived from national registers and patients were followed up from the age of 5 years to the end of 2012. Hazard rate ratios (HRRs) were estimated using stratified Cox regression models. Sibling data were used to disentangle individual- and familial-level effects of MSDP and to control for unmeasured familial confounding. RESULTS: At the population level, offspring exposed to MSDP were at increased risk for both severe depression [HRR 1.29, 95% confidence interval (CI) 1.22-1.36] and severe anxiety disorders (HRR 1.26, 95% CI 1.20-1.32) even when controlling for maternal and paternal traits. However, there was no association between MSDP and internalizing disorders when controlling for the mother's propensity for MSDP (depression: HRR 1.11, 95% CI 0.94-1.30; anxiety disorders: HRR 0.94, 95% CI 0.80-1.11) or comparing differentially exposed siblings (depression: HRR 1.18, 95% CI 0.75-1.89; anxiety disorders: HRR 0.87, 95% CI 0.55-1.36). CONCLUSIONS: The results suggest that familial background factors account for the association between MSDP and severe internalizing disorders not the specific exposure to MSDP.

High loading of polygenic risk in cases with chronic schizophrenia.

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.

Infections and exposure to anti-infective agents and the risk of severe mental disorders: a nationwide study.

OBJECTIVE: Severe infections are associated with increased risks of mental disorders; however, this is the first large-scale study investigating whether infections treated with anti-infective agents in the primary care setting increase the risks of schizophrenia and affective disorders. METHOD: We identified all individuals born in Denmark 1985-2002 (N = 1 015 447) and studied the association between infections treated with anti-infective agents and the subsequent risk of schizophrenia and affective disorders during 1995-2013. Cox regression analyses were adjusted for important confounders. RESULTS: Infections treated with anti-infective agents were associated with increased risks of schizophrenia by a hazard rate ratio (HRR) of 1.37 (95%-CI = 1.20-1.57) and affective disorders by a HRR of 1.64 (95%-CI = 1.48-1.82), fitting a dose-response and temporal relationship (P < 0.001). The excess risk was primarily driven by infections treated with antibiotics, whereas infections treated with antivirals, antimycotics, and antiparasitic agents were not significant after mutual adjustment. Individuals with infections requiring hospitalization had the highest risks for schizophrenia (HRR = 2.05; 95%-CI = 1.77-2.38) and affective disorders (HRR = 2.59; 95%-CI = 2.31-2.89). CONCLUSION: Infections treated with anti-infective agents and particularly infections requiring hospitalizations were associated with increased risks of schizophrenia and affective disorders, which may be mediated by effects of infections/inflammation on the brain, alterations of the microbiome, genetics, or other environmental factors.

COMT Val158Met and MTHFR C677T moderate risk of schizophrenia in response to childhood adversity.

OBJECTIVE: Mesolimbic dopamine sensitization has been hypothesized to be a mediating factor of childhood adversity (CA) on schizophrenia risk. Activity of catechol-O-methyltransferase (COMT) Val158Met increases mesolimbic dopamine signaling and may be further regulated by methylenetetrahydrofolate reductase (MTHFR) C677T. This study investigates the three-way interaction between CA, COMT, and MTHFR. METHODS: We conducted a nested case-control study on individuals born after 1981, linking population-based registers to study the three-way interaction. We included 1699 schizophrenia cases and 1681 controls, and used conditional logistic regression to report incidence rate ratios (IRRs). RESULTS: Childhood adversity was robustly associated with schizophrenia. No main genetic effects were observed. MTHFR C677T increased schizophrenia risk in a dose-dependent manner per MTHFR T allele (P = 0.005) consequent upon CA exposure. After inclusion of the significant (P = 0.03) COMT × MTHFR × CA interaction, the risk was further increased per high-activity COMT Val allele. Hence, exposed COMT Val/Val and MTHFR T/T carriers had an IRR of 2.76 (95% CI, 1.66-4.61). Additional adjustments for ancestry and parental history of mental illness attenuated the results with the interaction being only marginally significant. CONCLUSION: MTHFR C677T and COMT Val158Met interact with CA to increase risk of schizophrenia.

Risk of eating disorders in immigrant populations.

OBJECTIVE: The risk of certain psychiatric disorders is elevated among immigrants. To date, no population studies on immigrant health have addressed eating disorders. We examined whether risk of eating disorders in first- and second-generation immigrants differs from native-born Danes and Swedes. METHOD: All individuals born 1984-2002 (Danish cohort) and 1989-1999 (Swedish cohort) and residing in the respective country on their 10th birthday were included. They were followed up for the development of eating disorders based on out-patient and in-patient data. RESULTS: The risks of all eating disorder types were lower among first-generation immigrants compared to the native populations: Incidence-rate ratio (95% confidence interval) was 0.39 (0.29, 0.51) for anorexia nervosa, 0.60 (0.42, 0.83) for bulimia nervosa, and 0.62 (0.47, 0.79) for other eating disorders in Denmark and 0.27 (0.21, 0.34) for anorexia nervosa, 0.30 (0.18, 0.51) for bulimia nervosa, and 0.39 (0.32, 0.47) for other eating disorders in Sweden. Likewise, second-generation immigrants by both parents were at lower risk, whereas those with only one foreign-born parent were not. CONCLUSION: The decreased risk of eating disorders among immigrants is opposite to what has been observed for other psychiatric disorders, particularly schizophrenia. Possible explanations include buffering sociocultural factors and underdetection in health care.

Gender-age interaction in incidence rates of childhood emotional disorders.

BACKGROUND: The post-pubertal association of female gender with emotional disorder is a robust finding. However, studies exploring the association of gender and emotional disorders before puberty are few and present diverging results. The aim of this study was to present gender-specific incidence rates of emotional disorders throughout childhood. METHOD: This is a population-based cohort study of 907,806 Danish 3- to 18-year-olds. The outcome was assignment of an emotional disorder diagnosis based on in-patient and out-patient data from The Danish Psychiatric Central Register. Outcome measures were incidence rates and cumulative incidences for unipolar depressive disorder (ICD-10: F32-F33), anxiety disorders (ICD-10: F40-F42), and emotional disorders with onset specific to childhood (ICD-10: F93). RESULTS: Pre-pubertal incidence rates for depressive and anxiety disorders were higher for boys than girls. At age 12 years the pattern reversed. The cumulative incidence for any emotional disorder (F32-F33, F40-F42, F93) on the 11th birthday was 0.52% (95% CI 0.50-0.55) for boys and 0.31% (95% CI 0.29-0.33) for girls. On the 19th birthday cumulative incidence was 2.33% (95% CI 2.24-2.43) for boys and 3.77% (95% CI 3.64-3.90) for girls. The pre-pubertal male preponderance was also significant for depressive disorders (F32-F33, p = 0.00144) and anxiety disorders (F40-F42, F93, p < 0.00001) separately. CONCLUSIONS: Emotional disorders seem to display a male preponderance before the age of 12 years and a female preponderance thereafter. Studies exploring this gender-age interaction are needed. Still, the results question the general assumption that females throughout the lifespan are more at risk for emotional disorders than males.

Post-illness-onset risk of offending across the full spectrum of psychiatric disorders.

BACKGROUND: The link between psychotic disorders and violent offending is well established; knowledge about risk of post-illness-onset offending across the full spectrum of psychiatric disorders is lacking. We aimed to compare rates of any offending and violent offending committed after the onset of illness, according to diagnostic group, with population controls. METHOD: A 25% random sample of the Danish population (n = 521 340) was followed from their 15th birthday until offending occurred. Mental health status was considered as a time-varying exposure in a Poisson regression model used to examine the duration from service contact to the offence. RESULTS: Males with any psychiatric contact had an incidence rate ratio (IRR) of 2.91 [95% confidence interval (CI) 2.80-3.02] for any offending; 4.18 (95% CI 3.99-4.38) for violent offending. Associations were stronger for women (IRR 4.17, 95% CI 3.95-4.40 for any offending; 8.02, 95% CI 7.20-8.94 for violent offending). Risk was similar across diagnostic groups for any offending in males, while variation between diagnostic groups was seen for male violent and female offending, both any and violent. CONCLUSIONS: Risk of offending, particularly violent offending, was elevated across a range of mental disorders following first contact with mental health services. The extent of variation in strength of effect across diagnoses differed by gender.

A population-based study of the risk of schizophrenia and bipolar disorder associated with parent-child separation during development.

BACKGROUND: There is growing interest in the role of childhood adversities, including parental death and separation, in the etiology of psychotic disorders. However, few studies have used prospectively collected data to specifically investigate parental separation across development, or assessed the importance of duration of separation, and family characteristics. METHOD: We measured three types of separation not due to death: maternal, paternal, and from both parents, across the ages of 1-15 years among a cohort of 985 058 individuals born in Denmark 1971-1991 and followed to 2011. Associations with narrowly and broadly defined schizophrenia and bipolar disorder in the psychiatric register were assessed in terms of separation occurrence, age of separation, and number of years separated. Interactions with parental history of mental disorder were assessed. RESULTS: Each type of separation was associated with all three outcomes, adjusting for age, sex, birth period, calendar year, family history of mental disorder, urbanicity at birth and parental age. Number of years of paternal separation was positively associated with both schizophrenia and bipolar disorder. Associations between separation from both parents and schizophrenia were stronger when separation occurred at later ages, while those with bipolar disorder remained stable across development. The first occurrence of paternal separation appeared to increase risk more when it occurred earlier in childhood. Associations differed according to parental history of mental disorder, although in no situation was separation protective. CONCLUSIONS: Effects of parental separation may differ by type, developmental timing and family characteristics. These findings highlight the importance of considering such factors in studies of childhood adversity.

Parental history of psychiatric diagnoses and unipolar depression: a Danish National Register-based cohort study.

BACKGROUND: Depression is known to run in families, but the effects of parental history of other psychiatric diagnoses on depression rates are less well studied. Few studies have examined the impact of parental psychopathology on depression rates in older age groups. METHOD: We established a population-based cohort including all individuals born in Denmark after 1954 and alive on their 10th birthday (N = 29 76 264). Exposure variables were maternal and paternal history of schizophrenia, bipolar disorder, depression, anxiety or 'other' psychiatric diagnoses. Incidence rate ratios (IRRs) were estimated using Poisson regressions. RESULTS: Parental history of any psychiatric diagnosis increased incidence rates of outpatient (maternal: IRR 1.88, p < 0.0001; paternal: IRR 1.68, p < 0.0001) and inpatient (maternal: IRR 1.99, p < 0.0001; paternal: IRR 1.83, p < 0.0001) depression relative to no parental history. IRRs for parental history of non-affective disorders remained relatively stable across age groups, while IRRs for parental affective disorders (unipolar or bipolar) decreased with age from 2.29-3.96 in the youngest age group to 1.53-1.90 in the oldest group. IRR estimates for all parental diagnoses were similar among individuals aged ⩾41 years (IRR range 1.51-1.90). CONCLUSIONS: Parental history of any psychiatric diagnosis is associated with increased incidence rates of unipolar depression. In younger age groups, parental history of affective diagnoses is more strongly associated with rates of unipolar depression than non-affective diagnoses; however, this distinction disappears after age 40, suggesting that parental psychopathology in general, rather than any one disorder, confers risk for depression in middle life.

Genome-wide study of association and interaction with maternal cytomegalovirus infection suggests new schizophrenia loci.

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.

Time to subsequent live birth according to mode of delivery in the first birth.

OBJECTIVE: To estimate the rate and time to next live birth by mode of delivery. DESIGN: Hospital-based cohort. SETTING: Aarhus University Hospital (AUH), Denmark. POPULATION: All pregnant women attending AUH were invited to enroll in the Aarhus Birth Cohort (ABC) study between 1989 and 2010 (n = 91,625). METHODS: Women were followed from their first live birth until the subsequent live birth or until censoring due to study end using Cox regression models. MAIN OUTCOME MEASURES: Rate and time to subsequent live birth according to mode of delivery. RESULTS: 46,162 index live births were identified, of which 22,462 (49%) had a subsequent live birth. Women with any type of caesarean had a 6% reduction in the rate of subsequent live birth (HR 0.94, 95% CI 0.89, 0.98), which remained unchanged in the analysis by type (emergency, HR 0.95, 95% CI 0.89, 1.02; elective, HR 0.91, 95% CI 0.85, 0.98) compared with women who had a spontaneous vaginal delivery (SVD). Operative vaginal delivery was associated with an 8% reduction in subsequent live birth rates (HR 0.92, 95% CI 0.86, 0.98) and vaginal delivery complicated by shoulder dystocia with a 19% reduction compared with SVD. Median time to next birth in days was shortest in women with a first caesarean (994 days, 95% CI 973, 1026) and longest in women with a vaginal delivery complicated by shoulder dystocia (1065 days, 95% CI 994, 1191). In women with planned pregnancies, the shortest median time to second birth was in women with breech vaginal deliveries (859 days, 95% CI 737, 1089) and the longest in women with vaginal deliveries complicated by shoulder dystocia (1193 days, 95% CI 1028, 1430). CONCLUSION: The impact of mode of delivery on subsequent rate and time to next birth was minimal in this study. The greatest reduction was among women with assisted vaginal delivery complicated by shoulder dystocia. This study is strengthened by data on pregnancy planning as well as information on complications of pregnancy, delivery and neonatal morbidities, all of which may influence a woman's decision on subsequent birth.

Cardiovascular drug use and mortality in patients with schizophrenia or bipolar disorder: a Danish population-based study.

BACKGROUND: Cardiovascular (CV) co-morbidity is one of the major modifiable risk factors driving the excess mortality in individuals with schizophrenia or bipolar disorder. Population-based studies in this area are sparse. METHOD: We used Danish population registers to calculate incidence rate ratios (IRRs) for CV drug use, and mortality rate ratios comparing subjects with schizophrenia or bipolar disorder with subjects with no prior psychiatric hospitalization. RESULTS: IRRs for CV prescriptions were significantly decreased in patients with schizophrenia or bipolar disorder compared with the general population. Among persons without previous myocardial infarction (MI) or cerebrovascular disease, persons with schizophrenia or bipolar disorder had an up to 6- and 15-fold increased mortality from all causes or unnatural causes, respectively, compared with the general population, being most pronounced among those without CV treatment (16-fold increase). Among those with previous MI or cerebrovascular disease, excess all-cause and unnatural death was lower (up to 3-fold and 7-fold increased, respectively), but was similar in CV-treated and -untreated persons. CONCLUSIONS: The present study shows an apparent under-prescription of most CV drugs among patients with schizophrenia or bipolar disorder compared with the general population in Denmark. The excess of mortality by unnatural deaths in the untreated group suggests that the association between CV treatment and mortality may be confounded by severity of illness. However, our results also suggest that treatment of CV risk factors is neglected in these patients.

Family psychiatric morbidity of acute and transient psychotic disorders and their relationship to schizophrenia and bipolar disorder.

BACKGROUND: Although transient psychotic disorders are currently classified as a category separate from schizophrenia (SZ) and affective disorders, their distinctive features remain uncertain. This study examines the family psychiatric morbidity of the ICD-10 category of 'acute and transient psychotic disorders' (ATPDs), pointing out differences from SZ and bipolar disorder (BD). METHOD: From a cohort of 2.5 million persons, we identified all patients enrolled in the Danish Psychiatric Register who were ever admitted with ATPDs (n=2537), SZ (n = 10639) and BD disorder (n=5292) between 1996 and 2008. The relative risk (RR) of ATPDs, SZ and BD associated with psychiatric morbidity in first-degree relatives (FDRs) was calculated as the incidence rate ratio using Poisson regression. RESULTS: The RR of ATPDs [1.93, 95% confidence interval (CI) 1.76-2.11] was higher if patients with ATPDs had at least one FDR admitted with any mental disorder than patients without family psychiatric antecedents. An additional risk arose if they had FDRs admitted not only with ATPDs (RR 1.60, 95% CI 1.33-1.92) but also with SZ (RR 2.06, 95% CI 1.70-2.50) and/or BD (RR 1.55, 95% CI 1.23-1.96). Despite some overlap, the risk of SZ (RR 2.80, 95% CI 2.58-3.04) and BD (RR 3.68, 95% CI 3.29-4.12) was markedly higher if patients with SZ and BD had FDRs admitted with the same condition. CONCLUSIONS: These findings suggest that family psychiatric predisposition has a relatively modest impact on ATPDs and argue against a sharp differentiation of ATPDs from SZ and BD.

Association between genetic variation in a region on chromosome 11 and schizophrenia in large samples from Europe.

Recent molecular studies have implicated common alleles of small to moderate effect and rare alleles with larger effect sizes in the genetic architecture of schizophrenia (SCZ). It is expected that the reliable detection of risk variants with very small effect sizes can only be achieved through the recruitment of very large samples of patients and controls (that is tens of thousands), or large, potentially more homogeneous samples that have been recruited from confined geographical areas using identical diagnostic criteria. Applying the latter strategy, we performed a genome-wide association study (GWAS) of 1169 clinically well characterized and ethnically homogeneous SCZ patients from a confined area of Western Europe (464 from Germany, 705 from The Netherlands) and 3714 ethnically matched controls (1272 and 2442, respectively). In a subsequent follow-up study of our top GWAS results, we included an additional 2569 SCZ patients and 4088 controls (from Germany, The Netherlands and Denmark). Genetic variation in a region on chromosome 11 that contains the candidate genes AMBRA1, DGKZ, CHRM4 and MDK was significantly associated with SCZ in the combined sample (n=11 540; P=3.89 × 10(-9), odds ratio (OR)=1.25). This finding was replicated in 23 206 independent samples of European ancestry (P=0.0029, OR=1.11). In a subsequent imaging genetics study, healthy carriers of the risk allele exhibited altered activation in the cingulate cortex during a cognitive control task. The area of interest is a critical interface between emotion regulation and cognition that is structurally and functionally abnormal in SCZ and bipolar disorder.

Criminal conviction among offspring with parental history of mental disorder.

BACKGROUND: Offspring of parents with mental disorder are at risk of a range of adverse outcomes. We sought to establish whether such risks extend to offending by examining rates of criminal conviction, including conviction for violent and sexual offences, among offspring of parents with mental disorder compared to offspring without parental disorder. METHOD: From a random sample of the Danish population, a cohort aged ≤15 years (n=412,117) was followed for the occurrence of conviction between January 1981 and December 2006. Incidence rate ratios (IRRs) and cumulative incidences for offspring conviction by parental mental disorder status were calculated using a Cox regression model. Analyses were repeated for conviction for a serious first offence. RESULTS: Offspring with history of parental mental disorder had higher rates of conviction than those without parental disorder; rates were highest for those with two affected parents [IRR 3.39, 95% confidence interval (CI) 3.08-3.73]. The association persisted when parental gender, offspring gender and the nature of parental disorder were considered. Absolute rates were lower but relative rates higher for female offspring (IRR 3.26 for males with two affected parents, 4.52 for females). Similar patterns were seen for conviction for serious offences. Associations were attenuated after adjustment was made for family socio-economic position (SEP) and parental criminality. CONCLUSIONS: Offspring of parents with mental disorder represent a group at elevated risk of criminality. This raises the possibility of shared familial vulnerability for mental disorder and criminal behaviour, and highlights the need to consider early identification and intervention in this group.

Offending prior to first psychiatric contact: a population-based register study.

BACKGROUND: There is a well-established association between psychotic disorders and subsequent offending but the extent to which those who develop psychosis might have a prior history of offending is less clear. Little is known about whether the association between illness and offending exists in non-psychotic disorders. The aim of this study was to determine whether the association between mental disorder and offending is present prior to illness onset in psychotic and non-psychotic disorders. METHOD: In a nested case-control study, cases (n=101,890) with a first psychiatric contact during the period 1995 to 2006 were identified and matched by age and gender to population-based controls (n=2,236,195). Exposure was defined as prior criminal and violent offending. RESULTS: Males with one offence had an incidence rate ratio (IRR) of 2.32 [95% confidence interval (CI) 2.26-2.40] for psychiatric admission whereas two or more convictions yielded an IRR of 4.97 (95% CI 4.83-5.11). For violent offending the associations were stronger and IRRs of 3.97 (95% CI 3.81-4.12) and 6.18 (95% CI 5.85-6.52) were found for one and several offences respectively. Estimates for females were of a similar magnitude. The pattern was consistent across most diagnostic subgroups, although some variability in effect sizes was seen, and persisted after adjustment for substance misuse and socio-economic status (SES). CONCLUSIONS: A prior history of offending is present in almost one in five patients presenting to mental health services, which makes it an important issue for clinicians to consider when assessing current and future risks and vulnerabilities.