Quantifying the Impact of Rare and Ultra-rare Coding Variation across the Phenotypic Spectrum.

There is a limited understanding about the impact of rare protein-truncating variants across multiple phenotypes. We explore the impact of this class of variants on 13 quantitative traits and 10 diseases using whole-exome sequencing data from 100,296 individuals. Protein-truncating variants in genes intolerant to this class of mutations increased risk of autism, schizophrenia, bipolar disorder, intellectual disability, and ADHD. In individuals without these disorders, there was an association with shorter height, lower education, increased hospitalization, and reduced age at enrollment. Gene sets implicated from GWASs did not show a significant protein-truncating variants burden beyond what was captured by established Mendelian genes. In conclusion, we provide a thorough investigation of the impact of rare deleterious coding variants on complex traits, suggesting widespread pleiotropic risk.

Individual and combined effects of maternal anemia and prenatal infection on risk for schizophrenia in offspring.

BACKGROUND: Maternal iron deficiency and infection during pregnancy have individually been associated with increased risk of schizophrenia in the offspring, but possible interactions between the two remain unidentified thus far. Therefore, we determined the individual and combined effects of maternal infection during pregnancy and prepartum anemia on schizophrenia risk in the offspring. METHODS: We conducted a population-based study with individual record linkage of the Danish Civil Registration System, the Danish Hospital Register, and the Central Danish Psychiatric Register. In a cohort of Danish singleton births 1,403,183 born between 1977 and 2002, 6729 developed schizophrenia between 1987 and 2012. Cohort members were considered as having a maternal history of anemia if the mother had received a diagnosis of anemia at any time during the pregnancy. Maternal infection was defined based on infections requiring hospital admission during pregnancy. RESULTS: Maternal anemia and infection were both associated with increased risk of schizophrenia in unadjusted analyses (1.45-fold increase for anemia, 95% CI: 1.14-1.82; 1.32-fold increase for infection, 95% CI: 1.17-1.48). The effect of maternal infection remained significant (1.16-fold increase, 95% CI: 1.03-1.31) after adjustment for possible confounding factors. Combined exposure to anemia and an infection increased the effect size to a 2.49-fold increased schizophrenia risk (95% CI: 1.29-4.27). The interaction analysis, however, failed to provide evidence for multiplicative interactions between the two factors. CONCLUSION: Our findings indicate that maternal anemia and infection have additive but not interactive effects, and therefore, they may represent two independent risk factors of schizophrenia.

Somatic diseases and conditions before the first diagnosis of schizophrenia: a nationwide population-based cohort study in more than 900 000 individuals.

OBJECTIVE: Schizophrenia is associated with excess physical comorbidity. Yet, to our knowledge, large studies are lacking on the associations with somatic diseases before the onset of schizophrenia. The authors conducted a nationwide study of the full spectrum of treated somatic diseases before the first diagnosis of schizophrenia. METHOD: Nationwide sample of the Danish population consisting of singletons (n = 954351) born 1977-1993 and followed from birth to 2009, during which period 4371 developed schizophrenia. Somatic diagnoses at all general hospital contacts (admitted or outpatient care at a somatic hospital) from 1977 to 2009 were used as exposures. The incidence rate ratio (IRR) of schizophrenia was calculated using Poisson regression adjusted for confounders. RESULTS: Among the 4371 persons who developed schizophrenia from 1992 to 2009, a total of 4180 (95.6%) persons had a previous somatic hospital contact. A history of any somatic hospital contact was associated with an elevated risk of schizophrenia (IRR = 2.04, 95% CI = 1.77-2.37). A wide range of somatic diseases and conditions were associated with an increased risk of schizophrenia, including epilepsy (IRR = 2.26, 95% CI = 1.93-2.62), nutritional or metabolic disorders (IRR = 1.57, 95% CI = 1.39-1.77), circulatory system diseases (IRR = 1.63, 95% CI= 1.38-1.92), and brain injury (IRR = 1.58, 95% CI = 1.45-1.72). CONCLUSIONS: A wide range of potential etiological factors could have contributed to the observed associations, including genetic or physiological overlaps between conditions, and interacting immunological, behavioral, and neurodevelopmental factors.

Obsessive-compulsive disorder as a risk factor for schizophrenia: a nationwide study.

IMPORTANCE: Despite a remarkable co-occurrence of obsessive-compulsive disorder (OCD) and schizophrenia, little is known about the clinical and etiological relationship of these 2 disorders. Exploring the degree to which these disorders share etiological factors might provide useful implications for clinicians, researchers, and those with the disorders. OBJECTIVES: To assess whether patients with OCD experience an enhanced risk of developing schizophrenia and schizophrenia spectrum disorders and to determine whether a family history of OCD constitutes a risk factor for schizophrenia and schizophrenia spectrum disorders. DESIGN, SETTING, AND PARTICIPANTS: Using individual data from longitudinal nationwide Danish registers, we conducted a prospective cohort study with 45 million person-years of follow-up. All survival analyses were adjusted for sex, age, calendar year, parental age, and place of residence at the time of birth. A total of 3 million people born between January 1, 1955, and November 30, 2006, were followed up from January 1, 1995, through December 31, 2012. During this period, 30 556 people developed schizophrenia or schizophrenia spectrum disorders. MAIN OUTCOMES AND MEASURES: The presence of a prior diagnosis of OCD and the risk of a first lifetime diagnosis of schizophrenia and a schizophrenia spectrum disorder assigned by a psychiatrist in a hospital, outpatient clinic, or emergency department setting. Incidence rate ratios (IRRs) and accompanying 95% confidence intervals are used as measures of relative risk. RESULTS: The presence of prior diagnosis of OCD was associated with an increased risk of developing schizophrenia (IRR = 6.90; 95% CI, 6.25-7.60) and schizophrenia spectrum disorders (IRR = 5.77; 95% CI, 5.33-6.22) later in life. Similarly, offspring of parents diagnosed as having OCD had an increased risk of schizophrenia (IRR = 4.31; 95% CI, 2.72-6.43) and schizophrenia spectrum disorders (IRR = 3.10; 95% CI, 2.17-4.27). The results remained significant after adjusting for family history of psychiatric disorders and the patient's psychiatric history. CONCLUSIONS AND RELEVANCE: A diagnosis of OCD was associated with higher rates of schizophrenia and schizophrenia spectrum disorders. The observed increase in risk suggests that OCD, schizophrenia, and schizophrenia spectrum disorders probably lay on a common etiological pathway.

Hospital contacts with infection and risk of schizophrenia: a population-based cohort study with linkage of Danish national registers.

Infections and immune responses have been suggested to play an important role in the etiology of schizophrenia. Several studies have reported associations between maternal infections during pregnancy and the child's risk of schizophrenia; however, infection during childhood and adolescence unrelated to maternal infection during pregnancy has not been studied to nearly the same extent and the results are far from conclusive. Data were drawn from 2 population-based registers, the Danish Psychiatric Central Register and the Danish National Hospital Register. We used a historical population-based cohort design and selected all individuals born in Denmark between 1981 and 1996 (n = 843 390). We identified all individuals with a first-time hospital contact with schizophrenia from 1991 through 2010. Out of the 3409 individuals diagnosed with schizophrenia, a total of 1549 individuals had had a hospital contact with infection before their schizophrenia diagnosis (45%). Our results indicate that individuals who have had a hospital contact with infection are more likely to develop schizophrenia (relative risk [RR] = 1.41; 95% CI: 1.32-1.51) than individuals who had not had such a hospital contact. Bacterial infection was the type of infection that was associated with the highest risk of schizophrenia (RR = 1.63; 95% CI: 1.47-1.82). Our study does not exclude that a certain type of infection may have a specific effect; yet, it does suggest that schizophrenia is associated with a wide range of infections. This association may be due to inflammatory responses affecting the brain or genetic and environmental risk factors aggregating in families.

Population impact of familial and environmental risk factors for schizophrenia: a nationwide study.

Although several studies have examined the relative contributions of familial and environmental risk factors for schizophrenia, few have additionally examined the predictive power on the individual level and simultaneously examined the population impact associated with a wide range of familial and environmental risk factors. The authors present rate ratios (IRR), population-attributable risks (PAR) and sex-specific cumulative incidences of the following risk factors: parental history of mental illness, urban place of birth, advanced paternal age, parental loss and immigration status. We established a population-based cohort of 2,486,646million persons born in Denmark between 1 January 1955 and 31 December 1993 using Danish registers. We found that PAR associated with urban birth was 11.73%; PAR associated with one, respectively 2, parent(s) with schizophrenia was 2.67% and 0.12%. PAR associated with second-generation immigration was 0.70%. Highest cumulative incidence (CI=20.23%; 95% CI=18.10-22.62) was found in male offspring of 2 parents with schizophrenia. Cumulative incidences for male offspring or female offspring of a parent with schizophrenia were 9.53% (95% CI=7.71-11.79), and 4.89%, (95% CI 4.50-5.31). The study showed that risk factors with highest predictive power on the individual level have a relatively low population impact. The challenge in future studies with direct genetic data is to examine gene-environmental interactions that can move research beyond current approaches and seek to achieve higher predictive power on the individual level and higher population impact.

Association between parental hospital-treated infection and the risk of schizophrenia in adolescence and early adulthood.

It has been suggested that infection during perinatal life may lie at the etiological root of schizophrenia. It has thus been hypothesized that the origin of schizophrenia may lie either in direct fetal infection and/or in a generally increased familial susceptibility to infections, some of which may occur during pregnancy. We explored these 2 hypotheses by assessing maternal infection during pregnancy and maternal as well as paternal infection in general as predictors of schizophrenia in their offspring. We found a slightly increased risk to be associated with prenatal infection exposure. However, the effect of prenatal infection exposure was not statistically significantly different from the effect of infection exposure in general. Parental infection appeared to be associated with development of schizophrenia in adolescence and early adulthood. Our study does not exclude a specific effect of infection during fetal life; yet, it does suggest that schizophrenia is associated with an increased familial liability to develop severe infection.

Autoimmune diseases and severe infections as risk factors for schizophrenia: a 30-year population-based register study.

OBJECTIVE: Autoimmune diseases have been associated with an increased risk of schizophrenia. It has been suggested that brain-reactive autoantibodies are part of the mechanisms behind this association. Furthermore, an increased permeability of the blood-brain barrier has been observed during periods of infection and inflammation. The authors therefore investigated whether autoimmune diseases combined with exposures to severe infections may increase the risk of schizophrenia METHOD: Nationwide population-based registers in Denmark were linked, and the data were analyzed in a cohort study using survival analysis. All analyses were adjusted for calendar year, age, and sex. Incidence rate ratios and accompanying 95% confidence intervals (CIs) as measures of relative risk were used. RESULTS: A prior autoimmune disease increased the risk of schizophrenia by 29% (incidence rate ratio=1.29; 95% CI=1.18-1.41). Any history of hospitalization with infection increased the risk of schizophrenia by 60% (incidence rate ratio=1.60; 95% CI=1.56-1.64). When the two risk factors were combined, the risk of schizophrenia was increased even further (incidence rate ratio=2.25; 95% CI=2.04-2.46). The risk of schizophrenia was increased in a dose-response relationship, where three or more infections and an autoimmune disease were associated with an incidence rate ratio of 3.40 (95% CI=2.91-3.94). The results remained significant after adjusting for substance use disorders and family history of psychiatric disorders. Hospital contact with infection occurred in nearly 24% of individuals prior to a schizophrenia diagnosis. CONCLUSIONS: Autoimmune disease and the number of infections requiring hospitalization are risk factors for schizophrenia. The increased risk is compatible with an immunological hypothesis in subgroups of schizophrenia patients.

Association between prepartum maternal iron deficiency and offspring risk of schizophrenia: population-based cohort study with linkage of Danish national registers.

Recent findings suggest that maternal iron deficiency may increase the risk of schizophrenia-spectrum disorder in offspring. We initiated this study to determine whether maternal prepartum anemia influences offspring risk of schizophrenia. We conducted a population-based study with individual record linkage of the Danish Civil Registration System, the Danish Psychiatric Central Register, and the Danish National Hospital Register. In a cohort of 1,115,752 Danish singleton births from 1978 to 1998, cohort members were considered as having a maternal history of anemia if the mother had received a diagnosis of anemia at any time during the pregnancy. Cohort members were followed from their 10th birthday until onset of schizophrenia, death, or December 31, 2008, whichever came first. Adjusted for relevant confounders, cohort members whose mothers had received a diagnosis of anemia during pregnancy had a 1.60-fold (95% confidence interval = 1.16-2.15) increased risk of schizophrenia. Although the underlying mechanisms are unknown and independent replication is needed, our findings suggest that maternal iron deficiency increases offspring risk of schizophrenia.

Autoimmune diseases, bipolar disorder, and non-affective psychosis.

OBJECTIVE: Clinic-based studies of immune function, as well as comorbidity of autoimmune diseases, bipolar disorder, and schizophrenia, suggest a possible autoimmune etiology. Studies of non-affective psychosis and schizophrenia suggest common etiologies. The objective was to determine the degree to which 30 different autoimmune diseases are antecedent risk factors for bipolar disorder, schizophrenia, and non-affective psychosis. METHODS: A cohort of 3.57 million births in Denmark was linked to the Psychiatric Case Register and the National Hospital Register. There were 20,317 cases of schizophrenia, 39,076 cases of non-affective psychosis, and 9,920 cases of bipolar disorder. RESULTS: As in prior studies, there was a range of autoimmune diseases which predicted raised risk of schizophrenia in individuals who had a history of autoimmune diseases, and also raised risk in persons whose first-degree relatives had an onset of autoimmune disease prior to onset of schizophrenia in the case. These relationships also existed for the broader category of non-affective psychosis. Only pernicious anemia in the family was associated with raised risk for bipolar disorder (relative risk: 1.7), suggesting a small role for genetic linkage. A history of Guillain-Barré syndrome, Crohn's disease, and autoimmune hepatitis in the individual was associated with raised risk of bipolar disorder. CONCLUSIONS: The familial relationship of schizophrenia to a range of autoimmune diseases extends to non-affective psychosis, but not to bipolar disorder. The data suggest that autoimmune processes precede onset of schizophrenia, but also non-affective psychosis and bipolar disorder.