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.

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 were 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 nonaffective 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.Keywords autoimmune disease; bipolar disorder; epidemiology; non-affective psychosis; register; schizophrenia This paper extends earlier work on autoimmune diseases and schizophrenia (1) to bipolar disorder and disorders with features similar to schizophrenia, sometimes termed nonaffective psychosis. This new analysis, with more than twice as many observations, allows comparison of bipolar disorder to schizophrenia, as well as facilitating more precise study of the temporal relationship of autoimmune disease and the first diagnosis of bipolar disorder, schizophrenia, and non-affective psychosis. The presentation of these disorders in parallel fashion facilitates assessment of the value of the nosologic distinctions between them.The autoimmune diseases which have been studied most thoroughly in their relationship to bipolar disorder are the autoimmune thyroid diseases and multiple sclerosis (MS). The relationship between affective psychosis and thyroid disorder was noticed as early as 1888 (2). The metabolic slowing related to thyroid hormone deficiency could possibly be related to symptoms of depression (e.g., 3), but there is also a consistent association with psychosis, including a particular association, not always confirmed, with rapid-cycling bipolar disorder (4-6). The serotonin and thyroid systems are connected (7), and there are putative but unproven associa...

No abstract

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.