Introduction. This is an extensive revision of a prior application. Statistical power has been re-estimated using a new dataset: power is excellent even though some autoimmune diseases are rare. The sections on data analysis have been re-written to target the specific aims of the research. This revision includes more extensive explanation of the significance of the research. Since the prior submission, one paper has been accepted for the American Journal of Psychiatry, and two others submitted for publication. Background. Schizophrenia, bipolar disorder, and autism have been found to be associated with autoimmune (Al) diseases in several studies. The association suggests the Al and psychiatric disorders are etiologically linked. One possible explanation is pleiotropy, i.e., the expression of genes in several separate phenotypes; but a range of common environmental causes and pathogenetic chains may link the disorders. Schizophrenia has been positively associated with Al thyroid diseases, celiac disease, type 1 diabetes, and negatively with rheumatoid arthritis; bipolar disorder has been associated with Al thyroid diseases and Multiple Sclerosis, and autism has been associated with rheumatoid arthritis and Al thyroid disease. None of the relevant studies (except our own work on celiac disease and schizophrenia, and several studies of rheumatoid arthritis) has had sufficient power to detect even a strong purported association. Only a few studies have been population-based. Only our own work has considered more than a handful of Al diseases. The few studies including first degree relatives have been very small. The current state of scientific knowledge is at the precise point to benefit from credible epidemiologic research. Research Design. Study of Al diseases and three psychiatric disorders is proposed using record linkage in the entire population of 5 million persons in Denmark. The Central Population Register of Denmark assigns a unique number to each person, which is used in all registration systems there. The structure of the number minimizes error in data entry and permits linkage to first degree relatives. The registers to be linked include the psychiatric case register, the national patient register, a pharmacy register, registers of social and economic information, and assays related to celiac disease. Data allows ordering analyses temporally, to study relative risk for psychiatric disorders for those with prior Al diseases, in the cases or their relatives, as well as consequences of psychiatric disorders, and their treatments, for Al and other diseases. Implications. Results will provide clues to etiology of the psychiatric disorders, help prioritize inquiry into their possible autoimmune basis, provide unprecedented data on the prevalence and comorbidity of autoimmune diseases, and suggest parallel etiologies in both psychiatric and autoimmune diseases. ? ? ? ?

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Behavioral Genetics and Epidemiology Study Section (BGES)
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Rubio, Mercedes
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Johns Hopkins University
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