It is unknown how genetic variants conferring liability to psychiatric disorders survive in the population despite strong negative selection. However, this is key to understanding their etiology and designing studies to identify risk variants. Objectives: To examine the reproductive fitness of patients with schizophrenia and other psychiatric disorders vs their unaffected siblings and to evaluate the level of selection on causal genetic variants. Design: We measured the fecundity of patients with schizophrenia, autism, bipolar disorder, depression, anorexia nervosa, or substance abuse and their unaffected siblings compared with the general population. Setting: Population databases in Sweden, including the Multi-Generation Register and the Swedish Hospital Discharge Register. Participants: In total, 2.3 million individuals among the 1950 to 1970 birth cohort in Sweden. Main Outcome Measures: Fertility ratio (FR), reflecting the mean number of children compared with that of the general population, accounting for age, sex, family size, and affected status. Results: Except for women with depression, affected patients had significantly fewer children (FR range for those with psychiatric disorder, 0.23-0.93; PϽ10 Ϫ10). This reduction was consistently greater among men than women, suggesting that male fitness was particularly sensitive. Although sisters of patients with schizophrenia and bipolar disorder had increased fecundity (FR range, 1.02-1.03; PϽ.01), this was too small on its own to counterbalance the reduced fitness of affected patients. Brothers of patients with schizophrenia and autism showed reduced fecundity (FR range, 0.94-0.97; PϽ.001). Siblings of patients with depression and substance abuse had significantly increased fecundity (FR range, 1.01-1.05; PϽ10 Ϫ10). In the case of depression, this more than compensated for the lower fecundity of affected individuals. Conclusions: Our results suggest that strong selection exists against schizophrenia, autism, and anorexia nervosa and that these variants may be maintained by new mutations or an as-yet unknown mechanism. Bipolar disorder did not seem to be under strong negative selection. Vulnerability to depression, and perhaps substance abuse, may be preserved by balancing selection, suggesting the involvement of common genetic variants in ways that depend on other genes and on environment.
The Stockholm Public Health Cohort was set up within the Stockholm County Council public health surveys to inform on determinants and consequences of significant contributors to the current burden of disease. Participants are 89 268 randomly selected individuals from the adult population of Stockholm County. Baseline surveys took place in 2002, 2006 and 2010 via self-administered questionnaires. So far, participants recruited in 2002 were re-surveyed twice, in 2007 and 2010, and those enrolled in 2006 were re-surveyed once, in 2010. Self-reported data are regularly supplemented by information from national and regional health data and administrative registers, for study participants and their relatives (including their offspring). Available data are extensive and include a wide array of health, lifestyle, perinatal, demographic, socio-economic and familial factors. The cohort is an international resource for epidemiological research, and the data available to the research community for specific studies obtained approval from the Stockholm Public Health Cohort Steering Committee and the Stockholm Regional Ethical Review Board.
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