Fecundity of Patients With Schizophrenia, Autism, Bipolar Disorder, Depression, Anorexia Nervosa, or Substance Abuse vs Their Unaffected Siblings

Abstract

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.

Low load for disruptive mutations in autism genes and their biased transmission

“…Because individuals with ASD have drastically reduced fecundity (11), the net prediction is that these target genes should be under severe purifying selection, and hence have a reduced load of disruptive variants in the human gene pool. Here, we validate this prediction.…”

“…We computed that roughly half of the time in males, a DN LGD mutation within an autism gene will produce severe ASD (10). Because people with ASD have lower fecundity than the general population, a disruptive mutation in an autism gene will be under strong purifying selection and quickly eliminated from the population (11). A clear prediction is that autism genes will have a smaller load of disruptive mutations than "typical" genes, as we first observed for fragile X mental retardation protein (FMRP)-associated genes (5,12).…”

Genetic adaptation of the human circadian clock to day-length latitudinal variations and relevance for affective disorders

“…Large-scale studies based on historical registries have indicated that patients with SCZ have strongly reduced fecundity [53][54][55], whereas their siblings may have increased or decreased reproductive success depending on gender [53,54]. The overall effect calculated for affected patients and their siblings indicated that these families contribute fewer descendants to the new generation compared with families with no members affected by SCZ [53,54]. Similar results have been reported for BPD, although the decrease in fecundity seems to be less marked than that observed for SCZ [53,55].…”

Mental Disorders and Female Infertility

“…A more recent study used Swedish register data. The study reported no decrease in the number of children for women with life-time depression; small decreases in fecundity (fertility ratio between 0.70 and 0.95) in men with bipolar disorder, women with bipolar disorder, men with depression, women with anorexia nervosa, and men and women with substance abuse and a strong reduction of fecundity (FR between 0.2 and 0.5) in men and women with schizophrenia, men and women with autism and men with anorexia nervosa (Power et al, 2012).…”