title: Fecundity of patients with schizophrenia, autism, bipolar disorder, depression, anorexia nervosa, or substance abuse vs their unaffected siblings.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  Population databases in Sweden, including the Multi-Generation Register and the Swedish Hospital Discharge Register.
  
  
  METHODS
  In total, 2.3 million individuals among the 1950 to 1970 birth cohort in Sweden.
  
  
  METHODS
  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; P < 10-10). 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; P < .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; P < .001). Siblings of patients with depression and substance abuse had significantly increased fecundity (FR range, 1.01-1.05; P < 10-10). 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.
authors.affiliation: Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, England. robert.r.power@kcl.ac.uk
authors.forename: Robert A
authors.initials: RA
authors.lastname: Power
authors.forename: Simon
authors.initials: S
authors.lastname: Kyaga
authors.forename: Rudolf
authors.initials: R
authors.lastname: Uher
authors.forename: James H
authors.initials: JH
authors.lastname: MacCabe
authors.forename: Niklas
authors.initials: N
authors.lastname: Långström
authors.forename: Mikael
authors.initials: M
authors.lastname: Landen
authors.forename: Peter
authors.initials: P
authors.lastname: McGuffin
authors.forename: Cathryn M
authors.initials: CM
authors.lastname: Lewis
authors.forename: Paul
authors.initials: P
authors.lastname: Lichtenstein
authors.forename: Anna C
authors.initials: AC
authors.lastname: Svensson
mesh_terms: D000328:Adult; D000856:Anorexia Nervosa / Q000453:epidemiology / Q000235:genetics; D001321:Autistic Disorder / Q000453:epidemiology / Q000235:genetics; D001714:Bipolar Disorder / Q000453:epidemiology / Q000235:genetics; D003866:Depressive Disorder / Q000453:epidemiology / Q000235:genetics; D005260:Female; D005298:Fertility / Q000235:genetics / Q000502:physiology; D006801:Humans; D008297:Male; D001523:Mental Disorders / Q000453:epidemiology* / Q000235:genetics; D008875:Middle Aged; D012042:Registries; D012559:Schizophrenia / Q000453:epidemiology / Q000235:genetics; D012641:Selection, Genetic / Q000235:genetics / Q000502:physiology; D012737:Sex Factors; D035781:Siblings; D019966:Substance-Related Disorders / Q000453:epidemiology / Q000235:genetics