Increased number of offspring in first degree relatives of psychotic individuals: a partial explanation for the persistence of psychotic illnesses.
ABSTRACT As patients with psychotic illness have fewer offspring than controls, the persistence of psychotic illness is puzzling. We hypothesized that unaffected first-degree relatives of patients have more offspring than controls.
Probands were 4904, individuals with non-affective psychotic disorders identified from a hospitalization registry. Unaffected first degree relatives and matched controls were identified from the Israeli Population Registry. The number of offspring of unaffected parents, biological siblings and controls was ascertained.
Unaffected parents of psychotic patients had more offspring/person than controls; 4.5 +/- 2.7 vs. 3.4 +/- 2.2, P = 0.000. Unaffected parents from familial psychosis families (more than one affected family member) had 1.83 more offspring than controls; unaffected parents from non-familial psychosis families had 0.97 more offspring than controls (both P < 0.001).
These findings might imply that genes which increase susceptibility for schizophrenia may be associated with increased number of offspring, perhaps supplying a partial explanation for the persistence of psychosis.
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ABSTRACT: This article addresses the classic enigma about schizophrenia (SZ). The disease occurs with a lifetime prevalence of 1%, 80% of which is attributable to genetic factors. Females with SZ produce 50% as many children as normals, and males with SZ produce 25%. Genetic factors responsible for SZ should behave like lethal genes. Yet the prevalence of SZ remains around 1% throughout the world. How can that be? Additionally, CATIE concluded that the response of each individual with SZ to treatment with antipsychotic agents (effectiveness, side-effect profile, or long-term prognosis) cannot be predicted. Every case seems to be unique. Several recent publications have reported increased frequencies of single-nucleotide polymorphisms (SNPs) and of copy-number variants (CNVs) containing large regions of DNA in patients with SZ. These genetic perturbations often include neurodevelopmental genes. The overwhelming majority of SNPs and CNVs are post-fertilization mutations, occurring in somatic tissue, not germinal tissue. These mutations are a normal aspect of somatic cell division but occur more frequently in patients with SZ. Somatic mutations are not passed on to subsequent generations and therefore cannot account for the inheritance of SZ. Our speculation is that the genetic platform for SZ is the gene or genes that increase the number of de novo mutations in patients with SZ. We argue that balanced polymorphism is the most plausible hypothesis to account for the preservation of non-adaptive genes in nature-and, in particular, in SZ. Maladaptive genes in different combinations can confer increased fitness to the entire population, thus insuring their preservation in the gene pool. Somatic mutations explain both the sporadic occurrence of SZ within families and the wide variations in phenotypic expression of SZ. Increased frequency of somatic mutations may confirm greater overall fitness via balanced polymorphism to explain the maintenance of the SZ gene or genes within the human population.Harvard Review of Psychiatry 05/2012; 20(3):119-29. · 3.50 Impact Factor
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ABSTRACT: CONTEXT 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; 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.Archives of general psychiatry 11/2012; 70(1):1-8. · 12.26 Impact Factor
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ABSTRACT: There is substantial evidence that women with schizophrenia in many parts of the world have fewer children than their peers. Our objective was to analyze recent trends in general and age-specific fertility rates among women with schizophrenia in Ontario, Canada. We conducted a repeated cross-sectional population-based study from 1996 to 2009 using population-based linked administrative databases for the entire province of Ontario. Women aged 15-49 years were classified into schizophrenia and non-schizophrenia groups in each successive 12-month period. Annual general and age-specific fertility rates were derived. The general fertility rate (GFR) among women with schizophrenia was 1.16 times higher in 2007-2009 than in 1996-1998 (95% confidence interval [CI] 1.04-1.31). The annual GFR ratio of women with vs. without schizophrenia was 0.41 (95% CI 0.36-0.47) in 2009, which was slightly higher than the same ratio in 1996 of 0.30 (95% CI 0.25-0.35). Annual age-specific fertility rates (ASFR) increased over time among women with schizophrenia aged 20-24, 25-29, 35-39 and 40-44 years, but the increase was not always statistically significant. Among women aged 20-24 years, the ASFR ratio in women with vs. without schizophrenia was not significant by the end of the study period (0.93, 95% CI 0.70-1.22). The general fertility rate among women with schizophrenia appears to have increased modestly over the past 13 years. Clinical care and health policy should consider new strategies that focus on the mental health of women with schizophrenia as new mothers, while optimizing healthy pregnancies and child rearing.Schizophrenia Research 08/2012; 139:169-175. · 4.43 Impact Factor