Fecundity of patients with schizophrenia, autism, bipolar disorder, depression, anorexia nervosa, or substance abuse vs their unaffected siblings
Open accessAbstract
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.
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The remaining Altai-matching variation has the strongest correlation with protective benefit against serious fitness-reducing diseases (anorexia and schizophrenia).
“Supporting this interpretation, the remaining Altai-matching variation has the strongest correlation with protective benefit against serious fitness-reducing diseases (anorexia and schizophrenia)73.”
From Quantifying the contribution of Neanderthal introgression to the heritability of complex traits (2021) · cites this paper as [73]
The Anorexia Nervosa and Schizophrenia sections report reduced fecundity and negative selection associated with these disorders, supporting the description of them as fitness-reducing. The paper does not examine Altai-matching variation, protective benefit, or correlations with either disease, so it does not support the sentence’s central comparison. (LLM, conf=0.86)
Experimental — accuracy not yet measuredASD is associated with reduced fecundity, so variation associated with it is subject to natural selection.
“Because ASD is associated with reduced fecundity (Power et al., 2013), variation associated with it is subject to natural selection”
From Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism (2020) · cites this paper as Power et al., 2013
Other mental health disorders may contribute to a lower likelihood of having children.
“Given that other mental health disorders may contribute to a lower likelihood of having children as evidenced by previous research, 8”
From Association between depression and the likelihood of having children: a nationwide register study in Finland (2023) · cites this paper as [8]
Because ASD individuals have reduced fecundity, target genes should be under severe purifying selection and have reduced load of disruptive variants.
“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.”
From Low load for disruptive mutations in autism genes and their biased transmission (2015) · cites this paper as [11]
Disruptive mutations in autism genes face strong negative selection and are rapidly removed from the population.
“Because individuals with ASD have lower fecundity, such mutations in autism genes would be under strong negative selection pressure.”
From Low load for disruptive mutations in autism genes and their biased transmission (2015) · cites this paper as [11]
Schizophrenia has a lifetime risk of about 0.7% and heritability of 60-80% despite reduced reproductive fecundity.
“Schizophrenia is a psychiatric disorder with a lifetime risk of about 0.7%1 and a heritability of 60–80%2,3 despite greatly reduced reproductive fecundity4,5.”
From Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia (2016) · cites this paper as [5]
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Risk of psychiatric illness from advanced paternal age is not predominantly from de novo mutations
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Family history of mental and neurological disorders and risk of autism
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Uncovering steroidopathy in women with autism: a latent class analysis
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Quantifying the contribution of Neanderthal introgression to the heritability of complex traits
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“Supporting this interpretation, remaining 455 Altai-matching variation has the most significant correlation with protective benefit against 456 serious fitness-reducing diseases (anorexia, schizophrenia).(71) 457 Several limitations must be considered when interpreting our results.”
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Exploring boundaries for the genetic consequences of assortative mating for psychiatric traits
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Truncating mutations in RBM12 are associated with psychosis
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“10 accordingly, have the potential to mediate substantial risk to severe disorders that limit fecundity, 1 such as ASD (33).”
BackgroundGenomic Disorders in Psychiatry-What Does the Clinician Need to Know?
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Genetics of Autism Spectrum Disorders
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Evolutionary and genetic insights for clinical psychology
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Rare variants are common in schizophrenia
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- Authors
- Power, R. A., Kyaga, S., Uher, R., MacCabe, J. H., Långström, N., Landen, M., McGuffin, P., Lewis, C. M., Lichtenstein, P., & Svensson, A. C.
- Affiliations
- King's College London (GB)
- Corresponding author
- Power, Robert A.
- ORCID
- Venue
- JAMA Psychiatry
- Publisher
- American Medical Association (AMA)
- Published
- 2013-01-01
- Volume
- 70
- Issue
- 1
- Pages
- 22
- ISSN
- 2168-622X (ISSN-L)
- OpenAlex
- W2034813336
- Semantic Scholar
- b6e5c52df875a5c21bdd8a566172c403cedd18be
- Cited by
- 336
- References
- 63
- Citations by year
- 2026: 21 · 2025: 17 · 2024: 20 · 2023: 19 · 2022: 20 · 2021: 27 · 2020: 26 · 2019: 35 · 2018: 33 · 2017: 25 · 2016: 30 · 2015: 29 · 2014: 25 · 2013: 9
- FWCI
- 14.34
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Research Portal (King's College London) (submittedVersion, other-oa)
- Funders
- Karolinska Institutet
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Keywords
- fecundity, reproductive fitness, schizophrenia, autism spectrum disorder, bipolar disorder, depression, anorexia nervosa, substance abuse, siblings, natural selection, balancing selection, novel mutations, genetic susceptibility
- MeSH terms
- Adult, Anorexia Nervosa, Autistic Disorder, Mental Disorders, Bipolar Disorder, Depressive Disorder, Female, Fertility, Humans, Male, Middle Aged, Registries, Schizophrenia, Selection, Genetic, Sex Factors, Substance-Related Disorders, Siblings
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