The evolutionary paradox and the missing heritability of schizophrenia

  title={The evolutionary paradox and the missing heritability of schizophrenia},
  author={Jenny van Dongen and Dorret I. Boomsma},
  journal={American Journal of Medical Genetics Part B: Neuropsychiatric Genetics},
  • J. van Dongen, D. Boomsma
  • Published 1 March 2013
  • Psychology
  • American Journal of Medical Genetics Part B: Neuropsychiatric Genetics
Schizophrenia is one of the most detrimental common psychiatric disorders, occurring at a prevalence of approximately 1%, and characterized by increased mortality and reduced reproduction, especially in men. The heritability has been estimated around 70% and the genome‐wide association meta‐analyses conducted by the Psychiatric Genomics Consortium have been successful at identifying an increasing number of risk loci. Various theories have been proposed to explain why genetic variants that… 
Revisiting Schizophrenia from an Evolutionary Perspective: An Association Study of Recent Evolutionary Markers and Schizophrenia.
A neurodevelopmental basis of schizophrenia is reiterated and a promising avenue to investigate HAR-mediated mitochondrial dysfunction in schizophrenia etiology is opened up.
Schizophrenia risk and reproductive success: a Mendelian randomization study
The results suggest that increased genetic liability for schizophrenia does not confer a reproductive advantage.
Shifting the focus toward rare variants in schizophrenia to close the gap from genotype to phenotype
  • M. L. Bustamante, Luisa Herrera, H. Silva
  • Psychology
    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics
  • 2017
Cognitive disturbances could be useful in selecting cases that have a higher probability of carrying deleterious mutations, as well as on the correct ascertainment of sporadic cases for the identification of de novo variants.
Genomic Variation, Evolvability, and the Paradox of Mental Illness
Techniques for higher resolution, genomewide analysis have begun to illuminate the irregular and unpredictable behavior of the human genome, and the origins of neuropsychiatric disorders in particular and complex disease in general have been illuminated.
Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection
A new genome-wide association study of schizophrenia is reported, and through meta-analysis with existing data and integrating genomic fine-mapping with brain expression and chromosome conformation data, 50 novel associated loci and 145 loci are identified.
Evolutionary Perspectives on Genetic and Environmental Risk Factors for Psychiatric Disorders.
  • M. Keller
  • Psychology
    Annual review of clinical psychology
  • 2018
Two different types of evolutionary explanations that have been used to help understand human psychiatric disorders, mutation-selection-drift and balancing selection, offer frameworks for understanding why genetic variation in risk to psychiatric (and other) disorders exists, and each makes predictions that are now testable using whole-genome data.
Autism and Schizophrenia Are Disorders of Evolvability
The origins of autism and schizophrenia, their persistence and heterogeneity can be understood by integrating information from genomic science, the social brain and the evolution of socialization, intelligence and language.
Polygenic selection underlies evolution of human brain structure and behavioral traits
It is discovered that SNPs associated with some, but not all, behaviors and brain structure volumes are enriched in genomic regions under selection since divergence from Neanderthals ~600,000 years ago, and evidence for signatures of ancient and recent polygenic adaptation is shown.
Common schizophrenia alleles are enriched in mutation-intolerant genes and maintained by background selection
It is shown for the first time that the common variant association signal is highly enriched among genes that are intolerant to loss of function mutations and that variants in these genes persist in the population despite the low fecundity associated with the disorder through the process of background selection.
Genomic and network patterns of schizophrenia genetic variation in human evolutionary accelerated regions.
The results suggest that schizophrenia-associated loci enrich in genes near previously identified human accelerated regions (HARs), and that HARs are associated with potentially important functional roles in the genetic architecture of schizophrenia.


Adaptive evolution of genes underlying schizophrenia
Findings provide convergent evidence consistent with the hypothesis that schizophrenia represents, in part, a maladaptive by-product of adaptive changes during human evolution.
Genetic epidemiology and schizophrenia: a study of reproductive fitness
Resolving the paradox of common, harmful, heritable mental disorders: which evolutionary genetic models work best?
Only polygenic mutation-selection balance seems consistent with the data on mental disorder prevalence rates, fitness costs, the likely rarity of susceptibility alleles, and the increased risks of mental disorders with brain trauma, inbreeding, and paternal age.
The role of genetic variation in the causation of mental illness: an evolution-informed framework
  • R. Uher
  • Psychology, Biology
    Molecular Psychiatry
  • 2009
On the basis of a summary of evidence, it is concluded that the CDCV hypothesis is untenable for most types of mental illness and an alternative evolution-informed framework is proposed, which suggests that gene–environment interactions and rare genetic variants constitute most of the genetic contribution to mental illness.
Schizophrenia—an evolutionary enigma?
  • M. Brüne
  • Psychology
    Neuroscience & Biobehavioral Reviews
  • 2004
Reduced Fertility in Patients' Families Is Consistent with the Sexual Selection Model of Schizophrenia and Schizotypy
This paper formally demonstrates that reduced fertility in the families of schizophrenic patients does not constitute evidence against sexual selection on schizotypy-increasing alleles, and suggests that the fertility estimates derived from extant studies may be biased to an unknown extent.
Genetic overlap between autism, schizophrenia and bipolar disorder
It is shown that copy number variations are likely to be important risk factors for autism and schizophrenia, whereas common single-nucleotide polymorphism alleles have a role in all disorders, and some of the specific genetic loci implicated so far encode proteins that function in synaptic development and plasticity, and therefore may represent a common biological pathway for these disorders.
Schizophrenia in an Evolutionary Perspective
It seems that genetic markers for schizophrenia are not a sine qua non for symbolic thought and creativity, which would suggest that selection of genes associated with schizophrenia is not the evolutionary price paid for higher cognition in modern humans but that brain evolution was dependent upon separate genetic mechanisms.
Genetics and developmental stability: an integrative conjecture on aetiology and neurobiology of schizophrenia
  • T. Markow
  • Psychology, Medicine
    Psychological Medicine
  • 1992
The concept of developmental stability, its genetic basis, and a model for its potential role in explaining many of the puzzling features of schizophrenia are described.