How to cite this article: van Dongen J, Boomsma DI. 2013. The Evolutionary Paradox and the Missing Heritability of Schizophrenia. Am J Med Genet Part B 162B:122–136.
The evolutionary paradox and the missing heritability of schizophrenia†
Article first published online: 25 JAN 2013
Copyright © 2013 Wiley Periodicals, Inc.
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics
Volume 162, Issue 2, pages 122–136, March 2013
How to Cite
van Dongen, J. and Boomsma, D. I. (2013), The evolutionary paradox and the missing heritability of schizophrenia. Am. J. Med. Genet., 162: 122–136. doi: 10.1002/ajmg.b.32135
- Issue published online: 21 FEB 2013
- Article first published online: 25 JAN 2013
- Manuscript Accepted: 4 JAN 2013
- Manuscript Received: 27 JUL 2012
- European Research Council. Grant Number: ERC-230374
- missing heritability
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 predispose to schizophrenia persist in the population, despite the fitness reduction in affected individuals, a question known as the evolutionary paradox. In this review, we consider evolutionary perspectives of schizophrenia and of the empirical evidence that may support these perspectives. Proposed evolutionary explanations include balancing selection, fitness trade-offs, fluctuating environments, sexual selection, mutation-selection balance and genomic conflicts. We address the expectations about the genetic architecture of schizophrenia that are predicted by different evolutionary scenarios and discuss the implications for genetic studies. Several potential sources of “missing” heritability, including gene–environment interactions, epigenetic variation, and rare genetic variation are examined from an evolutionary perspective. A better understanding of evolutionary history may provide valuable clues to the genetic architecture of schizophrenia and other psychiatric disorders, which is highly relevant to genetic studies that aim to detect genetic risk variants. © 2013 Wiley Periodicals, Inc.