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Neurogenetics

Schizophrenia: missing heritability found?

Nature Reviews Neuroscience volume 10, page 543 (2009)Cite this article

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Thanks to the sharing of data between three large consortia, a meta-analysis was carried out on GWA study results from over 8,000 cases of schizophrenia and 19,000 controls of European descent. All three resulting papers report that only through the very large meta-analysis were the researchers able to see associations between schizophrenia and single nucleotide polymorphisms (SNPs) in or close to the major histocompatibility complex (MHC) on chromosome 6. Both Stefansson et al. and Shi et al. suggest a number of intriguing explanations for their findings. In particular, Stefansson et al. speculate that schizophrenia is a response to infection or that disease risk is related to month of birth. However, a definitive biological mechanism linking the disease to MHC function remains to be elucidated. It is also noteworthy that, using GWA studies, other diseases have shown 'hits' in the MHC, including neurological conditions (Alzheimer's disease) and autoimmune disorders (Crohn's disease, both types of diabetes and multiple sclerosis).

At the same time, the International Schizophrenia Consortium used a second approach: here, a test for polygenic inheritance was used instead of a conventional GWA study. This involved searching for genetic association under a model of several thousand alleles of very small effect that combine to produce a testable, quantitative 'score'. A large number of alleles, with weak individual association to schizophrenia, pointed to a highly polygenic model; these alleles were not shared with any non-psychiatric disorder tested but they did overlap with those associated with bipolar disorder. Furthermore, the common variants tagged by these markers may, as a whole, contribute at least one-third of the heritability of schizophrenia.

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References

ORIGINAL RESEARCH PAPERS

  1. The International Schizophrenia Consortium. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 1 Jul 2009 (doi: 10.1038/nature08185)

  2. Stefansson, H. et al. Common variants conferring risk of schizophrenia. Nature 1 Jul 2009 (doi: 10.1038/nature08186)

  3. Shi, J. et al. Common variants on chromosome 6p22.1 are associated with schizophrenia. Nature 1 Jul 2009 (doi: 10.1038/nature08192)

FURTHER READING

  1. Maher, B. Personal genomes: the case of the missing heritability. Nature 456, 18–21 (2008)

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  1. HudsonAlpha Institute for Biotechnology,

    Chris Gunter

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  1. Chris Gunter
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Gunter, C. Schizophrenia: missing heritability found?. Nat Rev Neurosci 10, 543 (2009). https://doi.org/10.1038/nrn2691

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  • DOI: https://doi.org/10.1038/nrn2691

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