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Six degrees of separation: on the prior probability that schizophrenia susceptibility genes converge on synapses, glutamate and NMDA receptors

Molecular Psychiatry volume 11, pages 981–983 (2006)Cite this article

It has been proposed that schizophrenia susceptibility genes converge upon synapses1, 2 and glutamate,1, 2, 3, 4 impacting particularly on N-methyl-D-aspartate receptor (NMDAR) signalling.1, 2, 4 One of the problems with the proposition concerns the prior probability that it is true. Much of the genome is expressed in the brain, many genes encode synaptic proteins,5 many synapses utilize glutamate,6 and most of these contain NMDARs.7 Thus, the proposition is inherently weak, as any randomly selected group of genes is likely to include a large fraction that converge on synapses, glutamate and NMDARs. This is akin to the ‘six degrees of separation’, postulated by Karinthy in 1929 regarding the relatedness of individuals, and recently extended not only to computational science and entertainment domains, but becoming relevant biologically as the extent of molecular interactions in biochemical pathways becomes apparent, and the concept of the ‘interactome’ emerges.8, 9 Here, we report a crude bioinformatics approach to assess the prior likelihood that schizophrenia genes would appear to converge on synapses, glutamate or NMDARs. We then show that the convergence is indeed greater than would have been expected by chance.

Two hundred and seven genes were randomly selected (nine at intervals along each autosome and X chromosome) using the UCSC Human Genome Browser (http://genome.ucsc.edu/cgi-bin/hgGateway) by someone (VAW) with no knowledge of schizophrenia genetics or the hypothesis being investigated. Alternative names for each gene were collated via links from this website. This list of terms was entered into a Medline search (to June 2006) for papers containing, in the title, abstract, or keyword list: {(gene name) AND (synapse OR synaptic OR glutamate OR NMDA)}. The abstracts of all papers thus identified (range: 0–1136) were then read and rated (by PJH) as to whether they provide data showing (1) a synaptic function or localization of the gene product, (2) an effect on glutamate transmission, which is not clearly exceeded by an effect on another neurotransmitter and (3) an influence on NMDAR expression or signalling. If the abstract was ambiguous, the whole paper was read; where ambiguity remained, rating erred on the side of inclusiveness (i.e. toward the null hypothesis). No attempt was made to quantify the evidence linking each gene to each parameter, merely to ascertain that there was at least one paper reporting such a link. For a list of the genes and their ratings, see Supplementary Material.

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Acknowledgements

This work was supported by the UK Medical Research Council and Stanley Medical Research Institute. We thank Kevin Bacon, Sharon Eastwood and Liz Tunbridge for their contributions.

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  1. Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK

    P J Harrison & V A West

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Correspondence to P J Harrison.

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Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)

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Harrison, P., West, V. Six degrees of separation: on the prior probability that schizophrenia susceptibility genes converge on synapses, glutamate and NMDA receptors. Mol Psychiatry 11, 981–983 (2006). https://doi.org/10.1038/sj.mp.4001886

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