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A family-based study of common polygenic variation and risk of schizophrenia

Molecular Psychiatry volume 16, pages 887–888 (2011)Cite this article

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Recent studies have suggested that a large number of common variants may, in aggregate, underlie a substantial proportion of the heritability of complex traits such as schizophrenia, multiple sclerosis and height, even though the effect of each individual variant is typically very small.1, 2, 3, 4, 5 A persistent concern for population-based genome-wide association studies, however, is that subtle population stratification could lead to bias. Although the abovementioned studies adhered to ‘best-practice’ for controlling bias in genome-wide association studies, some authors have speculated, with respect to the International Schizophrenia Consortium's schizophrenia study, that ‘cryptic population stratification could substantially affect (the results)’.6 In this study, we repeat the analysis described in ref. 1 using a family-based sample, to ask directly whether this is in fact a viable contention, as family-based designs, by definition, control for ‘cryptic population stratification’ completely.

We analyzed genome-wide association studies data on 694 parent-offspring schizophrenia trios from Bulgaria. Of these probands, 360 were cases in the original ISC manuscript. All samples were ascertained and genotyped on Affymetrix 6.0 arrays following the protocols described in ref. 1, with the exception that we further required single nucleotide polymorphisms (SNPs) to have greater than 99% genotyping and no more than one Mendel error. The original analysis in ref. 1 created ‘scores’ in case/control target samples, where the score per individual was a weighted sum of ‘risk alleles’, with the weights and the alleles determined by standard tests of association in an independent ‘discovery’ case/control sample. In this study, we designated the entire ISC sample (excluding all Bulgarian individuals) as the ‘discovery’ sample; our target comparison was between the transmitted and untransmitted alleles of the Bulgarian trios. In other words, we asked whether putative risk alleles from a case/control study tend to, on average, be overtransmitted to offspring with schizophrenia. This analysis does not constitute an independent replication of that in ref. 1 because of the overlapping cases; rather, our current purpose is solely to exclude bias because of cryptic population stratification as a possible source of inflated type I error.

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Authors and Affiliations

  1. Department of Psychiatry, Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    D M Ruderfer, P Sklar & S M Purcell

  2. Center for Human Genetics Research, Massachusetts General Hospital, Boston, MA, USA

    D M Ruderfer, P Sklar & S M Purcell

  3. Stanley Center for Psychiatric Research, Broad Institute, 7 Cambridge Center, Cambridge, MA, USA

    D M Ruderfer, K Chambert, J L Moran, P Sklar & S M Purcell

  4. Department of Psychological Medicine and Neurology, MRC Centre for Neuropsychiatric Genetics & Genomics, School of Medicine, Cardiff University, Heath Park, Cardiff, UK

    G Kirov, M J Owen & M C O'Donovan

Authors
  1. D M Ruderfer
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  2. G Kirov
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  3. K Chambert
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  4. J L Moran
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  5. M J Owen
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  6. M C O'Donovan
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  7. P Sklar
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  8. S M Purcell
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Correspondence to S M Purcell.

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Ruderfer, D., Kirov, G., Chambert, K. et al. A family-based study of common polygenic variation and risk of schizophrenia. Mol Psychiatry 16, 887–888 (2011). https://doi.org/10.1038/mp.2011.34

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