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Convergence of linkage, association and GWAS findings for a candidate region for bipolar disorder and schizophrenia on chromosome 4p

Molecular Psychiatry volume 16, pages 240–242 (2011)Cite this article

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Several strong candidate genes and regions have been implicated in bipolar disorder (BP) and schizophrenia (SCZ) through linkage and association studies. These disorders have also recently been studied in genome-wide association studies (GWAS), identifying further putative candidate loci, albeit with lower levels of significance and reproducibility than in GWAS of other complex disorders.1 Our study focuses on a well-established candidate region for psychiatric illness and independently implicates one of the top candidate genes to emerge from GWAS of BP.

The SORCS2 gene was first identified in a GWAS of BP,4 in which it was the second best hit. Three SORCS2 SNPs (rs4411993, rs7683874 and rs10937823) showed evidence of association in two independent samples, with the same alleles conferring the increase in risk in both samples (best P=0.000014 in the combined sample).4 SNP rs4411993 was subsequently analyzed as part of a meta-analysis, in which it showed a trend towards significance (P=0.054).6 We also tested these three SNPs and identified nominal evidence of association to BP with rs7683874 (P=0.024) and rs10937823 (P=0.031), but with the opposite alleles conferring the increase in risk. In a replication study of the 26 SNPs with strongest association from the three GWAS of BP, Ollila et al.7 also reported nominal association to these three SORCS2 SNPs (best P=0.0042) in a Finnish family-based cohort, with the same alleles as in our study conferring the increase in risk. Although this ‘flip–flop’ association may suggest spurious findings, it could also be a result of allelic heterogeneity, multi-locus effects or variable LD patterns between the samples, as, for example, observed between the GAPDH gene and Alzheimer's disease, owing to the variable inter-locus correlation between the GAPDH and APOE ɛ4 alleles in two different samples.8

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Author notes

  1. A Christoforou & S Le Hellard

    Present address: 5Current address: Dr Einar Martens’ Research Group for Biological Psychiatry, Centre for Medical Genetics and Molecular Medicine, University of Bergen, Haukeland University Hospital, Helse Bergen HF, 5021 Bergen, Norway,

Authors and Affiliations

  1. Medical Genetics Section, Centre for Molecular Medicine, The University of Edinburgh and The Institute of Genetics and Molecular Medicine, Molecular Medicine Centre, Western General Hospital, Edinburgh, UK

    A Christoforou, K A McGhee, S W Morris, P A Thomson, S Anderson, A McLean, H S Torrance, S Le Hellard, B S Pickard, W J Muir, D H Blackwood, D J Porteous & K L Evans

  2. Department of Psychology, Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, UK

    K A McGhee, P A Thomson, D J Porteous & K L Evans

  3. Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK

    D StClair

  4. Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK

    W J Muir & D H Blackwood

Authors
  1. A Christoforou
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  2. K A McGhee
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  6. A McLean
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Correspondence to A Christoforou.

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Christoforou, A., McGhee, K., Morris, S. et al. Convergence of linkage, association and GWAS findings for a candidate region for bipolar disorder and schizophrenia on chromosome 4p. Mol Psychiatry 16, 240–242 (2011). https://doi.org/10.1038/mp.2010.25

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