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Replication of GWAS of bipolar disorder: association of SNPs near CDH7 with bipolar disorder and visual processing

Molecular Psychiatry volume 15, pages 4–6 (2010)Cite this article

The six genome-wide association studies (GWAS) completed in bipolar disorder (BD)1, 2, 3, 4, 5, 6 have revealed some promising association signals that have been replicated in independent study samples,7 but the mechanism by which these genes increase disease susceptibility has remained unresolved. Here, our goal was (i) to replicate the best results from the study by Sklar et al., 20084 and also the highest ranking imputed SNPs from the WTCCC study1 and (ii) to define the effect of the associating SNPs on intermediate phenotypes of BD, reflecting disturbed circadian alignment and neuropsychological functioning. Our BD family sample comprises 723 individuals from 180 families from a Finnish population. We previously studied 26 SNPs from two BD GWASs, WTCCC and the study by Baum et al.,1, 2 and were able to replicate associations with DFNBP31, SORCS2 and SLC39A3 genes.7 In this study, we analyzed 50 new variants chosen from WTCCC and the study by Sklar et al.1, 4 against diagnostic categories of bipolar type I disorder (BDI) and broad mood disorder. In addition, we studied the effect of 26 SNPs from our previous GWAS replication and of the 50 SNPs genotyped here, on 10 quantitative items (listed in Supplementary Table 1) of circadian preference for daily activities from the Horne-Östberg Morningness–Eveningness Questionnaire,8 on six items of seasonal variation in mood and behavior (global seasonality score) from the Seasonal Pattern Assessment Questionnaire9 and on 22 neuropsychological test variables using the Wechsler Adult Intelligence Scale—Revised (WAIS-R), the Wechsler Memory Scale-Revised (WMS-R), the California Verbal Learning Test, the Stroop Color and Word Test and the Controlled Oral Word Association Test. Circadian and seasonality phenotypes were characterized from 127 individuals from 37 families, and neuropsychological phenotypes were characterized from 159 individuals from 65 families. Analyses of dichotomy phenotypes were carried out by FBAT (www.biostat.harvard.edu/~fbat) and those of quantitative phenotypes by QTDT,10 analyzing affected and unaffected individuals together. Age, gender and affection status were used as covariates in QTDT analyses.

SNP rs10982256 in DFNB31, which gave the strongest signal in our replication study,7 associated also with four items of seasonality (strongest signal with the routine fluctuation in sleep duration across seasons; P=0.005), as did two SNPs from the SORCS2 gene (P=0.046) (Table 1). In addition, one new variant from the WTCCC study, rs4027132 at 2p25.1, associated suggestively with bipolar type I disorder (P=0.042).

Table 1 SNPs associating with bipolar type I disorder or with mood disorder (P<0.05) and the P-values with detailed phenotypes of circadian clockwork, seasonal variation, and neuropsychological traits giving P-values <0.05
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Authors and Affiliations

  1. Public Health Genomics Unit and Institute for Molecular Medicine FIMM, National Institute for Health and Welfare, Helsinki, Finland

    P Soronen, H M Ollila, K Silander, O M Palo, L Peltonen & T Paunio

  2. Department of Physiology, Institute of Biomedicine, University of Helsinki, Helsinki, Finland

    H M Ollila & A Tuulio-Henriksson

  3. Department of Mental Health and Substance Abuse Services, National Institute for Health and Welfare, Helsinki, Finland

    M Antila, T Kieseppä, J Lönnqvist & T Partonen

  4. Department of Psychiatry, Helsinki University Central Hospital, Helsinki, Finland

    T Kieseppä & T Paunio

  5. Department of Medical Genetics, University of Helsinki, Helsinki, Finland

    L Peltonen

  6. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK,

    L Peltonen

  7. Department of Psychology, University of Helsinki, Helsinki, Finland

    A Tuulio-Henriksson

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  1. P Soronen
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Correspondence to T Paunio.

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

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Soronen, P., Ollila, H., Antila, M. et al. Replication of GWAS of bipolar disorder: association of SNPs near CDH7 with bipolar disorder and visual processing. Mol Psychiatry 15, 4–6 (2010). https://doi.org/10.1038/mp.2009.86

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