Genome-wide haplotype-based association analysis of major depressive disorder in Generation Scotland and UK Biobank

David M. Howard (Lead / Corresponding author), Lynsey S. Hall, Jonathan D. Hafferty, Zeng Yanni, Mark J. Adams, Toni-Kim Clarke, David J. Porteous, Reka Nagy, Caroline Hayward, Blair Smith, Alison D. Murray, Niamh M. Ryan, Kathryn L. Evans, Chris S. Haley, Ian J. Deary, Pippa A. Thomson, Andrew M. McIntosh

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    Abstract

    Genome-wide association studies using genotype data have had limited success in the identification of variants associated with major depressive disorder (MDD). Haplotype data provide an alternative method for detecting associations between variants in weak linkage disequilibrium with genotyped variants and a given trait of interest. A genome-wide haplotype association study for MDD was undertaken utilising a family-based population cohort, Generation Scotland: Scottish Family Health Study (n = 18 773), as a discovery cohort with a population-based cohort, UK Biobank, used as a replication cohort (n = 25 035). Fine mapping of haplotype boundaries was used to account for overlapping haplotypes that were potentially tagging the same causal variant. Within the discovery cohort, two haplotypes exceeded genome-wide significance (P < 5 x 10-8) for an association for MDD. One of these haplotypes was nominally significant in the replication cohort (P < 0.05) and was located in 6q21, a region which has been previously associated with bipolar disorder, a psychiatric disorder that is phenotypically and genetically correlated with MDD. Several haplotypes with P < 10-7 in the discovery cohort were also located within gene coding regions associated with diseases that are comorbid with MDD. The identification of such haplotypes potentially allows the causal stratification of MDD into biologically informative aetiological subtypes.
    Original languageEnglish
    Article number1263
    Pages (from-to)1-9
    Number of pages9
    JournalTranslational Psychiatry
    Volume7
    DOIs
    Publication statusPublished - 30 Nov 2017

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    Keywords

    • Haplotype association analysis
    • Major Depressive Disorder
    • Generation Scotland
    • UK Biobank
    • 6q21
    • Depression

    Cite this

    Howard, D. M., Hall, L. S., Hafferty, J. D., Yanni, Z., Adams, M. J., Clarke, T-K., Porteous, D. J., Nagy, R., Hayward, C., Smith, B., Murray, A. D., Ryan, N. M., Evans, K. L., Haley, C. S., Deary, I. J., Thomson, P. A., & McIntosh, A. M. (2017). Genome-wide haplotype-based association analysis of major depressive disorder in Generation Scotland and UK Biobank. Translational Psychiatry, 7, 1-9. [1263]. https://doi.org/10.1038/s41398-017-0010-9