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

David M. Howard; 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

doi:10.1038/s41398-017-0010-9

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 language	English
Article number	1263
Pages (from-to)	1-9
Number of pages	9
Journal	Translational Psychiatry
Volume	7
DOIs	https://doi.org/10.1038/s41398-017-0010-9
Publication status	Published - 30 Nov 2017

Keywords

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

ASJC Scopus subject areas

Psychiatry and Mental health
Cellular and Molecular Neuroscience
Biological Psychiatry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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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. Article 1263. https://doi.org/10.1038/s41398-017-0010-9

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

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.",

keywords = "Haplotype association analysis, Major Depressive Disorder, Generation Scotland, UK Biobank, 6q21, Depression",

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

note = "Generation Scotland received core funding from the Chief Scientist Office of the Scottish Government Health Directorate CZD/16/6 and the Scottish Funding Council HR03006. Genotyping of GS:SFHS was carried out by the Genetics Core Laboratory at the Wellcome Trust Clinical Research Facility, Edinburgh, Scotland and was funded by the UK{\textquoteright}s Medical Research Council and the Wellcome Trust (Wellcome Trust Strategic Award “STratifying Resilience and Depression Longitudinally” (STRADL) (Reference 104036/Z/14/Z).",

year = "2017",

month = nov,

day = "30",

doi = "10.1038/s41398-017-0010-9",

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journal = "Translational Psychiatry",

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Howard, DM, Hall, LS, Hafferty, JD, Yanni, Z, Adams, MJ, Clarke, T-K, Porteous, DJ, Nagy, R, Hayward, C, Smith, B, Murray, AD, Ryan, NM, Evans, KL, Haley, CS, Deary, IJ, Thomson, PA & McIntosh, AM 2017, 'Genome-wide haplotype-based association analysis of major depressive disorder in Generation Scotland and UK Biobank', Translational Psychiatry, vol. 7, 1263, pp. 1-9. https://doi.org/10.1038/s41398-017-0010-9

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AU - Howard, David M.

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AU - Hafferty, Jonathan D.

AU - Yanni, Zeng

AU - Adams, Mark J.

AU - Clarke, Toni-Kim

AU - Porteous, David J.

AU - Nagy, Reka

AU - Hayward, Caroline

AU - Smith, Blair

AU - Murray, Alison D.

AU - Ryan, Niamh M.

AU - Evans, Kathryn L.

AU - Haley, Chris S.

AU - Deary, Ian J.

AU - Thomson, Pippa A.

AU - McIntosh, Andrew M.

N1 - Generation Scotland received core funding from the Chief Scientist Office of the Scottish Government Health Directorate CZD/16/6 and the Scottish Funding Council HR03006. Genotyping of GS:SFHS was carried out by the Genetics Core Laboratory at the Wellcome Trust Clinical Research Facility, Edinburgh, Scotland and was funded by the UK’s Medical Research Council and the Wellcome Trust (Wellcome Trust Strategic Award “STratifying Resilience and Depression Longitudinally” (STRADL) (Reference 104036/Z/14/Z).

PY - 2017/11/30

Y1 - 2017/11/30

N2 - 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.

AB - 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.

KW - Haplotype association analysis

KW - Major Depressive Disorder

KW - Generation Scotland

KW - UK Biobank

KW - 6q21

KW - Depression

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DO - 10.1038/s41398-017-0010-9

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