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

Research output: Contribution to journal › Article › peer-review

19 Citations (Scopus)

8 Downloads (Pure)

Abstract

Cognitive performance is a heritable trait with a polygenic architecture for which several associated variants have been identified using genotype-based approaches. Haplotype-based analyses are a complimentary approach that take phase and parental origin into account, and potentially provide greater statistical power to detect lower frequency variants. The current study utilised three cohorts (Generation Scotland: Scottish Family Health Study, English Longitudinal Study of Aging and UK Biobank; n = 48,156) and conducted a genome-wide haplotype-based meta-analysis for cognition, as well as a targeted meta-analysis of several putative gene coding regions identified within previous studies. None of the analysed haplotypes provided evidence of a statistically significant association with cognition in either the individual cohorts or the meta-analysis. The haplotype with the lowest P-value overlapped with the D-amino acid oxidase activator (DAOA) gene coding region which has previously been associated with diseases known to impact upon cognitive ability. Another potentially interesting region, which was highlighted within the current genome-wide association analysis, was the butyrylcholinesterase (BCHE) gene coding region. This protein encoded by BCHE has been shown to influence the progression of Alzheimer’s disease and its role in cognition merits further investigation. The results of this study provide further evidence that there are likely to be many genetic variants of small effect contributing to the variance of cognitive ability.

Original language	English
Article number	1263
Journal	Translational Psychiatry
Volume	7
Early online date	30 Nov 2017
DOIs	https://doi.org/10.1038/s41398-017-0010-9
Publication status	Published - 2017

Bibliographical 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 the GS:SFHS samples was carried out by the Genetics Core Laboratory at the Wellcome Trust Clinical Research Facility, Edinburgh, Scotland and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award “STratifying Resilience and Depression Longitudinally” (STRADL) Reference 104036/Z/14/Z. YZ acknowledges support from China Scholarship Council. IJD is supported by the Centre for Cognitive Ageing and Cognitive Epidemiology which is funded by the Medical Research Council and the Biotechnology and Biological Sciences Research Council (MR/K026992/1). AMMcI and T-KC acknowledges support from the Dr Mortimer and Theresa Sackler Foundation.

We are grateful to all the families who took part, the general practitioners and the Scottish School of Primary Care for their help in recruiting them, and the whole Generation Scotland team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, healthcare assistants and nurses. Ethics approval for the study was given by the NHS Tayside committee on research ethics (reference 05/S1401/8)

Keywords

haplotype association analysis
cognition
intelligence
IQ Generation Scotland
UK Biobank
English Longitudinal Study of Aging

Access to Document

10.1038/s41398-017-0010-9Licence: CC BY

Genome-wide haplotype-based association analysis of major depressive disorder in Generation Scotland and UK Biobank
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Final published version, 1.12 MBLicence: CC BY

Cite this

Howard, D. M., Hall, L. S., Hafferty, J. D., Zeng, Y., Adams, M. J., Clarke, T.-K., Porteous, D. J., Nagy, R., Hayward, C., Smith, B. H., 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, Article 1263. https://doi.org/10.1038/s41398-017-0010-9

Howard, DM, Hall, LS, Hafferty, JD, Zeng, Y, Adams, MJ, Clarke, T-K, Porteous, DJ, Nagy, R, Hayward, C, Smith, BH, 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. https://doi.org/10.1038/s41398-017-0010-9

@article{0892ac64e16545c6a49e91305465dcc9,

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

abstract = "Cognitive performance is a heritable trait with a polygenic architecture for which several associated variants have been identified using genotype-based approaches. Haplotype-based analyses are a complimentary approach that take phase and parental origin into account, and potentially provide greater statistical power to detect lower frequency variants. The current study utilised three cohorts (Generation Scotland: Scottish Family Health Study, English Longitudinal Study of Aging and UK Biobank; n = 48,156) and conducted a genome-wide haplotype-based meta-analysis for cognition, as well as a targeted meta-analysis of several putative gene coding regions identified within previous studies. None of the analysed haplotypes provided evidence of a statistically significant association with cognition in either the individual cohorts or the meta-analysis. The haplotype with the lowest P-value overlapped with the D-amino acid oxidase activator (DAOA) gene coding region which has previously been associated with diseases known to impact upon cognitive ability. Another potentially interesting region, which was highlighted within the current genome-wide association analysis, was the butyrylcholinesterase (BCHE) gene coding region. This protein encoded by BCHE has been shown to influence the progression of Alzheimer{\textquoteright}s disease and its role in cognition merits further investigation. The results of this study provide further evidence that there are likely to be many genetic variants of small effect contributing to the variance of cognitive ability.",

keywords = "haplotype association analysis, cognition, intelligence, IQ Generation Scotland, UK Biobank, English Longitudinal Study of Aging",

author = "Howard, {David M.} and Hall, {Lynsey S} and Hafferty, {Jonathan D.} and Yanni Zeng and Adams, {Mark James} and Toni-Kim Clarke and Porteous, {David J.} and Reka Nagy and Caroline Hayward and Smith, {Blair H.} 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 the GS:SFHS samples was carried out by the Genetics Core Laboratory at the Wellcome Trust Clinical Research Facility, Edinburgh, Scotland and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award “STratifying Resilience and Depression Longitudinally” (STRADL) Reference 104036/Z/14/Z. YZ acknowledges support from China Scholarship Council. IJD is supported by the Centre for Cognitive Ageing and Cognitive Epidemiology which is funded by the Medical Research Council and the Biotechnology and Biological Sciences Research Council (MR/K026992/1). AMMcI and T-KC acknowledges support from the Dr Mortimer and Theresa Sackler Foundation. We are grateful to all the families who took part, the general practitioners and the Scottish School of Primary Care for their help in recruiting them, and the whole Generation Scotland team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, healthcare assistants and nurses. Ethics approval for the study was given by the NHS Tayside committee on research ethics (reference 05/S1401/8)",

year = "2017",

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

language = "English",

volume = "7",

journal = "Translational Psychiatry",

issn = "2158-3188",

publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Genome-wide haplotype-based association analysis of major depressive disorder in Generation Scotland and UK Biobank

AU - Howard, David M.

AU - Hall, Lynsey S

AU - Hafferty, Jonathan D.

AU - Zeng, Yanni

AU - Adams, Mark James

AU - Clarke, Toni-Kim

AU - Porteous, David J.

AU - Nagy, Reka

AU - Hayward, Caroline

AU - Smith, Blair H.

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 the GS:SFHS samples was carried out by the Genetics Core Laboratory at the Wellcome Trust Clinical Research Facility, Edinburgh, Scotland and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award “STratifying Resilience and Depression Longitudinally” (STRADL) Reference 104036/Z/14/Z. YZ acknowledges support from China Scholarship Council. IJD is supported by the Centre for Cognitive Ageing and Cognitive Epidemiology which is funded by the Medical Research Council and the Biotechnology and Biological Sciences Research Council (MR/K026992/1). AMMcI and T-KC acknowledges support from the Dr Mortimer and Theresa Sackler Foundation. We are grateful to all the families who took part, the general practitioners and the Scottish School of Primary Care for their help in recruiting them, and the whole Generation Scotland team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, healthcare assistants and nurses. Ethics approval for the study was given by the NHS Tayside committee on research ethics (reference 05/S1401/8)

PY - 2017

Y1 - 2017

N2 - Cognitive performance is a heritable trait with a polygenic architecture for which several associated variants have been identified using genotype-based approaches. Haplotype-based analyses are a complimentary approach that take phase and parental origin into account, and potentially provide greater statistical power to detect lower frequency variants. The current study utilised three cohorts (Generation Scotland: Scottish Family Health Study, English Longitudinal Study of Aging and UK Biobank; n = 48,156) and conducted a genome-wide haplotype-based meta-analysis for cognition, as well as a targeted meta-analysis of several putative gene coding regions identified within previous studies. None of the analysed haplotypes provided evidence of a statistically significant association with cognition in either the individual cohorts or the meta-analysis. The haplotype with the lowest P-value overlapped with the D-amino acid oxidase activator (DAOA) gene coding region which has previously been associated with diseases known to impact upon cognitive ability. Another potentially interesting region, which was highlighted within the current genome-wide association analysis, was the butyrylcholinesterase (BCHE) gene coding region. This protein encoded by BCHE has been shown to influence the progression of Alzheimer’s disease and its role in cognition merits further investigation. The results of this study provide further evidence that there are likely to be many genetic variants of small effect contributing to the variance of cognitive ability.

AB - Cognitive performance is a heritable trait with a polygenic architecture for which several associated variants have been identified using genotype-based approaches. Haplotype-based analyses are a complimentary approach that take phase and parental origin into account, and potentially provide greater statistical power to detect lower frequency variants. The current study utilised three cohorts (Generation Scotland: Scottish Family Health Study, English Longitudinal Study of Aging and UK Biobank; n = 48,156) and conducted a genome-wide haplotype-based meta-analysis for cognition, as well as a targeted meta-analysis of several putative gene coding regions identified within previous studies. None of the analysed haplotypes provided evidence of a statistically significant association with cognition in either the individual cohorts or the meta-analysis. The haplotype with the lowest P-value overlapped with the D-amino acid oxidase activator (DAOA) gene coding region which has previously been associated with diseases known to impact upon cognitive ability. Another potentially interesting region, which was highlighted within the current genome-wide association analysis, was the butyrylcholinesterase (BCHE) gene coding region. This protein encoded by BCHE has been shown to influence the progression of Alzheimer’s disease and its role in cognition merits further investigation. The results of this study provide further evidence that there are likely to be many genetic variants of small effect contributing to the variance of cognitive ability.

KW - haplotype association analysis

KW - cognition

KW - intelligence

KW - IQ Generation Scotland

KW - UK Biobank

KW - English Longitudinal Study of Aging

U2 - 10.1038/s41398-017-0010-9

DO - 10.1038/s41398-017-0010-9

M3 - Article

SN - 2158-3188

VL - 7

JO - Translational Psychiatry

JF - Translational Psychiatry

M1 - 1263

ER -

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

Abstract

Bibliographical note

Keywords

Access to Document

Fingerprint

Cite this