Haplotype-based association analysis of general cognitive ability in Generation Scotland, the English Longitudinal Study of Ageing, and UK Biobank

David M. Howard; Mark J. Adams; Toni-Kim Clarke; Eleanor M. Wigmore; Yanni Zeng; Saskia P. Hagenaars; Donald M. Lyall; Pippa A. Thomson; Kathryn L. Evans; David J. Porteous; Reka Nagy; Caroline Hayward; Chris S. Haley; Blair H. Smith; Alison D. Murray; G. David Batty; Ian J. Deary; Andrew M. McIntosh

doi:10.12688/wellcomeopenres.12171.1

Haplotype-based association analysis of general cognitive ability in Generation Scotland, the English Longitudinal Study of Ageing, and UK Biobank

David M. Howard^* (Corresponding Author), Mark J. Adams, Toni-Kim Clarke, Eleanor M. Wigmore, Yanni Zeng, Saskia P. Hagenaars, Donald M. Lyall, Pippa A. Thomson, Kathryn L. Evans, David J. Porteous, Reka Nagy, Caroline Hayward, Chris S. Haley, Blair H. Smith, Alison D. Murray, G. David Batty, Ian J. Deary, Andrew M. McIntosh

^*Corresponding author for this work

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

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Abstract

BACKGROUND: Cognitive ability is a heritable trait with a polygenic architecture, for which several associated variants have been identified using genotype-based and candidate gene approaches. Haplotype-based analyses are a complementary technique that take phased genotype data into account, and potentially provide greater statistical power to detect lower frequency variants.

METHODS: In the present analysis, three cohort studies (n total = 48,002) were utilised: Generation Scotland: Scottish Family Health Study (GS:SFHS), the English Longitudinal Study of Ageing (ELSA), and the UK Biobank. A genome-wide haplotype-based meta-analysis of cognitive ability was performed, as well as a targeted meta-analysis of several gene coding regions.

RESULTS: None of the assessed haplotypes provided evidence of a statistically significant association with cognitive ability in either the individual cohorts or the meta-analysis. Within the meta-analysis, the haplotype with the lowest observed P-value overlapped with the D-amino acid oxidase activator ( DAOA) gene coding region. This coding region has previously been associated with bipolar disorder, schizophrenia and Alzheimer's disease, which have all been shown to impact upon cognitive ability. Another potentially interesting region highlighted within the current genome-wide association analysis (GS:SFHS: P = 4.09 x 10 (-7)), was the butyrylcholinesterase ( BCHE) gene coding region. The protein encoded by BCHE has been shown to influence the progression of Alzheimer's disease and its role in cognitive ability merits further investigation.

CONCLUSIONS: Although no evidence was found for any haplotypes with a statistically significant association with cognitive ability, our results did provide further evidence that the genetic variants contributing to the variance of cognitive ability are likely to be of small effect.

Original language	English
Article number	61
Pages (from-to)	1-13
Number of pages	13
Journal	Wellcome open research
Volume	2
Early online date	10 Aug 2017
DOIs	https://doi.org/10.12688/wellcomeopenres.12171.1
Publication status	Published - 2017

Bibliographical note

Grant information
This work was supported by the Wellcome Trust [104036]; Medical Research Council and the Biotechnology and Biological Sciences Research Council [MR/K026992/1]; the Scottish Government Health Directorate [CZD/16/6]; the Scottish Funding Council [HR03006]; the Dr. Mortimer and Theresa Sackler Foundation; and the China Scholarship Council.

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Acknowledgements
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. This research has been conducted using the UK Biobank Resource – application number 4844. We are grateful to both the UK Biobank and the English Longitudinal Study of Ageing and their participants.

Keywords

Journal Article

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10.12688/wellcomeopenres.12171.1Licence: CC BY

Haplotype-based association analysis of general cognitive ability in Generation Scotland, the English Longitudinal Study of Ageing, and UK Biobank [version 1; referees: 2 approved]
Copyright: © 2017 Howard DM et al. This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. https://creativecommons.org/licenses/by/4.0/
Final published version, 978 KBLicence: CC BY

Cite this

Howard, D. M., Adams, M. J., Clarke, T-K., Wigmore, E. M., Zeng, Y., Hagenaars, S. P., Lyall, D. M., Thomson, P. A., Evans, K. L., Porteous, D. J., Nagy, R., Hayward, C., Haley, C. S., Smith, B. H., Murray, A. D., Batty, G. D., Deary, I. J., & McIntosh, A. M. (2017). Haplotype-based association analysis of general cognitive ability in Generation Scotland, the English Longitudinal Study of Ageing, and UK Biobank. Wellcome open research, 2, 1-13. [61]. https://doi.org/10.12688/wellcomeopenres.12171.1

Howard, DM, Adams, MJ, Clarke, T-K, Wigmore, EM, Zeng, Y, Hagenaars, SP, Lyall, DM, Thomson, PA, Evans, KL, Porteous, DJ, Nagy, R, Hayward, C, Haley, CS, Smith, BH, Murray, AD, Batty, GD, Deary, IJ & McIntosh, AM 2017, 'Haplotype-based association analysis of general cognitive ability in Generation Scotland, the English Longitudinal Study of Ageing, and UK Biobank', Wellcome open research, vol. 2, 61, pp. 1-13. https://doi.org/10.12688/wellcomeopenres.12171.1

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abstract = "BACKGROUND: Cognitive ability is a heritable trait with a polygenic architecture, for which several associated variants have been identified using genotype-based and candidate gene approaches. Haplotype-based analyses are a complementary technique that take phased genotype data into account, and potentially provide greater statistical power to detect lower frequency variants.METHODS: In the present analysis, three cohort studies (n total = 48,002) were utilised: Generation Scotland: Scottish Family Health Study (GS:SFHS), the English Longitudinal Study of Ageing (ELSA), and the UK Biobank. A genome-wide haplotype-based meta-analysis of cognitive ability was performed, as well as a targeted meta-analysis of several gene coding regions.RESULTS: None of the assessed haplotypes provided evidence of a statistically significant association with cognitive ability in either the individual cohorts or the meta-analysis. Within the meta-analysis, the haplotype with the lowest observed P-value overlapped with the D-amino acid oxidase activator ( DAOA) gene coding region. This coding region has previously been associated with bipolar disorder, schizophrenia and Alzheimer's disease, which have all been shown to impact upon cognitive ability. Another potentially interesting region highlighted within the current genome-wide association analysis (GS:SFHS: P = 4.09 x 10 (-7)), was the butyrylcholinesterase ( BCHE) gene coding region. The protein encoded by BCHE has been shown to influence the progression of Alzheimer's disease and its role in cognitive ability merits further investigation.CONCLUSIONS: Although no evidence was found for any haplotypes with a statistically significant association with cognitive ability, our results did provide further evidence that the genetic variants contributing to the variance of cognitive ability are likely to be of small effect.",

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author = "Howard, {David M.} and Adams, {Mark J.} and Toni-Kim Clarke and Wigmore, {Eleanor M.} and Yanni Zeng and Hagenaars, {Saskia P.} and Lyall, {Donald M.} and Thomson, {Pippa A.} and Evans, {Kathryn L.} and Porteous, {David J.} and Reka Nagy and Caroline Hayward and Haley, {Chris S.} and Smith, {Blair H.} and Murray, {Alison D.} and Batty, {G. David} and Deary, {Ian J.} and McIntosh, {Andrew M.}",

note = "Grant information This work was supported by the Wellcome Trust [104036]; Medical Research Council and the Biotechnology and Biological Sciences Research Council [MR/K026992/1]; the Scottish Government Health Directorate [CZD/16/6]; the Scottish Funding Council [HR03006]; the Dr. Mortimer and Theresa Sackler Foundation; and the China Scholarship Council. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Acknowledgements 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. This research has been conducted using the UK Biobank Resource – application number 4844. We are grateful to both the UK Biobank and the English Longitudinal Study of Ageing and their participants.",

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T1 - Haplotype-based association analysis of general cognitive ability in Generation Scotland, the English Longitudinal Study of Ageing, and UK Biobank

AU - Howard, David M.

AU - Adams, Mark J.

AU - Clarke, Toni-Kim

AU - Wigmore, Eleanor M.

AU - Zeng, Yanni

AU - Hagenaars, Saskia P.

AU - Lyall, Donald M.

AU - Thomson, Pippa A.

AU - Evans, Kathryn L.

AU - Porteous, David J.

AU - Nagy, Reka

AU - Hayward, Caroline

AU - Haley, Chris S.

AU - Smith, Blair H.

AU - Murray, Alison D.

AU - Batty, G. David

AU - Deary, Ian J.

AU - McIntosh, Andrew M.

N1 - Grant information This work was supported by the Wellcome Trust [104036]; Medical Research Council and the Biotechnology and Biological Sciences Research Council [MR/K026992/1]; the Scottish Government Health Directorate [CZD/16/6]; the Scottish Funding Council [HR03006]; the Dr. Mortimer and Theresa Sackler Foundation; and the China Scholarship Council. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Acknowledgements 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. This research has been conducted using the UK Biobank Resource – application number 4844. We are grateful to both the UK Biobank and the English Longitudinal Study of Ageing and their participants.

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N2 - BACKGROUND: Cognitive ability is a heritable trait with a polygenic architecture, for which several associated variants have been identified using genotype-based and candidate gene approaches. Haplotype-based analyses are a complementary technique that take phased genotype data into account, and potentially provide greater statistical power to detect lower frequency variants.METHODS: In the present analysis, three cohort studies (n total = 48,002) were utilised: Generation Scotland: Scottish Family Health Study (GS:SFHS), the English Longitudinal Study of Ageing (ELSA), and the UK Biobank. A genome-wide haplotype-based meta-analysis of cognitive ability was performed, as well as a targeted meta-analysis of several gene coding regions.RESULTS: None of the assessed haplotypes provided evidence of a statistically significant association with cognitive ability in either the individual cohorts or the meta-analysis. Within the meta-analysis, the haplotype with the lowest observed P-value overlapped with the D-amino acid oxidase activator ( DAOA) gene coding region. This coding region has previously been associated with bipolar disorder, schizophrenia and Alzheimer's disease, which have all been shown to impact upon cognitive ability. Another potentially interesting region highlighted within the current genome-wide association analysis (GS:SFHS: P = 4.09 x 10 (-7)), was the butyrylcholinesterase ( BCHE) gene coding region. The protein encoded by BCHE has been shown to influence the progression of Alzheimer's disease and its role in cognitive ability merits further investigation.CONCLUSIONS: Although no evidence was found for any haplotypes with a statistically significant association with cognitive ability, our results did provide further evidence that the genetic variants contributing to the variance of cognitive ability are likely to be of small effect.

AB - BACKGROUND: Cognitive ability is a heritable trait with a polygenic architecture, for which several associated variants have been identified using genotype-based and candidate gene approaches. Haplotype-based analyses are a complementary technique that take phased genotype data into account, and potentially provide greater statistical power to detect lower frequency variants.METHODS: In the present analysis, three cohort studies (n total = 48,002) were utilised: Generation Scotland: Scottish Family Health Study (GS:SFHS), the English Longitudinal Study of Ageing (ELSA), and the UK Biobank. A genome-wide haplotype-based meta-analysis of cognitive ability was performed, as well as a targeted meta-analysis of several gene coding regions.RESULTS: None of the assessed haplotypes provided evidence of a statistically significant association with cognitive ability in either the individual cohorts or the meta-analysis. Within the meta-analysis, the haplotype with the lowest observed P-value overlapped with the D-amino acid oxidase activator ( DAOA) gene coding region. This coding region has previously been associated with bipolar disorder, schizophrenia and Alzheimer's disease, which have all been shown to impact upon cognitive ability. Another potentially interesting region highlighted within the current genome-wide association analysis (GS:SFHS: P = 4.09 x 10 (-7)), was the butyrylcholinesterase ( BCHE) gene coding region. The protein encoded by BCHE has been shown to influence the progression of Alzheimer's disease and its role in cognitive ability merits further investigation.CONCLUSIONS: Although no evidence was found for any haplotypes with a statistically significant association with cognitive ability, our results did provide further evidence that the genetic variants contributing to the variance of cognitive ability are likely to be of small effect.

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Haplotype-based association analysis of general cognitive ability in Generation Scotland, the English Longitudinal Study of Ageing, and UK Biobank

Abstract

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