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

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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 languageEnglish
Article number61
Pages (from-to)1-13
Number of pages13
JournalWellcome open research
Early online date10 Aug 2017
Publication statusPublished - 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.

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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