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.
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)
- haplotype association analysis
- IQ Generation Scotland
- UK Biobank
- English Longitudinal Study of Aging