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Habitual Coffee Consumption and Cognitive Function: a Mendelian www.nature.com/scientificreports OPEN Habitual cofee consumption and cognitive function: a Mendelian randomization meta-analysis in up Received: 18 September 2017 Accepted: 24 April 2018 to 415,530 participants Published: xx xx xxxx Ang Zhou1, Amy E. Taylor2,3, Ville Karhunen4,5, Yiqiang Zhan6, Suvi P. Rovio7, Jari Lahti 8,9, Per Sjögren10, Liisa Byberg11, Donald M. Lyall 12, Juha Auvinen4,13, Terho Lehtimäki14, Mika Kähönen15, Nina Hutri-Kähönen16, Mia Maria Perälä17, Karl Michaëlsson11, Anubha Mahajan 18, Lars Lind19, Chris Power20, Johan G. Eriksson21,22, Olli T. Raitakari7,23, Sara Hägg 6, Nancy L. Pedersen6, Juha Veijola24,25, Marjo-Riitta Järvelin4,26,27,13, Marcus R. Munafò 2,3, Erik Ingelsson28,29,30, David J. Llewellyn31 & Elina Hyppönen1,20,32 Cofee’s long-term efect on cognitive function remains unclear with studies suggesting both benefts and adverse efects. We used Mendelian randomization to investigate the causal relationship between habitual cofee consumption and cognitive function in mid- to later life. This included up to 415,530 participants and 300,760 cofee drinkers from 10 meta-analysed European ancestry cohorts. In each cohort, composite cognitive scores that capture global cognition and memory were computed using available tests. A genetic score derived using CYP1A1/2 (rs2472297) and AHR (rs6968865) was chosen 1Australian Centre for Precision Health, University of South Australia, Adelaide, Australia. 2MRC Integrative Epidemiology Unit (IEU) at the University of Bristol, Bristol, UK. 3UK Centre for Tobacco and Alcohol Studies (UKCTAS) and School of Experimental Psychology, University of Bristol, Bristol, UK. 4Center for Life Course Health Research, University of Oulu, Oulu, Finland. 5Oulu University Hospital, Oulu, Finland. 6Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. 7Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland. 8Helsinki Collegium for Advanced Studies, Helsinki, Finland. 9Department of Psychology and Logopedics, Faculty of medicine, University of Helsinki, Helsinki, Finland. 10Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism. Uppsala University, Uppsala, Sweden. 11Department of Surgical Sciences, Orthopaedics, Uppsala University, Uppsala, Sweden. 12Institute of Health & Wellbeing, University of Glasgow, Glasgow, UK. 13Unit of Primary Health Care, Oulu University Hospital, Oulu, Finland. 14Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland. 15Department of Clinical Physiology, Tampere University Hospital and Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland. 16Department of Pediatrics, Tampere University Hospital and Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland. 17Department of Public Health Solutions, National Institute for Health and Welfare, Helsinki, Finland. 18Wellcome Centre for Human Genetics, Nuffield Department of Medicine, Oxford, OX3 7BN, UK. 19Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala, Sweden. 20Population, Policy and Practice, UCL Great Ormond Street Institute of Child Health, London, WC1N 1EH, UK. 21Department of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. 22Folkhälsan Research Center, Helsinki, Finland. 23Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland. 24Department of Psychiatry, Research Unit of Clinical Neuroscience, University of Oulu, Oulu, Finland. 25Department of Psychiatry, University Hospital of Oulu, Oulu, Finland. 26Department of Epidemiology and Biostatistics, MRC–PHE Centre for Environment & Health, School of Public Health, Imperial College London, London, UK. 27Biocenter Oulu, University of Oulu, Oulu, Finland. 28Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA. 29Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden. 30Stanford Cardiovascular Institute, Stanford University, CA, 94305, USA. 31University of Exeter Medical School, Exeter, United Kingdom. 32South Australian Health and Medical Research Institute, Adelaide, Australia. Correspondence and requests for materials should be addressed to E.H. (email: [email protected]) SCIENTIFIC REPORTS | (2018) 8:7526 | DOI:10.1038/s41598-018-25919-2 1 www.nature.com/scientificreports/ as a proxy for habitual cofee consumption. Null associations were observed when examining the associations of the genetic score with global and memory cognition (β = −0.0007, 95% C.I. −0.009 to 0.008, P = 0.87; β = −0.001, 95% C.I. −0.005 to 0.002, P = 0.51, respectively), with high consistency between studies (Pheterogeneity > 0.4 for both). Domain specifc analyses using available cognitive measures in the UK Biobank also did not support efects by habitual cofee intake for reaction time, pairs matching, reasoning or prospective memory (P ≥ 0.05 for all). Despite the power to detect very small efects, our meta-analysis provided no evidence for causal long-term efects of habitual cofee consumption on global cognition or memory. Cofee is one of the most widely consumed beverages worldwide1. Its health benefts and risks have long been debated, with some studies suggesting reductions in the risk of various diseases2–5 and mortality6–8, while other studies have suggested a potential increase in cardiovascular risk9. Comprised of over 1,000 chemical compounds, cofee gains its popularity through its acute stimulatory efects, which are attributed to the pharmacological activity of cafeine1. Cafeine can readily cross the blood-brain bar- rier, and is believed to exert its neurocognitive efects by antagonizing adenosine receptors in the central nervous system1. Large-scale meta-analyses of prospective studies suggested that higher cofee consumption is associated with a lower risk for Alzheimer’s disease10,11, while a recent genetic study using summary data from large con- sortia did not support a causal association12. Studies on the efects of cofee consumption on specifc cognitive domains have yielded mixed results for executive function and memory, with some suggesting benefts, and others showing null or adverse efects13–15. Inconsistent fndings may refect methodological problems commonly seen with dietary exposures including confounding and reverse causation, the latter being particularly important in this case given that cafeine intake is typically one of the frst behaviors to be altered when the individual’s health status declines16. Randomised clinical trials are the gold standard for testing causal efects, however, these are expensive to undertake and it is difcult to examine infuences of prolonged exposures. An alternative is Mendelian random- ization, also called “nature’s randomised trial”, which is a non-invasive and cost-efective observational approach to identify possible causal associations17. In Mendelian randomization, causality is inferred from the association between exposure-related genetic variants and the outcome of interest18,19. As genotypes are assigned (at random) at conception they will not be generally afected by disease or social and lifestyle factors, allowing us to over- come some of the common problems with observational epidemiology. For a commonly used addictive stimulant such as cafeine, which has been proposed to have both adverse and benefcial efects on cognitive outcomes14,20, Mendelian randomization is therefore an attractive approach to use as it allows us to address issues both in rela- tion to safety and preventative potential. Genome-wide association studies to date have identifed 8 loci infuencing habitual cofee intakes21,22. Two common genetic variants have the strongest efects and known biological mechanisms, one located between the cytochrome P450 1A1 (CYP1A1) and CYP1A2 gene regions (rs2472297) and the other 51 kb upstream the aryl-hydrocarbon receptor (AHR) gene (rs6968865)23. CYP1A2 accounts for ~95% of hepatic cafeine clearance, and AHR plays a key role in metabolizing xenobiotics and inducing the transcription of CYP1A224. In this study, including individual level data for up to 415,530 European ancestry participants, we examined the causal associ- ation between genetically instrumented habitual cofee intake, and cognitive function in mid- to later-life, with the aim of establishing causal evidence for potential long-term cognitive efects of cofee consumption. Given the variants infuencing patterns of cofee consumption also afect cafeine intake and clearance23–25, secondary analyses were conducted with respect to habitual tea and cafeine intakes. Methods Study population. Data came from 10 European cohorts including the 1958 British birth cohort (1958BC), UK Biobank, Mothers of Avon Longitudinal Study of Parents and Children (ALSPAC-M), Northern Finland Birth Cohorts 1966 (NFBC1966), Cardiovascular Risk in Young Finns Study (YFS), Helsinki Birth Cohort Study (HBCS), Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS), Uppsala Longitudinal Study of Adult Men (ULSAM), Swedish twin registry (STR) and TwinGene studies. Participants in each study have pro- vided an informed consent, and each study is covered by ethical approvals from
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