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      Habitual coffee consumption and cognitive function: a Mendelian randomization meta-analysis in up to 415,530 participants

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          Abstract

          Coffee’s long-term effect on cognitive function remains unclear with studies suggesting both benefits and adverse effects. We used Mendelian randomization to investigate the causal relationship between habitual coffee consumption and cognitive function in mid- to later life. This included up to 415,530 participants and 300,760 coffee 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 as a proxy for habitual coffee 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 (P heterogeneity > 0.4 for both). Domain specific analyses using available cognitive measures in the UK Biobank also did not support effects by habitual coffee intake for reaction time, pairs matching, reasoning or prospective memory (P ≥ 0.05 for all). Despite the power to detect very small effects, our meta-analysis provided no evidence for causal long-term effects of habitual coffee consumption on global cognition or memory.

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          Most cited references 40

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          The new NHGRI-EBI Catalog of published genome-wide association studies (GWAS Catalog)

          The NHGRI-EBI GWAS Catalog has provided data from published genome-wide association studies since 2008. In 2015, the database was redesigned and relocated to EMBL-EBI. The new infrastructure includes a new graphical user interface (www.ebi.ac.uk/gwas/), ontology supported search functionality and an improved curation interface. These developments have improved the data release frequency by increasing automation of curation and providing scaling improvements. The range of available Catalog data has also been extended with structured ancestry and recruitment information added for all studies. The infrastructure improvements also support scaling for larger arrays, exome and sequencing studies, allowing the Catalog to adapt to the needs of evolving study design, genotyping technologies and user needs in the future.
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            Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression

            Background: The number of Mendelian randomization analyses including large numbers of genetic variants is rapidly increasing. This is due to the proliferation of genome-wide association studies, and the desire to obtain more precise estimates of causal effects. However, some genetic variants may not be valid instrumental variables, in particular due to them having more than one proximal phenotypic correlate (pleiotropy). Methods: We view Mendelian randomization with multiple instruments as a meta-analysis, and show that bias caused by pleiotropy can be regarded as analogous to small study bias. Causal estimates using each instrument can be displayed visually by a funnel plot to assess potential asymmetry. Egger regression, a tool to detect small study bias in meta-analysis, can be adapted to test for bias from pleiotropy, and the slope coefficient from Egger regression provides an estimate of the causal effect. Under the assumption that the association of each genetic variant with the exposure is independent of the pleiotropic effect of the variant (not via the exposure), Egger’s test gives a valid test of the null causal hypothesis and a consistent causal effect estimate even when all the genetic variants are invalid instrumental variables. Results: We illustrate the use of this approach by re-analysing two published Mendelian randomization studies of the causal effect of height on lung function, and the causal effect of blood pressure on coronary artery disease risk. The conservative nature of this approach is illustrated with these examples. Conclusions: An adaption of Egger regression (which we call MR-Egger) can detect some violations of the standard instrumental variable assumptions, and provide an effect estimate which is not subject to these violations. The approach provides a sensitivity analysis for the robustness of the findings from a Mendelian randomization investigation.
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              Mendelian randomization: using genes as instruments for making causal inferences in epidemiology.

              Observational epidemiological studies suffer from many potential biases, from confounding and from reverse causation, and this limits their ability to robustly identify causal associations. Several high-profile situations exist in which randomized controlled trials of precisely the same intervention that has been examined in observational studies have produced markedly different findings. In other observational sciences, the use of instrumental variable (IV) approaches has been one approach to strengthening causal inferences in non-experimental situations. The use of germline genetic variants that proxy for environmentally modifiable exposures as instruments for these exposures is one form of IV analysis that can be implemented within observational epidemiological studies. The method has been referred to as 'Mendelian randomization', and can be considered as analogous to randomized controlled trials. This paper outlines Mendelian randomization, draws parallels with IV methods, provides examples of implementation of the approach and discusses limitations of the approach and some methods for dealing with these.
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                Author and article information

                Contributors
                Elina.Hypponen@unisa.edu.au
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                14 May 2018
                14 May 2018
                2018
                : 8
                Affiliations
                [1 ]ISNI 0000 0000 8994 5086, GRID grid.1026.5, Australian Centre for Precision Health, , University of South Australia, ; Adelaide, Australia
                [2 ]ISNI 0000 0004 1936 7603, GRID grid.5337.2, MRC Integrative Epidemiology Unit (IEU) at the University of Bristol, ; Bristol, UK
                [3 ]ISNI 0000 0004 1936 7603, GRID grid.5337.2, UK Centre for Tobacco and Alcohol Studies (UKCTAS) and School of Experimental Psychology, , University of Bristol, ; Bristol, UK
                [4 ]ISNI 0000 0001 0941 4873, GRID grid.10858.34, Center for Life Course Health Research, , University of Oulu, ; Oulu, Finland
                [5 ]ISNI 0000 0004 4685 4917, GRID grid.412326.0, Oulu University Hospital, ; Oulu, Finland
                [6 ]ISNI 0000 0004 1937 0626, GRID grid.4714.6, Department of Medical Epidemiology and Biostatistics, , Karolinska Institutet, ; Stockholm, Sweden
                [7 ]ISNI 0000 0001 2097 1371, GRID grid.1374.1, Research Centre of Applied and Preventive Cardiovascular Medicine, , University of Turku, ; Turku, Finland
                [8 ]Helsinki Collegium for Advanced Studies, Helsinki, Finland
                [9 ]ISNI 0000 0004 0410 2071, GRID grid.7737.4, Department of Psychology and Logopedics, Faculty of medicine, , University of Helsinki, ; Helsinki, Finland
                [10 ]ISNI 0000 0004 1936 9457, GRID grid.8993.b, Department of Public Health and Caring Sciences, , Clinical Nutrition and Metabolism. Uppsala University, ; Uppsala, Sweden
                [11 ]ISNI 0000 0004 1936 9457, GRID grid.8993.b, Department of Surgical Sciences, , Orthopaedics, Uppsala University, ; Uppsala, Sweden
                [12 ]ISNI 0000 0001 2193 314X, GRID grid.8756.c, Institute of Health & Wellbeing, , University of Glasgow, ; Glasgow, UK
                [13 ]ISNI 0000 0004 4685 4917, GRID grid.412326.0, Unit of Primary Health Care, , Oulu University Hospital, ; Oulu, Finland
                [14 ]ISNI 0000 0001 2314 6254, GRID grid.5509.9, Department of Clinical Chemistry, , Fimlab Laboratories and Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Life Sciences, University of Tampere, ; Tampere, Finland
                [15 ]ISNI 0000 0001 2314 6254, GRID grid.5509.9, Department of Clinical Physiology, , Tampere University Hospital and Faculty of Medicine and Life Sciences, University of Tampere, ; Tampere, Finland
                [16 ]ISNI 0000 0001 2314 6254, GRID grid.5509.9, Department of Pediatrics, , Tampere University Hospital and Faculty of Medicine and Life Sciences, University of Tampere, ; Tampere, Finland
                [17 ]ISNI 0000 0001 1013 0499, GRID grid.14758.3f, Department of Public Health Solutions, , National Institute for Health and Welfare, ; Helsinki, Finland
                [18 ]ISNI 0000 0004 1936 8948, GRID grid.4991.5, Wellcome Centre for Human Genetics, Nuffield Department of Medicine, ; Oxford, OX3 7BN, UK
                [19 ]ISNI 0000 0004 1936 9457, GRID grid.8993.b, Department of Medical Sciences, , Cardiovascular Epidemiology, Uppsala University, ; Uppsala, Sweden
                [20 ]ISNI 0000000121901201, GRID grid.83440.3b, Population, Policy and Practice, , UCL Great Ormond Street Institute of Child Health, ; London, WC1N 1EH UK
                [21 ]ISNI 0000 0004 0410 2071, GRID grid.7737.4, Department of General Practice and Primary Health Care, , University of Helsinki and Helsinki University Hospital, ; Helsinki, Finland
                [22 ]ISNI 0000 0004 0409 6302, GRID grid.428673.c, Folkhälsan Research Center, ; Helsinki, Finland
                [23 ]ISNI 0000 0004 0628 215X, GRID grid.410552.7, Department of Clinical Physiology and Nuclear Medicine, , Turku University Hospital, ; Turku, Finland
                [24 ]ISNI 0000 0001 0941 4873, GRID grid.10858.34, Department of Psychiatry, , Research Unit of Clinical Neuroscience, University of Oulu, ; Oulu, Finland
                [25 ]ISNI 0000 0004 4685 4917, GRID grid.412326.0, Department of Psychiatry, , University Hospital of Oulu, ; Oulu, Finland
                [26 ]ISNI 0000 0001 2113 8111, GRID grid.7445.2, Department of Epidemiology and Biostatistics, , MRC–PHE Centre for Environment & Health, School of Public Health, Imperial College London, ; London, UK
                [27 ]ISNI 0000 0001 0941 4873, GRID grid.10858.34, Biocenter Oulu, University of Oulu, ; Oulu, Finland
                [28 ]ISNI 0000000419368956, GRID grid.168010.e, Department of Medicine, , Division of Cardiovascular Medicine, Stanford University School of Medicine, ; Stanford, CA 94305 USA
                [29 ]ISNI 0000 0004 1936 9457, GRID grid.8993.b, Department of Medical Sciences, , Molecular Epidemiology and Science for Life Laboratory, Uppsala University, ; Uppsala, Sweden
                [30 ]ISNI 0000000419368956, GRID grid.168010.e, Stanford Cardiovascular Institute, Stanford University, ; CA, 94305 USA
                [31 ]ISNI 0000 0004 1936 8024, GRID grid.8391.3, University of Exeter Medical School, ; Exeter, United Kingdom
                [32 ]GRID grid.430453.5, South Australian Health and Medical Research Institute, ; Adelaide, Australia
                Article
                25919
                10.1038/s41598-018-25919-2
                5951917
                29760501
                © The Author(s) 2018

                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/.

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