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Genetic risk, incident stroke, and the benefits of adhering to a healthy lifestyle: cohort study of 306 473 UK Biobank participants

BMJ 2018; 363 doi: (Published 24 October 2018) Cite this as: BMJ 2018;363:k4168
  1. Loes CA Rutten-Jacobs, senior postdoctoral researcher12,
  2. Susanna C Larsson, associate professor3,
  3. Rainer Malik, postdoctoral fellow4,
  4. Kristiina Rannikmäe, senior clinical research fellow56,
  5. MEGASTROKE consortium,
  6. International Stroke Genetics Consortium,
  7. Cathie L Sudlow, professor567,
  8. Martin Dichgans, professor489,
  9. Hugh S Markus, professor2,
  10. Matthew Traylor, senior research associate2
  1. 1German Center for Neurodegenerative diseases (DZNE), Population Health Sciences, Sigmund-Freud-Strasse 27, 53127 Bonn, Germany
  2. 2Department of Clinical Neurosciences, Stroke Research Group, University of Cambridge, UK
  3. 3Unit of Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
  4. 4Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany
  5. 5Centre for Medical Informatics, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK
  6. 6Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
  7. 7Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
  8. 8Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
  9. 9German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
  1. Correspondence to: LCA Rutten-Jacobs Loes.Rutten-Jacobs{at} (at @ruttenjacobs on Twitter)
  • Accepted 17 September 2018


Objective To evaluate the associations of a polygenic risk score and healthy lifestyle with incident stroke.

Design Prospective population based cohort study.

Setting UK Biobank Study, UK.

Participants 306 473 men and women, aged 40-73 years, recruited between 2006 and 2010.

Main outcome measure Hazard ratios for a first stroke, estimated using Cox regression. A polygenic risk score of 90 single nucleotide polymorphisms previously associated with stroke was constructed at P<1×10−5 to test for an association with incident stroke. Adherence to a healthy lifestyle was determined on the basis of four factors: non-smoker, healthy diet, body mass index <30 kg/m2, and regular physical exercise.

Results During a median follow-up of 7.1 years (2 138 443 person years), 2077 incident strokes (1541 ischaemic stroke, 287 intracerebral haemorrhage, and 249 subarachnoid haemorrhage) were ascertained. The risk of incident stroke was 35% higher among those at high genetic risk (top third of polygenic score) compared with those at low genetic risk (bottom third): hazard ratio 1.35 (95% confidence interval 1.21 to 1.50), P=3.9×10−8. Unfavourable lifestyle (0 or 1 healthy lifestyle factors) was associated with a 66% increased risk of stroke compared with a favourable lifestyle (3 or 4 healthy lifestyle factors): 1.66 (1.45 to 1.89), P=1.19×10−13. The association with lifestyle was independent of genetic risk stratums.

Conclusion In this cohort study, genetic and lifestyle factors were independently associated with incident stroke. These results emphasise the benefit of entire populations adhering to a healthy lifestyle, independent of genetic risk.


  • Contributors: LCAR-J and MT conceived the study. LCAR-J and MT wrote the first and successive drafts of the manuscript. LCAR-J and MT analysed the data. SCL contributed to study conception and design. All authors revised the manuscript for important intellectual content. LCAR-J and MT had full access to the data and take responsibility for the integrity of the data and the accuracy of the data analysis. LCAR-J is the guarantor. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

  • Funding: This work was in part supported by a British Heart Foundation programme grant (RG/16/4/32218). LCAR-J was supported by a British Heart Foundation immediate research fellowship (FS/15/61/31626). CLS is chief scientist for UK Biobank. The main sources of funding for CLS’s salary are UK Biobank and the Scottish funding Council. MD received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 666881 (SVDs@target) and from the DFG through the CRC 1123 (B3) and the Munich Cluster for Systems Neurology (EXC 1010 SyNergy). HSM is supported by a National Institute for Health Research (NIHR) senior investigator award, and his work is supported by the Cambridge Universities NIHR Comprehensive Biomedical Research Centre. The funding sources had no role in the design or conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript. The MEGASTROKE project received funding from sources specified at

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at and declare: no support from any organisation for the submitted work; HSM has been paid for delivering educational presentations for AstraZeneca; no other financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

  • Ethical approval: UK Biobank received ethical approval from the research ethics committee (reference 13/NW/0382). All participants provided informed consent to participate. The present analyses were conducted under UK Biobank application number 19463.

  • Data sharing: The genetic and phenotypic UK Biobank data are available on application to the UK Biobank ( Summary statistics from the MEGASTROKE meta-analysis of genome wide association studies in stroke and stroke subtypes are available from

  • Transparency: The lead author (LCAR-J) affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; that discrepancies from the study as planned have been explained, and that the paper conforms to transparency policy of the International Committee of Medical Journal Editors uniform requirement for manuscripts submitted to biomedical journals.

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