Modification effect of ideal cardiovascular health metrics on genetic association with incident heart failure in the China Kadoorie Biobank and the UK Biobank

Abstract Background Both genetic and cardiovascular factors contribute to the risk of developing heart failure (HF), but whether idea cardiovascular health metrics (ICVHMs) offset the genetic association with incident HF remains unclear. Objectives To investigate the genetic association with incident HF as well as the modification effect of ICVHMs on such genetic association in Chinese and British populations. Methods An ICVHMs based on smoking, drinking, physical activity, diets, body mass index, waist circumference, blood pressure, blood glucose, and blood lipids, and a polygenic risk score (PRS) for HF were constructed in the China Kadoorie Biobank (CKB) of 96,014 participants and UK Biobank (UKB) of 335,782 participants which were free from HF and severe chronic diseases at baseline. Results During the median follow-up of 11.38 and 8.73 years, 1451 and 3169 incident HF events were documented in CKB and UKB, respectively. HF risk increased monotonically with the increase of PRS per standard deviation (CKB: hazard ratio [HR], 1.19; 95% confidence interval [CI], 1.07, 1.32; UKB: 1.07; 1.03, 1.11; P for trend < 0.001). Each point increase in ICVHMs was associated with 15% and 20% lower risk of incident HF in CKB (0.85; 0.81, 0.90) and UKB (0.80; 0.77, 0.82), respectively. Compared with unfavorable ICVHMs, favorable ICVHMs was associated with a lower HF risk, with 0.71 (0.44, 1.15), 0.41 (0.22, 0.77), and 0.48 (0.30, 0.77) in the low, intermediate, and high genetic risk in CKB and 0.34 (0.26, 0.44), 0.32 (0.25, 0.41), and 0.37 (0.28, 0.47) in UKB (P for multiplicative interaction > 0.05). Participants with low genetic risk and favorable ICVHMs, as compared with high genetic risk and unfavorable ICVHMs, had 56~72% lower risk of HF (CKB 0.44; 0.28, 0.70; UKB 0.28; 0.22, 0.37). No additive interaction between PRS and ICVHMs was observed (relative excess risk due to interaction was 0.05 [−0.22, 0.33] in CKB and 0.04 [−0.14, 0.22] in UKB). Conclusions In CKB and UKB, genetic risk and ICVHMs were independently associated with the risk of incident HF, which suggested that adherence to favorable cardiovascular health status was associated with a lower HF risk among participants with all gradients of genetic risk.

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Diet quality indices, genetic risk and risk of cardiovascular disease and mortality: a longitudinal analysis of 77 004 UK Biobank participants

BMJ Open ◽

10.1136/bmjopen-2020-045362 ◽

2021 ◽

Vol 11 (4) ◽

pp. e045362

Author(s):

Katherine M Livingstone ◽

Gavin Abbott ◽

Steven J Bowe ◽

Joey Ward ◽

Catherine Milte ◽

...

Keyword(s):

Risk Score ◽

Diet Quality ◽

Genetic Risk ◽

Lower Risk ◽

Polygenic Risk Score ◽

Uk Biobank ◽

Quality Indices ◽

Polygenic Risk ◽

All Cause Mortality ◽

Cvd Mortality

ObjectivesTo examine associations of three diet quality indices and a polygenic risk score with incidence of all-cause mortality, cardiovascular disease (CVD) mortality, myocardial infarction (MI) and stroke.DesignProspective cohort study.SettingUK Biobank, UK.Participants77 004 men and women (40–70 years) recruited between 2006 and 2010.Main outcome measuresA polygenic risk score was created from 300 single nucleotide polymorphisms associated with CVD. Cox proportional HRs were used to estimate independent effects of diet quality and genetic risk on all-cause mortality, CVD mortality, MI and stroke risk. Dietary intake (Oxford WebQ) was used to calculate Recommended Food Score (RFS), Healthy Diet Indicator (HDI) and Mediterranean Diet Score (MDS).ResultsNew all-cause (n=2409) and CVD (n=364) deaths and MI (n=1141) and stroke (n=748) events were identified during mean follow-ups of 7.9 and 7.8 years, respectively. The adjusted HR associated with one-point higher RFS for all-cause mortality was 0.96 (95% CI: 0.94 to 0.98), CVD mortality was 0.94 (95% CI: 0.90 to 0.98), MI was 0.97 (95% CI: 0.95 to 1.00) and stroke was 0.94 (95% CI: 0.91 to 0.98). The adjusted HR for all-cause mortality associated with one-point higher HDI and MDS was 0.97 (95% CI: 0.93 to 0.99) and 0.95 (95% CI: 0.91 to 0.98), respectively. The adjusted HR associated with one-point higher MDS for stroke was 0.93 (95% CI: 0.87 to 1.00). There was little evidence of associations between HDI and risk of CVD mortality, MI or stroke. There was evidence of an interaction between diet quality and genetic risk score for MI.ConclusionHigher diet quality predicted lower risk of all-cause mortality, independent of genetic risk. Higher RFS was also associated with lower risk of CVD mortality and MI. These findings demonstrate the benefit of following a healthy diet, regardless of genetic risk.

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Relationships of sleep traits with lung cancer risk: a prospective cohort study in UK Biobank

SLEEP ◽

10.1093/sleep/zsab089 ◽

2021 ◽

Author(s):

Junxing Xie ◽

Meng Zhu ◽

Mengmeng Ji ◽

Jingyi Fan ◽

Yanqian Huang ◽

...

Keyword(s):

Lung Cancer ◽

Cancer Risk ◽

Sleep Duration ◽

Genetic Risk ◽

Lung Cancer Risk ◽

Polygenic Risk Score ◽

Uk Biobank ◽

High Genetic Risk ◽

Sleep Behaviors ◽

Incident Cases

Abstract Study objectives To prospectively investigate the association between sleep traits and lung cancer risk, accounting for the interactions with genetic predisposition of lung cancer. Methods We included 469,691 individuals free of lung cancer at recruitment from UK Biobank, measuring sleep behaviors with a standardized questionnaire and identifying incident lung cancer cases through linkage to national cancer and death registries. We estimated multivariable adjusted hazard ratios (HR) for lung cancer (2,177 incident cases) across four sleep traits (sleep duration, chronotype, insomnia and snoring), and examined the interaction and joint effects with a lung cancer polygenic risk score. Results A U-shaped association was observed for sleep duration and lung cancer risk, with a 18% higher risk (95% confidence interval (CI): 1.07-1.30) for short sleepers and a 17% higher risk (95%CI: 1.02-1.34) for long sleepers compared with normal sleepers (7-8 h/day). Evening preference was associated with elevated lung cancer risk compared with morning preference (HR: 1.25; 95%CI: 1.07-1.46), but no association was found for insomnia or snoring. Compared to participants with favorable sleep traits and low genetic risk, those with both unfavorable sleep duration (<7 hours or >8 hours) or evening preference and high genetic risk showed the greatest lung cancer risk (HRsleep duration: 1.83; 95%CI: 1.47-2.27; HRchronotype: 1.85; 95%CI: 1.34-2.56). Conclusions Both unfavorable sleep duration and evening chronotype were associated with increased lung cancer incidence, especially for those with low to moderate genetic risk. These results indicate that sleep behaviors as modifiable risk factors may have potential implications for lung cancer risk.

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Association of social isolation, loneliness, and genetic risk with incidence of dementia: UK Biobank cohort study

10.1101/2020.02.25.20027177 ◽

2020 ◽

Author(s):

Marko Elovainio ◽

Jari Lahti ◽

Matti Pirinen ◽

Laura Pulkki-Råback ◽

Anni Malmberg ◽

...

Keyword(s):

Cohort Study ◽

Social Isolation ◽

Genetic Risk ◽

Significant Risk ◽

Polygenic Risk Score ◽

List Type ◽

Uk Biobank ◽

High Genetic Risk ◽

Increased Risk ◽

Socially Isolated

ObjectiveTo examine the associations of social isolation and loneliness with incident dementia by level of genetic risk.DesignProspective population-based cohort study.Setting and participants155 074 men and women (mean age 64.1, SD 2.9 years) from the UK Biobank Study, recruited between 2006 and 2010.Main exposuresSelf-reported social isolation and loneliness, and polygenic risk score for Alzheimer’s disease with low (lowest quintile), intermediate (quintiles 2 to 4), and high (highest quintile) risk categories.Main outcomeIncident all-cause dementia ascertained using electronic health records.ResultsOverall, 8.6% of participants reported that they were socially isolated and 5.5% were lonely. During a mean follow-up of 8.8 years (1.36 million person-years), 1444 (0.9% of the total sample) were diagnosed with dementia. Social isolation, but not loneliness, was associated with increased risk of dementia (hazard ratio 1.62, 95% confidence interval 1.38 to 1.90). Of the participants who were socially isolated and had high genetic risk, 4.2% (2.9% to 5.5%) were estimated to develop dementia compared with 3.1% (2.7% to 3.5%) in participants who were not socially isolated but had high genetic risk. The corresponding estimated incidence in the socially isolated and not isolated were 3.9% (3.1% to 4.6%) and 2.5% (2.2% to 2.6%) in participants with intermediate genetic risk.ConclusionSocially isolated individuals are at increased risk of dementia at all levels of genetic risk.What is already known on this topicSocial isolation and loneliness have been associated with increased risk of dementiaIt is not known whether this risk is modified or confounded by genetic risk of dementiaWhat this study addsThis is the first study to show that social isolation is associated with increased risk of dementia across the spectrum of genetic riskLoneliness, although considered as a significant risk for multiple health problems, seems to be associated with dementia only when combined with high genetic risk

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Associations of genetic risk and smoking with incident chronic obstructive pulmonary disease

European Respiratory Journal ◽

10.1183/13993003.01320-2021 ◽

2021 ◽

pp. 2101320

Author(s):

Pei-Dong Zhang ◽

Xi-Ru Zhang ◽

Ao Zhang ◽

Zhi-Hao Li ◽

Dan Liu ◽

...

Keyword(s):

Chronic Obstructive Pulmonary Disease ◽

Pulmonary Disease ◽

Genetic Risk ◽

Chronic Obstructive ◽

Polygenic Risk Score ◽

Obstructive Pulmonary Disease ◽

Current Smoking ◽

High Genetic Risk ◽

Genome Wide ◽

Genome Wide Significance

BackgroundGenetic and smoking contribute to chronic obstructive pulmonary disease (COPD), but whether a combined polygenic risk score (PRS) is associated with incident COPD and whether it has a synergistic effect on the smoking remains unclear. We aimed to investigate the association of PRS with COPD and explore whether smoking behaviors could modify such association.MethodsMultivariable Cox proportional models were used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) for the association of the PRS and smoking with COPD.ResultsThe study included 439 255 participants (mean age 56.5; 53.9% female), with a median follow-up of 9.0 years. The PRSlasso containing 2.5 million variants showed better discrimination and a stronger association for incident COPD than the PRS279 containing 279 genome-wide significance variants. Compared with the low genetic risk, the HRs of the medium and high genetic risk were 1.39 (95% CI, 1.31–1.48) and 2.40 (95% CI, 2.24–2.56), respectively. The HR of high genetic risk and current smoking was 11.62 (95% CI, 10.31–13.10) times of low genetic risk and never smoking. There were significant interactions between the PRSlasso and smoking status for incident COPD (p for interaction<0.001). From low genetic risk to high genetic risk, the HRs of current smoking increased from 4.32 (95% CI, 3.69–5.06) to 6.89 (95% CI, 6.21–7.64), and the population-attributable risks of smoking increased from 42.7% to 61.1%.ConclusionPRS constructed from millions of variants below genome-wide significance showed significant associations with incident COPD. Participants with a high genetic risk may be more susceptible to developing COPD when exposed to smoking.

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Abstract MP03: Plasma Sphingolipids and Risks of Heart Failure and Atrial Fibrillation in Older Adults: The Cardiovascular Health Study

Circulation ◽

10.1161/circ.137.suppl_1.mp03 ◽

2018 ◽

Vol 137 (suppl_1) ◽

Author(s):

Rozenn N Lemaitre ◽

Paul N Jensen ◽

Barbara McKnight ◽

Andrew Hoofnagle ◽

Irena B King ◽

...

Keyword(s):

Heart Failure ◽

Atrial Fibrillation ◽

Fatty Acid ◽

Lower Risk ◽

Cardiovascular Health ◽

Biological Activities ◽

Experimental Studies ◽

Health Study ◽

Cardiovascular Health Study

Introduction: Ceramides and sphingomyelins (sphingolipids) are circulating lipids involved in multiple physiological pathways relevant to heart failure (HF) and atrial fibrillation (AF), including apoptosis, oxidative stress, and inflammation. Experimental studies suggest that sphingolipids with different saturated fatty acids exhibit different biological activities, but their relationships with HF and AF are unknown. Hypothesis: Higher levels of plasma ceramide and sphingomyelin that contain the fatty acid 16:0 are associated with higher risks of HF and AF; and higher levels of ceramides and sphingomyelins that contain the fatty acid 20:0, 22:0 or 24:0 are associated with lower risks. Methods: We measured sphingolipids in the Cardiovascular Health Study (CHS) in plasma samples from 1994-95 (N=4026) or from 1992-93 (N=586). We assessed the separate associations of the levels of 8 sphingolipids with risks of incident HF and incident AF using Cox regression. A p-value threshold of 0.006 was used to account for multiple testing. Results: Among 4,612 participants, 1179 incident HF and 1198 incident AF occurred during >40,000 person-years of follow-up. In adjusted analyses, higher levels of Cer-16 (ceramide with 16:0) and SM-16 (sphingomyelin with 16:0) were associated with higher risk of incident HF, but not with risk of incident AF (Table). In contrast, higher levels of Cer-20, Cer-22 and Cer-24 were each associated with lower risk of AF, but not with risk of HF. Higher levels of SM-20, SM-22, and SM-24 tended to be associated with lower risks of AF and HF, with only the association of SM-20 with AF significant. Conclusions: Plasma levels of ceramide and sphingomyelin with 16:0 show different associations with HF and AF than species with 20:0, 22:0 or 24:0. Associations of Cer-16 and SM-16 specifically with higher risk of HF may be due to a role of apoptosis in HF. The novel findings that Cer-20, Cer-22, and Cer-24 are associated with lower risk of AF warrant further examination of the role of these sphingolipids in protecting from AF.

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Sugary beverage intake and genetic risk of dementia in relation to incident dementia and brain structure: evidence from the UK Biobank

10.21203/rs.3.rs-882320/v1 ◽

2021 ◽

Author(s):

Hui Chen ◽

Jie Chen ◽

Yaying Cao ◽

Yuhao Sun ◽

Liyan Huang ◽

...

Keyword(s):

White Matter ◽

Brain Structure ◽

Genetic Risk ◽

Grey Matter ◽

White Matter Hyperintensities ◽

Polygenic Risk Score ◽

Uk Biobank ◽

Sweetened Beverages ◽

Incident Dementia ◽

Common Genetic Variants

Abstract Importance: Sugary beverage intake was associated with higher risk of dementia, but the specific amounts and types related to it and its interactions with genetic predisposition to dementia remained poorly understood.Objective: To investigate the relation of sugary beverage intake and genetic preposition to the long-term risk of dementia and brain structure.Design, Setting, and Participants: We leveraged data of 187,994 UK Biobank participants without dementia at baseline and followed them until March 2021.Exposures: Intake of sugary beverages (SBs, one unit=250 ml), including sugar-sweetened beverages (SSB), artificially-sweetened beverages (ASB), and natural sweet juices (NSJ), was assessed using repeated web-based 24-h dietary recall from 2009 to 2012. A polygenic risk score (PRS) was calculated to capture each participant’s load of common genetic variants related to the risk of dementia.Main Outcomes and Measures: Incident dementia was identified through hospital admissions and death registries. Brain magnetic resonance imaging was conducted in a subgroup of 12,566 participants in 2014.Results: During a total of 1,790,996 person-years of follow up, 1,351 incident dementia cases were identified. Higher intake of SSB and ASB (>2 units/d v. none) was independently associated with a substantially increased risk of dementia (p-trend=0.013 for SSB, and <0.001 for ASB). The corresponding multivariable-adjusted hazard ratio [HR] and 95% confidence intervals [CI] were 1.47 (1.13~1.92), and 1.41 (1.00~1.99), respectively. The significant association of ASB was observed among ASB consumptions regardless of the intake level. In contrast, moderate intake of NSJ (0~1 unit/d v. none) was related to a decreased risk of dementia (HR=0.80, 0.71~0.90) and a larger volume of brain grey matter (beta=0.03, 0.01~0.06) and a lower volume of white matter hyperintensities (beta=-0.08, -0.13~-0.02). Moreover, the genetic risks were significantly magnified by higher intake of SSB and ASB, and was instead attenuated by moderate intake of NSJ (P-interaction<0.002).Conclusions and Relevance: Higher intake of SSB and ASB was associated with higher risk of dementia, especially among individuals at high genetic risk for dementia. Inversely, moderate NSJ intake was associated with a reduced risk of dementia, possibly through the beneficial role maintaining brain grey matter volume and reducing white matter hyperintensities.

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Abstract MP13: Polygenic Susceptibility to Atrial Fibrillation is Associated With Silent Cerebrovascular Disease in Stroke-Free Persons Without Atrial Fibrillation

Stroke ◽

10.1161/str.52.suppl_1.mp13 ◽

2021 ◽

Vol 52 (Suppl_1) ◽

Author(s):

Cameron Both ◽

Julian Acosta ◽

Natalia Szejko ◽

Kevin N Vanent ◽

Audrey C Leasure ◽

...

Keyword(s):

Atrial Fibrillation ◽

White Matter ◽

Cerebrovascular Disease ◽

Genetic Risk ◽

Community Dwelling ◽

Uk Biobank ◽

High Genetic Risk ◽

History Of ◽

The Uk ◽

Study Participants

Introduction: Clinically silent cerebrovascular disease is present in 40% of persons over the age of 60. We hypothesize that polygenic susceptibility to atrial fibrillation is associated with the burden of white matter disease in persons without atrial fibrillation or history of ischemic stroke. Methods: We conducted a nested genetic and neuroimaging study within the UK Biobank, a large cohort study that enrolled community dwelling Britons aged 40 to 65 at recruitment. We used data on a subcohort of patients evaluated with brain MRIs. The volume of white matter hyperintensities (WMH) was estimated using the BIANCA lesion segmentation tool. Genomic data was ascertained via genotyping with the Affymetrix UK Biobank Axiom array followed by imputation with 1000 Genomes reference panels. To model the polygenic susceptibility to atrial fibrillation (AFIB), we constructed a polygenic risk score (PRS) using 957 independent genetic risk variants known to significantly associate with atrial fibrillation. We used logistic and linear regression to test for association between the PRS and WMH. Results: A total of 38,914 study participants underwent brain MRI imaging in the UK Biobank. Of these, we excluded 124 (0.3%) with a history of stroke and 926 (2.4%) with AFIB. 37,864 study participants were included in this study, of which 19,059 (50.3%) had WMH. High genetic risk of AFIB was not associated with no-versus-any WMH (p=0.51). When evaluating persons with WMH lesions, high genetic risk of AFIB was associated with higher WMH volume (per 1 SD increase of the PRS, beta 0.019, SE 0.006; p=0.01). Gender was an important effect modifier of this association (interaction p=0.03): while high genetic risk of AFIB was associated with a significant increase in WMH volume in females (per 1 SD increase of the PRS, beta 0.03, SE 0.008; p<0.001), no association was found for males (p=0.99). Conclusions: Polygenic susceptibility to atrial fibrillation is associated with more severe silent cerebrovascular disease in persons without atrial fibrillation. Further research should evaluate whether this genetic information can be used to identify persons for tailored diagnostic or therapeutic interventions.

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Quantifying the extent to which index event biases influence large genetic association studies

10.1101/074781 ◽

2016 ◽

Author(s):

Hanieh Yaghootkar ◽

Michael P. Bancks ◽

Sam E. Jones ◽

Aaron McDaid ◽

Robin Beaumont ◽

...

Keyword(s):

Type 2 Diabetes ◽

Genetic Association ◽

Genetic Risk ◽

Association Studies ◽

Genetic Association Studies ◽

Population Based ◽

Uk Biobank ◽

Index Event ◽

Risk Alleles

AbstractAs genetic association studies increase in size to 100,000s of individuals, subtle biases may influence conclusions. One possible bias is “index event bias” (IEB), also called “collider bias”, caused by the stratification by, or enrichment for, disease status when testing associations between gene variants and a disease-associated trait. We first provided a statistical framework for quantifying IEB then identified real examples of IEB in a range of study and analytical designs. We observed evidence of biased associations for some disease alleles and genetic risk scores, even in population-based studies. For example, a genetic risk score consisting of type 2 diabetes variants was associated with lower BMI in 113,203 type 2 diabetes controls from the population based UK Biobank study (−0.010 SDs BMI per allele, P=5E-4), entirely driven by IEB. Three of 11 individual type 2 diabetes risk alleles, and 10 of 25 hypertension alleles were associated with lower BMI at p<0.05 in UK Biobank when analyzing disease free individuals only, of which six hypertension alleles remained associated at p<0.05 after correction for IEB. Our analysis suggested that the associations between CCND2 and TCF7L2 diabetes risk alleles and BMI could (at least partially) be explained by IEB. Variants remaining associated after correction may be pleiotropic and include those in CYP17A1 (allele associated with hypertension risk and lower BMI). In conclusion, IEB may result in false positive or negative associations in very large studies stratified or strongly enriched for/against disease cases.

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Polygenic risk score, healthy lifestyles, and risk of incident depression

Translational Psychiatry ◽

10.1038/s41398-021-01306-w ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Zhi Cao ◽

Hongxi Yang ◽

Yixuan Ye ◽

Yuan Zhang ◽

Shu Li ◽

...

Keyword(s):

Risk Score ◽

Genetic Risk ◽

Lifestyle Factors ◽

Polygenic Risk Score ◽

Healthy Lifestyles ◽

Current Smoking ◽

Polygenic Risk ◽

High Genetic Risk ◽

Moderate Alcohol Intake ◽

The Uk

AbstractGenetic factors increase the risk of depression, but the extent to which this can be offset by modifiable lifestyle factors is unknown. We investigated whether a combination of healthy lifestyles is associated with lower risk of depression regardless of genetic risk. Data were obtained from the UK Biobank and consisted of 339,767 participants (37–73 years old) without depression between 2006 and 2010. Genetic risk was categorized as low, intermediate, or high according to polygenic risk score for depression. A combination of healthy lifestyles factors—including no current smoking, regular physical activity, a healthy diet, moderate alcohol intake and a body mass index <30 kg/m2—was categorized into favorable, intermediate, and unfavorable lifestyles. The risk of depression was 22% higher among those at high genetic risk compared with those at low genetic risk (HR = 1.22, 95% CI: 1.14–1.30). Participants with high genetic risk and unfavorable lifestyle had a more than two-fold risk of incident depression compared with low genetic risk and favorable lifestyle (HR = 2.18, 95% CI: 1.84–2.58). There was no significant interaction between genetic risk and lifestyle factors (P for interaction = 0.69). Among participants at high genetic risk, a favorable lifestyle was associated with nearly 50% lower relative risk of depression than an unfavorable lifestyle (HR = 0.51, 95% CI: 0.43–0.60). We concluded that genetic and lifestyle factors were independently associated with risk of incident depression. Adherence to healthy lifestyles may lower the risk of depression regardless of genetic risk.

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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 ◽

10.1136/bmj.k4168 ◽

2018 ◽

pp. k4168 ◽

Cited By ~ 32

Author(s):

Loes CA Rutten-Jacobs ◽

Susanna C Larsson ◽

Rainer Malik ◽

Kristiina Rannikmäe ◽

Cathie L Sudlow ◽

...

Keyword(s):

Cohort Study ◽

Risk Score ◽

Genetic Risk ◽

Cox Regression ◽

Healthy Lifestyle ◽

Lifestyle Factors ◽

Polygenic Risk Score ◽

Uk Biobank ◽

Polygenic Risk ◽

Increased Risk

AbstractObjectiveTo evaluate the associations of a polygenic risk score and healthy lifestyle with incident stroke.DesignProspective population based cohort study.SettingUK Biobank Study, UK.Participants306 473 men and women, aged 40-73 years, recruited between 2006 and 2010.Main outcome measureHazard 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<1×10−5to 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.ResultsDuring 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.ConclusionIn 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.

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