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Genetic associations of adult height with risk of cardioembolic and other subtypes of ischemic stroke: A mendelian randomization study in multiple ancestries

['Andrew B. Linden', 'Clinical Trial Service Unit', 'Epidemiological Studies Unit', 'Nuffield Department Of Population Health', 'University Of Oxford', 'Oxford', 'United Kingdom', 'Robert Clarke', 'Imen Hammami', 'Jemma C. Hopewell']

Date: 2022-04

Abstract Background Taller adult height is associated with lower risks of ischemic heart disease in mendelian randomization (MR) studies, but little is known about the causal relevance of height for different subtypes of ischemic stroke. The present study examined the causal relevance of height for different subtypes of ischemic stroke. Methods and findings Height-associated genetic variants (up to 2,337) from previous genome-wide association studies (GWASs) were used to construct genetic instruments in different ancestral populations. Two-sample MR approaches were used to examine the associations of genetically determined height with ischemic stroke and its subtypes (cardioembolic stroke, large-artery stroke, and small-vessel stroke) in multiple ancestries (the MEGASTROKE consortium, which included genome-wide studies of stroke and stroke subtypes: 60,341 ischemic stroke cases) supported by additional cases in individuals of white British ancestry (UK Biobank [UKB]: 4,055 cases) and Chinese ancestry (China Kadoorie Biobank [CKB]: 10,297 cases). The associations of genetically determined height with established cardiovascular and other risk factors were examined in 336,750 participants from UKB and 58,277 participants from CKB. In MEGASTROKE, genetically determined height was associated with a 4% lower risk (odds ratio [OR] 0.96; 95% confidence interval [CI] 0.94, 0.99; p = 0.007) of ischemic stroke per 1 standard deviation (SD) taller height, but this masked a much stronger positive association of height with cardioembolic stroke (13% higher risk, OR 1.13 [95% CI 1.07, 1.19], p < 0.001) and stronger inverse associations with large-artery stroke (11% lower risk, OR 0.89 [0.84, 0.95], p < 0.001) and small-vessel stroke (13% lower risk, OR 0.87 [0.83, 0.92], p < 0.001). The findings in both UKB and CKB were directionally concordant with those observed in MEGASTROKE, but did not reach statistical significance: For presumed cardioembolic stroke, the ORs were 1.08 (95% CI 0.86, 1.35; p = 0.53) in UKB and 1.20 (0.77, 1.85; p = 0.43) in CKB; for other subtypes of ischemic stroke in UKB, the OR was 0.97 (95% CI 0.90, 1.05; p = 0.49); and for other nonlacunar stroke and lacunar stroke in CKB, the ORs were 0.89 (0.80, 1.00; p = 0.06) and 0.99 (0.88, 1.12; p = 0.85), respectively. In addition, genetically determined height was also positively associated with atrial fibrillation (available only in UKB), and with lean body mass and lung function, and inversely associated with low-density lipoprotein (LDL) cholesterol in both British and Chinese ancestries. Limitations of this study include potential bias from assortative mating or pleiotropic effects of genetic variants and incomplete generalizability of genetic instruments to different populations. Conclusions The findings provide support for a causal association of taller adult height with higher risk of cardioembolic stroke and lower risk of other ischemic stroke subtypes in diverse ancestries. Further research is needed to understand the shared biological and physical pathways underlying the associations between height and stroke risks, which could identify potential targets for treatments to prevent stroke.

Author summary Why was this study done? Taller people have lower risks of ischemic stroke and heart disease, but higher risks of atrial fibrillation. However, little is known about the effects of height on the risks of different subtypes of ischemic stroke (cardioembolic stroke, large-artery stroke, and small-vessel stroke).

Understanding the shared biological and physical pathways underlying the associations between height and stroke risks could identify potential targets for treatments to prevent stroke.

Mean height and the rates of different stroke subtypes vary considerably across different income and ancestry populations, and, therefore, investigation across diverse ancestries is important. What did the researchers do and find? We used a mendelian randomization (MR) approach to study the association between genetic variants for height and risk of ischemic stroke subtypes in populations with different ancestries.

Genetic variants associated with taller height were associated with higher risks of cardioembolic stroke and lower risks of large-artery and small-vessel stroke.

The findings were consistent across populations of different genetic ancestries and use of different analytical methods. What do these findings mean? The findings support a causal association of taller adult height with higher risks of atrial fibrillation and cardioembolic stroke and lower risks of other ischemic stroke subtypes.

Further research is needed to clarify the biological and physical pathways underlying the associations of height with ischemic stroke subtypes, which could identify novel targets for treatments to prevent stroke.

Citation: Linden AB, Clarke R, Hammami I, Hopewell JC, Guo Y, Whiteley WN, et al. (2022) Genetic associations of adult height with risk of cardioembolic and other subtypes of ischemic stroke: A mendelian randomization study in multiple ancestries. PLoS Med 19(4): e1003967. https://doi.org/10.1371/journal.pmed.1003967 Academic Editor: Joshua Z. Willey, Columbia University, UNITED STATES Received: January 5, 2021; Accepted: March 16, 2022; Published: April 22, 2022 Copyright: © 2022 Linden et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability: MEGASTROKE data are publicly available for download at https://www.megastroke.org/download.html, on condition that researchers adhere to the rules for use of MEGASTROKE data for publications, available at https://www.megastroke.org/index.html. UK Biobank data are available on application to bona fide researchers for health-related research in the public interest. Details regarding registration and access to the UK Biobank data, including access conditions and fees, are available at https://www.ukbiobank.ac.uk/enable-your-research/register. China Kadoorie Biobank data sharing is subject to the Data Access Policy for the Nuffield Department of Population Health, University of Oxford, available at https://www.ndph.ox.ac.uk/files/about/ndph-data-access-policy-1.pdf. Data from baseline, first and second resurveys, and disease follow-up are available under the China Kadoorie Biobank Open Access Data Policy to bona fide researchers. Sharing of genotyping data is constrained by the Administrative Regulations on Human Genetic Resources of the People’s Republic of China. Access to these and certain other data is available through collaboration with China Kadoorie Biobank researchers. Full details of the China Kadoorie Biobank Data Sharing Policy are available at www.ckbiobank.org. The GIANT Consortium genome-wide association study summary statistics for height are publicly available for download at https://portals.broadinstitute.org/collaboration/giant/index.php/GIANT_consortium_data_files. Biobank Japan genome-wide association study summary statistics for height are publicly available for download at http://jenger.riken.jp/en/result. Funding: The China Kadoorie Biobank study was supported by the Kadoorie Charitable Foundation (https://www.kadooriecharitablefoundation.com; ZC), the UK Wellcome Trust (https://wellcome.org; ZC grant numbers: 202922/Z/16/Z, 104085/Z/14/Z, 088158/Z/09/Z), the National Natural Science Foundation of China (https://www.nsfc.gov.cn/english/site_1/index.html; ZC grant numbers: 81390540, 81390541, 81390544), and the National Key Research and Development Program of China (http://en.most.gov.cn/programmes1/200610/t20061009_36224.htm; ZC grant numbers: 2016YFC0900500, 2016YFC0900501, 2016YFC0900504, 2016YFC1303904). The Clinical Trial Service Unit, University of Oxford, also acknowledges support from the UK Medical Research Council (https://mrc.ukri.org; ZC grant number: MC_UU_00017/1; SP grant number: MC_UU_00017/5), the British Heart Foundation (https://www.bhf.org.uk; RC grant number: CH/1996001/9454; JCH grant number: FS/14/55/30806), the British Heart Foundation Oxford Centre for Research Excellence (https://www.cardioscience.ox.ac.uk/bhf-centre-of-research-excellence; RC, SP and JCH grant number: RE/18/3/34214), and Cancer Research UK (https://www.cancerresearchuk.org; ZC grant number: C500/A16896). ABL was supported by the Clarendon Fund (https://www.ox.ac.uk/clarendon) and by a Nuffield Department of Population Health Early Career Research Fellowship (https://www.ndph.ox.ac.uk). The MEGASTROKE project received funding from sources specified at https://www.megastroke.org/acknowledgements.html. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: WNW was supported by the Chief Scientist Office during the conduct of the study, and by the Alzheimer’s Society, the British Heart Foundation, and the UK Stroke Association outside the submitted work. Abbreviations: BMI, body mass index; CI, confidence interval; CKB, China Kadoorie Biobank; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; GIANT, Genetic Investigation of Anthropometric Traits; GWAS, genome-wide association study; HDL, high-density lipoprotein; HR, hazard ratio; LD, linkage disequilibrium; LDL, low-density lipoprotein; MR, mendelian randomization; MR–PRESSO, Mendelian Randomization Pleiotropy RESidual Sum and Outlier; OR, odds ratio; SD, standard deviation; SNP, single nucleotide polymorphism; STROBE-MR, Strengthening the Reporting of Observational Studies in Epidemiology using Mendelian Randomization; TOAST, Trial of ORG 10 172 in Acute Stroke Treatment; UKB, UK Biobank

Introduction Taller people have lower risks of atherosclerotic diseases, ischemic stroke, and heart disease, but higher risks of atrial fibrillation and venous thromboembolism [1–3]. The associations of height with ischemic stroke subtypes have not been reported, but it would be of interest to know whether these vary between atherosclerotic and cardioembolic stroke subtypes. In observational studies, any such associations could reflect confounding by socioeconomic status or other known or unknown correlates of height that are risk factors for cardiovascular diseases. Alternatively, the associations could be causal and could possibly be mediated through physical effects of height on body structure (including lean body mass or lung function) [4–7]. Increasingly, mendelian randomization (MR) analyses have been used to assess the causal relevance of risk factors for diseases by using genetic variants associated with risk factors of interest as instrumental variables [8]. The allocation of genetic variants to gametes (and hence offspring) is determined randomly at meiosis. Therefore, the random distribution of variants for a trait, such as height, between individuals can be used to minimize the effects of confounding by risk factors and provide support for the causal relevance of the trait for disease outcomes. Previous MR studies have reported that genetically determined differences in adult height were inversely associated with ischemic heart disease [4] and hypertension [2], but positively associated with atrial fibrillation [2,3], venous thromboembolism [2], and vasculitis [2]. However, the associations of genetically determined height with ischemic stroke and ischemic stroke subtypes have not been reliably established as previous studies have focused analyses on total stroke rather than on individual stroke pathological types and their main subtypes [2,9]. The present study examined the observational and genetic associations (using MR approaches) of height with (i) ischemic stroke and subtypes of ischemic stroke in the MEGASTROKE consortium (an international collaboration on the genetics of stroke) and in 2 large prospective studies conducted in the United Kingdom and China [10,11]; and (ii) established cardiovascular risk factors and anthropometric traits in the 2 large prospective studies.

Discussion In this large MR study of height and ischemic stroke, there were modest inverse associations of both genetically determined and measured height with overall ischemic stroke in populations from multiple ancestries. However, these masked much stronger directionally opposing associations of height with cardioembolic versus other ischemic stroke subtypes. In MEGASTROKE (multiple ancestries), a 1 SD genetically determined taller height was associated with 13% higher risk (OR 1.13 [95% CI 1.07, 1.19]; p < 0.001) of cardioembolic stroke, but with 11% lower (OR 0.89 [0.84, 0.95]; p < 0.001) and 13% lower (OR 0.87 [0.83, 0.92]; p < 0.001) risks of large-artery stroke and small-vessel stroke, respectively. In UKB and CKB, the different associations of measured height with ischemic stroke subtypes were concordant with those in MEGASTROKE. However, the genetic associations in UKB and CKB, although consistent, had less power to reliably demonstrate differences between the different ischemic stroke subtypes. Nevertheless, the similar findings from observational and MR approaches across 3 different populations provide support for height being causally related to ischemic stroke subtypes. To the best of our knowledge, this is the first large genetic study to examine the associations of height with ischemic stroke subtypes and furthermore included multiple ancestries. A previous study reported an OR of 0.88 (95% CI 0.82, 0.95) per 1 SD taller genetically determined height with ischemic heart disease [4], which is similar to association with large-artery stroke in the present study and could be a reflection of a shared underlying process affecting height and atherosclerosis. The present study used MR approaches that minimize biases from residual confounding and reverse causality that can bias observational studies. Furthermore, in a range of MR sensitivity analyses, the findings remained consistent irrespective of the methodology used for estimation and found no evidence to support any major influence of horizontal pleiotropy. For example, the associations of genetically determined height with the stroke subtypes remained similar when SNPs most strongly associated (at p < 0.001) with length of education, LDL cholesterol, blood pressure and other cardiovascular risk factors were excluded from the genetic instrument. The modest impact of excluding SNPs most strongly associated with cardiovascular risk factors suggests that any mediating effect of such traits is likely to be low. However, LDL cholesterol has previously been shown to be causally associated with increased risk of ischemic stroke in populations of both European and Chinese ancestries [21], with the strongest association observed with large-artery stroke and little association seen with cardioembolic stroke [27]. Thus, the inverse association of genetically determined height with LDL cholesterol levels in both UKB and CKB could explain some of the inverse associations of height with large-artery stroke and, to a lesser extent, with small-vessel stroke, although the mechanism by which height might cause this is unclear. Genetically determined taller height was also associated with lower mean levels of blood pressure in both studies (about 1 mm Hg lower in UKB, but only 0.1 mm Hg in CKB; Table 1); based on the UKB effect, this would be expected to translate to about 3% proportional lower risk of ischemic stroke and 2% to 5% proportional lower risk of each ischemic stroke subtype [28]. By contrast with the consistency of the genetic associations, the observational associations were not as consistent between UKB and CKB, possibly reflecting differences in residual confounding in the observational analyses (e.g., by socioeconomic factors, as blood pressure and height are positively correlated with income in China [29]) or reverse causality (e.g., due to LDL-lowering medication), illustrating the advantage of MR analyses. The associations of height with ischemic stroke subtypes may reflect a direct causal effect of body dimensions on stroke subtypes or the effects of some other correlated anthropometric trait (such as lean body mass) on the diseases. Previous MR studies have suggested that greater lung function may act as a possible mediator of the protective effect of height on ischemic heart disease [5]. In both UKB and CKB, taller height was associated with higher lung function and so lung function could account for some of the protective effects of height [5]. This study provides novel support for the causal relevance of height for cardioembolic stroke, the most disabling consequence of atrial fibrillation. Previous studies have supported the causal relevance of height and lean body mass for atrial fibrillation [6,7] and suggested that greater lean body mass is the chief anthropometric risk factor (stronger than height) for atrial fibrillation [7]. Larger left atrial diameter, present in taller people, has also been associated with higher risks of atrial fibrillation and embolism from cardiac sources [30], but whether these associations are mediated by lean body mass or some other physical aspect of body dimensions has not been previously studied. Higher levels of lean body mass have also been positively associated with other physical measures, such as carotid intima-media thickness, left ventricular mass, and cardiac wall thickness, but not with atherosclerosis [31]. The opposing associations of height with cardioembolic and other ischemic stroke subtypes highlight the importance of considering ischemic stroke subtypes as distinct diseases. Studies examining the associations of risk factors with overall ischemic stroke may incorrectly estimate medically relevant associations of some risk factors with individual ischemic stroke subtypes. Many studies (e.g., UKB, with follow-up based on electronic health records) and cardiovascular trials do not currently have detailed and reliable ischemic stroke subtyping, limiting their use for causal inference. Subtyping is also important in clinical practice for prevention of stroke recurrence, where the impact of treatments, such as statins or anticoagulants, may vary in patients at particular risk for different ischemic stroke subtypes [27]. Men and women in CKB were 10 and 8 cm shorter (about 1.5 SD), respectively, than their counterparts in UKB (S1 Table). If the MR associations in Fig 2 are assumed to be causal, this would translate to adults in China having a higher risk of some ischemic stroke subtypes (particularly for large-artery stroke and small-vessel stroke subtypes) and a lower risk of cardioembolic stroke compared with Europeans. In CKB, genetically determined height was associated with a modestly, albeit not statistically, significant lower OR for all ischemic stroke subtypes. The present study also had several limitations. Genotypes associated with height, education, blood pressure, and several chronic diseases have been shown to be correlated within spouse pairs (i.e., indicative of assortative mating), which can lead to indirect effects of genotypes in offspring, in violation of MR assumptions [32]. Family-based studies have reported that such indirect genetic effects of nontransmitted alleles could explain about 12% of the genetic effect on height [33]. As desirable traits such as higher income, taller height, and healthy traits tend to cluster in mates, assortative mating could explain some of the protective associations of taller height, but is unlikely to explain the adverse associations of height with atrial fibrillation and cardioembolic stroke. A further limitation is that studies differed in the methodology used to classify ischemic stroke subtypes, and reliable subtyping was not available in all of the populations studied. As cardioembolic stroke has been reported to account for 22% of ischemic stroke cases in a global meta-analysis [34] and over half of cases in a Canadian registry study [35], the relatively low number of presumed cardioembolic stroke cases observed in both UKB and CKB may be an underestimate of the true incidence of cardioembolic strokes. While height has been estimated to have a SNP-based heritability of about 50% in both Europeans [19] and East Asians [20], it is likely that genetic instruments derived in European populations may not perform as well in other ancestry populations, due to differences in allele frequencies and LD structure, but can still provide valid causal inferences [21,22]. The genetic risk scores for height used in UKB (based on an independent largely European ancestry-based GWAS) explained 19.7% of the variance in height in UKB, but the genetic risk score used in CKB (based on a large GWAS of height in a European population [18] and a smaller GWAS of height in a Japanese population) [20] explained only 15.2% of the variance in height in CKB. The present multiple ancestry analysis in MEGASTROKE may therefore have underestimated the causal effects of height if the (European ancestry derived) genetic risk score used was associated with smaller differences in height in the non-European ancestry populations. The findings in the present study highlight important differences in the causal pathways between stroke subtypes and the need to distinguish such subtypes not only in clinical practice, but also in cardiovascular trials, electronic health records, and population studies. Although height is not a modifiable risk factor, recognition that taller individuals have increased risk of cardioembolic stroke may guide clinicians to screen for atrial fibrillation or other risk factors for cardioembolic stroke when managing an individual’s overall risk [3]. Further research is needed to understand the shared biological and physical pathways underlying the associations of height with stroke subtypes. The strong association of genetically determined height with physical measurements such as lean body mass and lung function and with atrial fibrillation suggest that these may be mediators of some of the associations with height. Further study, such as multivariable MR with robust instruments (probably sex specific, because of the substantial differences in anthropometric measures by sex), could yield further insight into the direct and indirect effects of height through other factors on the risks of ischemic stroke subtypes. In conclusion, the present genetic studies provide novel and reliable findings that support a causal association of taller adult height with higher risks of atrial fibrillation and cardioembolic stroke and lower risks of other ischemic stroke subtypes. These findings raise the possibility of investigating whether including height as a risk factor in risk prediction tools would improve screening and primary prevention of cardioembolic stroke and of whether understanding the shared biological and physical pathways involved in height may offer novel targets for treatment to prevent cardioembolic stroke.

Acknowledgments The China Kadoorie Biobank study is jointly coordinated by the University of Oxford and the Chinese Academy of Medical Sciences. Members of the MEGASTROKE consortium are listed in S2 Text. The research included in the present report used data obtained from the UKB resource under application 10 061. Genotyping data were exported from China to the Oxford CKB International Coordinating Centre under Data Export Approvals 2014–13 and 2015–39 from the Office of Chinese Human Genetic Resource Administration.

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