Genetic associations of adult height with risk of cardioembolic and other subtypes of ischemic stroke: A mendelian randomization study in multiple ancestries release_x6g7vho2dfhqfkwulxsknentsm

by Andrew B. Linden, Robert Clarke, Imen Hammami, Jemma C Hopewell, Yu Guo, William Whiteley, Kuang Lin, Iain Turnbull, Yiping Chen, Canqing YU, Jun Lv, Alison Offer (+6 others)

Published in PLoS Medicine by Public Library of Science (PLoS).

2022   Volume 19, Issue 4, e1003967

Abstract

<jats:sec id="sec001"> <jats:title>Background</jats:title> 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. </jats:sec> <jats:sec id="sec002"> <jats:title>Methods and findings</jats:title> 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; <jats:italic>p</jats:italic> = 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], <jats:italic>p</jats:italic> &lt; 0.001) and stronger inverse associations with large-artery stroke (11% lower risk, OR 0.89 [0.84, 0.95], <jats:italic>p</jats:italic> &lt; 0.001) and small-vessel stroke (13% lower risk, OR 0.87 [0.83, 0.92], <jats:italic>p</jats:italic> &lt; 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; <jats:italic>p</jats:italic> = 0.53) in UKB and 1.20 (0.77, 1.85; <jats:italic>p</jats:italic> = 0.43) in CKB; for other subtypes of ischemic stroke in UKB, the OR was 0.97 (95% CI 0.90, 1.05; <jats:italic>p</jats:italic> = 0.49); and for other nonlacunar stroke and lacunar stroke in CKB, the ORs were 0.89 (0.80, 1.00; <jats:italic>p</jats:italic> = 0.06) and 0.99 (0.88, 1.12; <jats:italic>p</jats:italic> = 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. </jats:sec> <jats:sec id="sec003"> <jats:title>Conclusions</jats:title> 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. </jats:sec>
In application/xml+jats format

Archived Files and Locations

application/pdf  1.5 MB
file_e4jg4unw3bghnlzvuaht75p6im
journals.plos.org (publisher)
web.archive.org (webarchive)
Read Archived PDF
Preserved and Accessible
Type  article-journal
Stage   published
Date   2022-04-22
Language   en ?
Journal Metadata
Open Access Publication
In DOAJ
In ISSN ROAD
In Keepers Registry
ISSN-L:  1549-1277
Work Entity
access all versions, variants, and formats of this works (eg, pre-prints)
Catalog Record
Revision: e0cd2cc4-3813-4b81-98d8-3d3962b40ada
API URL: JSON