Genetic associations of adult height with risk of cardioembolic and other subtypes of ischaemic stroke: a Mendelian randomisation study in multiple ancestries

Background: Taller adult height is associated with lower risks of ischaemic heart disease in both observational and Mendelian randomisation studies, but little is known about the causal relevance of height for different subtypes of ischaemic stroke and the mechanisms involved. Methods: Height-associated genetic variants (up to 2,931) from previous genome-wide association studies were used to construct genetic instruments in different populations. Two-sample Mendelian randomisation approaches were used to examine the associations of genetically-determined height with ischaemic stroke and its subtypes in multiple ancestries (MEGASTROKE: 60,341 ischaemic stroke cases) supported by additional cases in Europeans (UK Biobank: 4,055 cases) and in Chinese (China Kadoorie Biobank: 10,297 cases). The associations of genetically-determined height with established cardiovascular and other risk factors were also examined in Europeans (UK Biobank: 336,750 participants) and Chinese (China Kadoorie Biobank: 58,277 participants). Results: Genetically-determined height was inversely associated with ischaemic stroke (4% [95% CI: 1-7] lower risk per 1 standard deviation taller height in MEGASTROKE). This masked much stronger opposing associations of height with different subtypes, with a 12% (95% CI: 6-17) higher risk of cardioembolic stroke, 11% (6-16) lower risk of large-artery stroke, and 14% (9-18) lower risk of small-vessel stroke. Genetically-determined height was strongly positively associated with atrial fibrillation, lean body mass and lung function, and inversely associated with levels of LDL cholesterol and blood pressure in both Europeans and Chinese. Conclusions: In multiple ancestries, genetic associations support the causal relevance of taller adult height for higher risk of cardioembolic stroke (in addition to atrial fibrillation) and lower risk of other ischaemic strokes, highlighting the need to properly differentiate subtypes of ischaemic stroke in both clinical practice and research.