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Differences in Common Genetic Predisposition to Ischemic Stroke by Age and Sex
Matthew Traylor1, Loes C A Rutten-Jacobs2, Elizabeth G Holliday2
1From the Stroke Research Group, Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom (M.T., L.C.A.R.-J., S.B., H.S.M.); School of Medicine and Public Health (E.G.H.) School of Nursing and Midwifery (J.M.M.), University of Newcastle, Callaghan, Newcastle, Australia; Clinical Research Design, IT and Statistical Support Unit, Hunter Medical Research Institute, New Lambton Heights, Newcastle, Australia (E.G.H., C.L.); Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität, Munich, Germany (R.M., M.D.); Centre for Clinical Brain Sciences and Institute for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom (C.S.); Stroke Prevention Research Unit, Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford, United Kingdom (P.M.R.); Hunter Medical Research Institute, New Lambton Heights, Newcastle, Australia (J.M.M.); Stroke Research Program, School of Medicine and Adelaide Center for Neuroscience Research, University of Adelaide, Adelaide, South Australia, Australia (S.A.K.); Department of Cerebrovascular Disease, IRCCS Istituto Neurologico Carlo Besta, Milan, Italy (G.B.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (M.D.); Department of Neurology, John Hunter Hospital, New Lambton Heights, Newcastle, Australia (C.L.); Department of Medical and Molecular Genetics, King's College London, London, United Kingdom (C.M.L.); and Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, United Kingdom (C.M.L.). mt628@medschl.cam.ac.uk.
Background And Purpose:
Evidence from epidemiological studies points to differences in factors predisposing to stroke by age and sex. Whether these arise because of different genetic influences remained untested. Here, we use data from 4 genome-wide association data sets to study the relationship between genetic influence on stroke with both age and sex.
Methods:
Using genomic-relatedness-matrix restricted maximum likelihood methods, we performed 4 analyses: (1) we calculated the genetic correlation between groups divided by age and (2) by sex, (3) we calculated the heritability of age-at-stroke-onset, and (4) we evaluated the evidence that heritability of stroke is greater in women than in men.
Results:
We found that genetic factors influence age at stroke onset (h2 [SE]=18.0 [6.8]; P=0.0038), with a trend toward a stronger influence in women (women: h2 [SE]=21.6 [3.5]; Men: h2 [SE]=13.9 [2.8]). Although a moderate proportion of genetic factors was shared between sexes (rG [SE]=0.68 [0.16]) and between younger and older cases (rG [SE]=0.70 [0.17]), there was evidence to suggest that there are genetic susceptibility factors that are specific to sex (P=0.037) and to younger or older groups (P=0.056), particularly for women (P=0.0068). Finally, we found a trend toward higher heritability of stroke in women although this was not significantly greater than in men (P=0.084).
Conclusions:
Our results indicate that there are genetic factors that are either unique to or have a different effect between younger and older age groups and between women and men. Performing large, well-powered genome-wide association study analyses in these groups is likely to uncover further associations.
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