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Differences in Genetic Predisposition to Stroke by Age and Sex
Study Questions:
Are there sex and age differences in the genetic contributions to ischemic stroke risk?
Methods:
The authors pooled data from four genome-wide association studies of stroke done in Europe and Australia. The subjects were genotyped using commercial arrays and 381,428 single-nucleotide polymorphisms were identified. Genomic-relatedness-matrix restricted maximum likelihood analyses (GTCAs) were used to examine the following: age at stroke onset as a quantitative trait, genetic correlation between groups by median age, genetic correlation between groups by sex, and higher heritability of stroke in women than men. GTCA is a technique that can estimate the genetic impact of a condition by using DNA from unrelated individuals rather than the standard approach of examining families. The age of onset as a quantitative trait analysis examined the extent that genetic factors influence age of first stroke. The median age analysis estimated the genetic correlation (rG) between the oldest cases (>72) and the youngest cases (<71). The genetic correlation between groups by sex analysis estimated the rG between stroke cases divided by sex. The evaluation of higher heritability in women than men calculated the heritability of stroke in both sexes.
Results:
There were 5,706 ischemic stroke cases and 7,623 controls in the analyses. Women were older (mean 71.9, standard deviation [SD] 14.5) than men (mean 67.8, SD 12.9) at age of first stroke (p = 9.9 x 10-37). Age of stroke onset was heritable (h2 [SE] = 18.0 [6.8]; p = 0.0038), and this effect was stronger for women than men. There was moderate genetic correlation between younger and older stroke patients (rG [SE] = 0.70 [0.17]), but when the analysis was stratified by sex, a significant difference was found in women, but not men. In the analysis of genetic correlation by sex, the authors found a significant genetic correlation (rG [SE] = 0.68 [0.16]) between sexes, suggesting that a significant portion of the genetic susceptibility factors for stroke are shared between women and men; however, there were also significant differences between the sexes, arguing for specific susceptibility factors for each sex. The analysis of heritability by sex found higher heritability in women (h2 [SE] = 21.6 [3.5]) than men (h2 [SE] = 13.9 [2.8]), although this difference was not significant (p = 0.084).
Conclusions:
The authors found that genetic susceptibility to stroke differs by age and sex. The impact of genetic factors on first stroke is stronger in women than men. While there are genetic effects at play in patients who have a stroke at younger and older ages in both women and men, the effects of genetics on age of stroke seem to be stronger in women.
Perspective:
There are differences in stroke risk factors and outcome after stroke between men and women. It is unknown how much genetic factors contribute to these differences. Prior genome-wide association studies have identified multiple loci that contribute to the risk of stroke, but how these genetic factors interact with age and sex is less clear. This study shows that there are differences in the genetic contribution to stroke risk by age and sex. While genetic factors influence the risk of stroke, they also appear to influence the age of first stroke. These interactions seem to be stronger in women than men. The findings from this study should spur additional work looking at age- and sex-specific genetic influences on ischemic stroke.
Keywords: Age of Onset, DNA, Genetic Predisposition to Disease, Genome-Wide Association Study, Genomics, Glucosides, Ischemia, Nucleotides, Risk Factors, Risk, Stroke, Thiazoles, Sex
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