Abstract
ObjectivePrior studies have shown that there is an inverse association between birth weight and stroke in adulthood; however, whether such association is causal remains yet known and those studies cannot distinguish between the direct fetal effect and the indirect maternal effect. The aim of the study is to untangle such relationship using novel statistical genetic approaches.MethodsWe first utilized linkage disequilibrium score regression (LDSC) and Genetic analysis incorporating Pleiotropy and Annotation (GPA) to estimate the overall genetic correlation between birth weight and stroke. Then, with a set of valid birth-weight instruments which had adjusted fetal and maternal effects, we performed a two-sample Mendelian randomization (MR) to evaluate its causal effect on stroke based summary statistics from large scale genome-wide association study (GWAS) (n = 264,498 for birth weight and 446,696 for stroke). We further validated the MR results with extensive sensitivity analyses.ResultsBoth LDSC and GPA demonstrated significant evidence of shared maternal genetic foundation between birth weight and stroke, with the genetic correlation estimated to −0.176. However, no fetal genetic correlation between birth weight and stroke was detected. Furthermore, the inverse variance weighted MR demonstrated the maternally causal effect of birth weight on stroke was 1.12 (95% confidence interval [CI] 1.00–1.27). The maternal ORs of birth weight on three subtypes of stroke including cardioembolic stroke (CES), large artery stroke (LAS) and small vessel stroke (SVS) were 1.16 (95% CI 0.93–1.43), 1.50 (95% CI 1.14–1.96) and 1.47 (95% CI 1.15–1.87), respectively. In contrast, no fetal causal associations were found between birth weight and stroke or the subtypes. Those results were robust against extensive sensitivity analyses, with Egger regression ruling out the possibility of pleiotropy and multivariable MR excluding the likelihood of confounding or mediation effects of other risk factors of stroke.ConclusionThis study provides empirically supportive evidence on the fetal developmental origins of stroke and its subtypes. However, further investigation is warranted to understand the pathophysiological role of low birth weight in developing stroke.
Highlights
Stroke is primarily caused by brain infarction or intracerebral hemorrhage (ICH) with a neurological deficit of sudden onset (Malik et al, 2018), and it represents one of the leading causes of morbidity and mortality worldwide (Kyu et al, 2018; Roth et al, 2018)
We further validated the Mendelian randomization (MR) results with extensive sensitivity analyses. Both linkage disequilibrium score regression (LDSC) and Genetic analysis incorporating Pleiotropy and Annotation (GPA) demonstrated significant evidence of shared maternal genetic foundation between birth weight and stroke, with the genetic correlation estimated to −0.176
The maternal odds ratio (OR) of birth weight on three subtypes of stroke including cardioembolic stroke (CES), large artery stroke (LAS) and small vessel stroke (SVS) were 1.16, 1.50 and 1.47, respectively
Summary
Stroke is primarily caused by brain infarction (i.e., ischemic stroke) or intracerebral hemorrhage (ICH) with a neurological deficit of sudden onset (Malik et al, 2018), and it represents one of the leading causes of morbidity and mortality worldwide (Kyu et al, 2018; Roth et al, 2018). The role of early fetal growth even before birth was recognized and the hypothesized adverse determinants in utero are related to the risk of developing stroke in adulthood (Eriksson et al, 2000) – a hypothesis referred to as the fetal origins of adult chronic diseases which was first proposed in the late 1980s (Barker, 1990; Lucas et al, 1999; Barker et al, 2002) This hypothesis for fetal developmental programming states the fetus has to adapt to adverse intrauterine exposures (e.g., under-nutrition) by slowing the growth of body, resulting in low birth weight (a commonly employed index of exposure on early growth for intrauterine environment). Many observational studies have provided evidence showing low birth weight associated with enhanced susceptibility to stroke in later life (Rich-Edwards et al, 1997; see Supplementary Table S1 for more information)
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