Dataset Information

Birth Weight and Stroke in Adult Life: Genetic Correlation and Causal Inference With Genome-Wide Association Data Sets.

ABSTRACT:

Objective

Prior 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.

Methods

We 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.

Results

Both 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.

Conclusion

This 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.

SUBMITTER: Wang T

PROVIDER: S-EPMC7301963 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Purpose: Birth weight has a profound long-term impact on individual's predisposition to various diseases at adulthood-a hypothesis commonly referred to as the fetal origins of adult diseases. However, it is not fully clear to what extent the fetal origins of adult diseases hypothesis holds and it is also not completely known what types of adult diseases are causally affected by birth weight. Materials and methods: Mendelian randomization using multiple genetic instruments associated with birth weight was performed to explore the causal relationship between birth weight and adult diseases. The causal relationship between birth weight and 21 adult diseases as well as 38 other complex traits was examined based on data collected from 37 large-scale genome-wide association studies with up to 340,000 individuals of European ancestry. Causal effects of birth weight were estimated using inverse-variance weighted methods. The identified causal relationships between birth weight and adult diseases were further validated through extensive sensitivity analyses, bias calculation, and simulations. Results: Among the 21 adult diseases, three were identified to be inversely causally affected by birth weight after the Bonferroni correction. The measurement unit of birth weight was defined as its standard deviation (i.e., 488 g), and one unit lower birth weight was causally related to an increased risk of coronary artery disease (CAD), myocardial infarction (MI), type 2 diabetes (T2D), and BMI-adjusted T2D, with the estimated odds ratios of 1.34 [95% confidence interval (CI) 1.17-1.53], 1.30 (95% CI 1.13-1.51), 1.41 (95% CI 1.15-1.73), and 1.54 (95% CI 1.25-1.89), respectively. All these identified causal associations were robust across various sensitivity analyses that guard against various confounding due to pleiotropy or maternal effects as well as reverse causation. In addition, analysis on 38 additional complex traits did not identify candidate traits that may mediate the causal association between birth weight and CAD/MI/T2D. Conclusions: The results suggest that lower birth weight is causally associated with an increased risk of CAD, MI, and T2D in later life, supporting the fetal origins of adult diseases hypothesis.