Birth Weight and Stroke in Adult Life: Genetic Correlation and Causal Inference With Genome-Wide Association Data Sets
Birth Weight and Stroke in Adult Life: Genetic Correlation and Causal Inference With Genome-Wide Association Data Sets
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DOI：
10.3389/fnins.2020.00479
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发表时间：
2020-06-11
影响因子：
4.3
通讯作者：
Zeng, Ping
中科院分区：
文献类型：
--
作者：
Wang, Ting;Tang, Zaixiang;Zeng, Ping
目的已有研究表明，成年后出生体重与中风之间存在负相关，但这种相关性是否为因果关系尚不清楚，这些研究不能区分直接的胎儿效应和间接的母体效应。这项研究的目的是使用新的统计遗传学方法来解开这种关系。方法我们首次使用连锁不平衡分数回归(LDSC)和结合Pleiotroy and Annotation的遗传分析(GPA)来估计出生体重和卒中之间的总体遗传相关性。然后，使用一套调整了胎儿和母亲影响的有效出生体重测量仪，我们进行了两样本孟德尔随机化(MR)，以评估其对中风的因果影响，这是基于大规模全基因组关联研究(GWAS)的汇总统计数据(n=264,498，出生体重和446,696)。我们通过广泛的敏感性分析进一步验证了MR结果。结果LDSC和GPA均显示出生体重和卒中具有共同的母体遗传基础，遗传相关系数估计为-0.176。然而，没有检测到出生体重和中风之间的胎儿遗传相关性。此外，逆方差加权MR显示，出生体重对中风的母亲因果效应为1.12(95%可信区间[CI]1.00-1.27)。出生体重对心栓性卒中(CES)、大动脉卒中(LAS)和小血管卒中(SVS)的母亲OR值分别为1.16(95%CI为0.93~1.43)、1.50(95%CI为1.14~1.96)和1.47(95%CI为1.15~1.87)。相反，没有发现出生体重和中风或亚型之间的胎儿因果关系。这些结果对广泛的敏感性分析是稳健的，Egger回归排除了多效性和多变量MR的可能性，排除了中风其他危险因素的混杂或中介影响的可能性。结论本研究为卒中及其亚型的胎儿发育起源提供了经验性证据。然而，有必要进行进一步的研究，以了解低出生体重在卒中发展中的病理生理学作用。
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.