DataSheet1_Educational attainment and offspring birth weight: A bidirectional Mendelian randomization study.docx

Background: The association between educational attainment (EA) and offspring birth weight (BW) has been reported by several traditional epidemiological studies. However, evidence for this association tends to be mixed and confounded. This study aimed to investigate the causal association between EA of parents and offspring BW.
Methods: Here, we carried out a two-sample bidirectional Mendelian randomization (MR) analysis to examine the causal association between EA of males (n = 131,695) and females (n = 162,028) and offspring BW using genetic instruments. Summary statistics of EA associated single nucleotide polymorphisms (SNPs) were extracted from a GWAS incorporating 293,723 individuals of European descent performed by the Social Science Genetic Association Consortium (SSGAC), and the effects of these SNPs on offspring BW were estimated using a GWAS meta-analysis of 86,577 participants of European descent from 25 studies. Univariable MR analyses were conducted using the inverse-variance weighted (IVW) method and four other methods. Further sensitivity analyses were carried out to test the viability of the results. Multivariable MR was used to examine the confounders between the exposure and outcome.
Results: The result shows evidence that the offspring BW is positively causally affected by female EA. Each one standard deviation (SD) increase in female EA was associated with 0.24 SD higher of offspring BW (95% confidence interval [CI], 0.10 to 0.37, p < 0.001 for the IVW method). Similarly, change in offspring BW was 0.21 SD (95% CI: 0.07 to 0.34, p = 2.82 × 10–3) per one SD higher in male EA. No causal effect of BW on EA was found by any of the five methods. The causal association between female EA and offspring BW maintained after adjusting for alcoholic drinks per week and BMI. The effect of male EA on offspring BW was attenuated when we adjusted for BMI and alcoholic drinks per week using multivariable MR analysis.
Conclusion: Our study indicated that female EA is positively causally associated with offspring BW. The association between male EA and offspring BW may be confounded by alcoholic drinks per week and BMI.

背景：多项传统流行病学研究均已报道教育程度（Educational Attainment, EA）与子代出生体重（Offspring Birth Weight, BW）之间存在关联。然而，此类关联的相关证据往往存在不一致性且易受混杂因素干扰。本研究旨在探究父母的教育程度与子代出生体重之间的因果关联。
方法：本研究采用两样本双向孟德尔随机化（two-sample bidirectional Mendelian randomization, MR）分析方法，借助遗传工具变量，探究男性（n=131695）与女性（n=162028）的教育程度与子代出生体重之间的因果关联。教育程度相关单核苷酸多态性（single nucleotide polymorphisms, SNPs）的汇总统计量来源于社会科学遗传关联联合会（Social Science Genetic Association Consortium, SSGAC）开展的一项纳入293723名欧洲血统个体的全基因组关联研究（Genome-Wide Association Study, GWAS）；上述单核苷酸多态性对子代出生体重的效应则通过对来自25项研究、共86577名欧洲血统参与者的全基因组关联研究荟萃分析进行估算。单变量孟德尔随机化分析采用逆方差加权（inverse-variance weighted, IVW）法及其他四种方法开展。后续进一步开展敏感性分析以验证研究结果的可靠性。多变量孟德尔随机化分析则用于探究暴露因素与结局之间的混杂因素。
结果：研究结果表明，女性教育程度对子代出生体重存在正向因果影响。女性教育程度每增加1个标准差（standard deviation, SD），子代出生体重平均升高0.24个标准差（95%置信区间[CI]：0.10~0.37，逆方差加权法检验p<0.001）。类似地，男性教育程度每增加1个标准差，子代出生体重升高0.21个标准差（95%CI：0.07~0.34，p=2.82×10^-3）。五种分析方法均未发现子代出生体重对教育程度存在因果效应。在校正每周饮酒量与体质指数（Body Mass Index, BMI）后，女性教育程度与子代出生体重之间的因果关联依然保持显著。通过多变量孟德尔随机化分析校正体质指数与每周饮酒量后，男性教育程度对子代出生体重的效应出现减弱。
结论：本研究表明，女性教育程度与子代出生体重存在正向因果关联；而男性教育程度与子代出生体重之间的关联可能受每周饮酒量及体质指数的混杂影响。