Shared genetic links between Birth weight and developmental-behavioral disorders

Background: While observational studies have linked birth weight to developmental-behavioral disorders, establishing genetic correlations and causal relationships remains challenging due to potential confounding factors.
Method: We assessed genetic correlations between birth weight and developmental-behavioral disorders using linkage disequilibrium score regression (LDSC). Pleiotropic loci and genes were identified through Pleiotropy Analysis under Composite Null Hypothesis (PLACO). Causal relationships were investigated via Mendelian randomization (MR) analysis.
Result: Significant negative genetic correlations were observed between ADHD and birth weight (fetal: rg=-0.087, 95%CI -0.134 to -0.040; maternal: rg=-0.088, 95%CI -0.139 to -0.0337; maternal effect: rg=-0.107, 95%CI -0.183 to -0.030). We identified 41 pleiotropic genes enriched in cardiovascular, brain, and liver tissues, and 122 pleiotropic loci through eQTL integration. However, MR analysis revealed no causal associations between birth weight and developmental behavioral disorders.
Conclusion: These analyses establish both shared genetic etiology and biological pleiotropy underlying birth weight and developmental-behavioral disorder associations.

研究背景：尽管观察性研究已证实出生体重与发育行为障碍存在关联，但由于潜在混杂因素的存在，明确二者的遗传相关关系与因果关联仍颇具挑战。
研究方法：本研究采用连锁不平衡评分回归（linkage disequilibrium score regression, LDSC）评估出生体重与发育行为障碍间的遗传相关；通过复合零假设多效性分析（Pleiotropy Analysis under Composite Null Hypothesis, PLACO）识别多效性位点与基因；借助孟德尔随机化（Mendelian randomization, MR）分析探究二者的因果关联。
研究结果：本研究观察到注意缺陷多动障碍（ADHD）与出生体重间存在显著负向遗传相关（胎儿层面：rg=-0.087，95%置信区间-0.134至-0.040；母亲层面：rg=-0.088，95%置信区间-0.139至-0.0337；母体效应层面：rg=-0.107，95%置信区间-0.183至-0.030）。共识别出41个富集于心血管、大脑及肝脏组织的多效性基因，以及通过表达数量性状基因座（expression Quantitative Trait Locus, eQTL）整合得到的122个多效性位点。然而孟德尔随机化分析显示，出生体重与发育行为障碍间未存在因果关联。
研究结论：本研究明确了出生体重与发育行为障碍关联背后存在共同的遗传病因学基础与生物学多效性机制。