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.

背景：尽管观察性研究已将出生体重与发育行为障碍建立关联，但由于潜在混杂因素的存在，明确二者的遗传相关性与因果关系仍颇具挑战。方法：本研究采用连锁不平衡得分回归（linkage disequilibrium score regression, LDSC）分析出生体重与发育行为障碍之间的遗传相关性；通过复合零假设下的多效性分析（Pleiotropy Analysis under Composite Null Hypothesis, PLACO）鉴定多效性位点与基因；并借助孟德尔随机化（Mendelian randomization, MR）分析探究二者的因果关系。结果：注意缺陷多动障碍（attention-deficit/hyperactivity disorder, ADHD）与出生体重之间存在显著负向遗传相关性：胎儿层面rg=-0.087，95%置信区间（CI）为-0.134至-0.040；母体层面rg=-0.088，95%置信区间为-0.139至-0.0337；母体效应层面rg=-0.107，95%置信区间为-0.183至-0.030。本研究通过整合表达数量性状位点（expression quantitative trait locus, eQTL）数据，鉴定出41个富集于心血管、脑与肝脏组织的多效性基因，以及122个多效性位点。但孟德尔随机化分析结果显示，出生体重与发育行为障碍之间未发现因果关联。结论：本研究的一系列分析证实，出生体重与发育行为障碍之间的关联存在共同的遗传病因学基础与生物学多效性机制。