Extensive sex differences in depression-linked variants functionally assayed in mouse brain [Hippocampus]

Here, we selected >1000 variants from over 30 depression-associated loci using brain epigenomic data, and functionally assayed them using in vivo functional assays in the mouse brain to examine sex-by-genotype interactions. We identify extensive sex-by-allele effects in mature hippocampus, suggesting genetic risk and thus disease mechanisms may be distinct between the sexes. Unbiased informatics approaches indicated a role for nuclear hormone receptors, which was supported by . Further, comparative analysis of allelic function in the neonatal mouse brain, during a key between developmental neonates during the masculinizing testosterone surge, and in the adult hippocampus—a region of interest in depression pathology—but not at 10 days old, a older hormonally quiescent developmental stage juveniles. Our study provides novel insights into depression genetics as influenced by age, biological sex, and cell type, and provides a framework for in vivo parallel assays at a scale not previously shown possible to functionally define interactions between sex and disease variation. n=5 replicates each of AAV9-transduced adult mouse brain tissues: male total hippocampus, female total hippocampus, male Vglut1+ translating-ribosome affinity purification immunoprecipitated RNA fraction, female Vglut1+ translating-ribosome affinity purification immunoprecipitated RNA fraction. Additional grant information: 571009 - Joseph Dougherty - Simons Foundation

本研究利用大脑表观基因组数据，从30余个抑郁症相关基因座（loci）中筛选出1000余个变异位点，并通过小鼠脑内的体内功能实验对其开展功能验证，以探究性别-基因型交互作用。我们在成熟海马体中发现了广泛的等位基因-性别效应，提示遗传风险及对应的疾病机制可能存在性别差异。无偏信息学方法揭示了核激素受体（nuclear hormone receptors）的潜在作用，该结论得到了相关证据的支撑。此外，我们分别在睾酮雄性化关键窗口期的新生小鼠大脑、成年海马体——抑郁症病理研究的目标脑区——中对等位基因功能进行了比较分析，但未在10日龄这一激素活性静止的幼年发育阶段观测到此类效应。本研究为解析受年龄、生物学性别及细胞类型调控的抑郁症遗传学机制提供了全新见解，并构建了一套可开展大规模体内平行实验的研究框架，该实验规模此前尚未实现，可用于功能性界定性别与疾病变异间的交互作用。

样本信息：AAV9（腺相关病毒9型，adeno-associated virus serotype 9）转导的成年小鼠脑组织每组均设置5个生物学重复，具体分组如下：雄性全海马体、雌性全海马体、雄性Vglut1+（囊状谷氨酸转运体1，vesicular glutamate transporter 1）翻译型核糖体亲和纯化免疫沉淀RNA组分、雌性Vglut1+翻译型核糖体亲和纯化免疫沉淀RNA组分。

资助项目信息：571009 —— Joseph Dougherty —— 西蒙斯基金会（Simons Foundation）