Gene regulatory activity associated with PCOS reveals DENND1A-dependent testosterone production

Polycystic Ovary Syndrome (PCOS) is a leading cause of infertility. About 5 million women in the US have PCOS, making it the most prevalent endocrine disorder among menstruating people. Despite that prevalence, the underlying causes remain unknown. Genome-wide association studies (GWAS) have identified non-coding genetic variation associated with PCOS risk and identifying the underlying molecular mechanisms is currently a major opportunity for improving diagnosis and treatment. We report the discovery of gene regulatory mechanisms that help explain genetic association with PCOS in the GATA4, FSHB and DENND1A loci. We based those findings using a combination of high throughput reporter assays, CRISPR-based epigenome editing, and genetic association analysis from PCOS case and control populations. In addition, we found that elevated endogenous DENND1A expression causes elevated testosterone levels, a hallmark PCOS phenotype. These results further highlight the potential for combining genetic variant analyses with experimental approaches to fine map genetic associations with disease risk. 3 input STARR-seq libraries, 3 output STARR-seq libraries in H295R and COV434 cell lines; 2 replicates of ATAC-seq libraries for H295R and COV434 cell lines; 4 replicates each of H295R cells treated with 10uM forskolin or DMSO control

多囊卵巢综合征（Polycystic Ovary Syndrome, PCOS）是不孕症的首要致病因素。美国约有500万女性罹患该病，使其成为月经人群中最为普遍的内分泌紊乱疾病。尽管患病率颇高，但其潜在致病机制仍未明确。全基因组关联研究（Genome-wide association studies, GWAS）已发现与PCOS风险相关的非编码遗传变异，而阐明其潜在分子机制目前是改善该病诊断与治疗的重要契机。本研究揭示了可解释GATA4、FSHB及DENND1A基因座与PCOS遗传关联的基因调控机制。相关发现依托高通量报告基因检测、基于CRISPR的表观基因组编辑技术，以及针对PCOS病例与对照人群的遗传关联分析联合完成。此外，本研究发现内源性DENND1A表达上调会导致睾酮水平升高，这是PCOS的典型表型特征。上述结果进一步凸显了将遗传变异分析与实验方法相结合，以精细定位疾病风险相关遗传关联的研究潜力。本数据集包含：H295R与COV434细胞系中的3个输入STARR-seq文库、3个输出STARR-seq文库；H295R与COV434细胞系的ATAC-seq文库各2次生物学重复；分别用10μM福司柯林（forskolin）或二甲基亚砜（DMSO）对照处理的H295R细胞，每组各设置4次生物学重复。