Department of Endocrinology and Diabetes, Royal Perth Hospital, Perth, WA, 6009, Australia.
Medical School, University of Western Australia, Nedlands, WA, Australia.
BMC Genomics. 2024 Feb 26;25(1):208. doi: 10.1186/s12864-024-09990-w.
Polycystic ovary syndrome (PCOS) is a complex multifactorial disorder with a substantial genetic component. However, the clinical manifestations of PCOS are heterogeneous with notable differences between lean and obese women, implying a different pathophysiology manifesting in differential body mass index (BMI). We performed a meta-analysis of genome-wide association study (GWAS) data from six well-characterised cohorts, using a case-control study design stratified by BMI, aiming to identify genetic variants associated with lean and overweight/obese PCOS subtypes.
The study comprised 254,588 women (5,937 cases and 248,651 controls) from individual studies performed in Australia, Estonia, Finland, the Netherlands and United States of America, and separated according to three BMI stratifications (lean, overweight and obese). Genome-wide association analyses were performed for each stratification within each cohort, with the data for each BMI group meta-analysed using METAL software. Almost half of the total study population (47%, n = 119,584) were of lean BMI (≤ 25 kg/m). Two genome-wide significant loci were identified for lean PCOS, led by rs12000707 within DENND1A (P = 1.55 × 10) and rs2228260 within XBP1 (P = 3.68 × 10). One additional locus, LINC02905, was highlighted as significantly associated with lean PCOS through gene-based analyses (P = 1.76 × 10). There were no significant loci observed for the overweight or obese sub-strata when analysed separately, however, when these strata were combined, an association signal led by rs569675099 within DENND1A reached genome-wide significance (P = 3.22 × 10) and a gene-based association was identified with ERBB4 (P = 1.59 × 10). Nineteen of 28 signals identified in previous GWAS, were replicated with consistent allelic effect in the lean stratum. There were less replicated signals in the overweight and obese groups, and only 4 SNPs were replicated in each of the three BMI strata.
Genetic variation at the XBP1, LINC02905 and ERBB4 loci were associated with PCOS within unique BMI strata, while DENND1A demonstrated associations across multiple strata, providing evidence of both distinct and shared genetic features between lean and overweight/obese PCOS-affected women. This study demonstrated that PCOS-affected women with contrasting body weight are not only phenotypically distinct but also show variation in genetic architecture; lean PCOS women typically display elevated gonadotrophin ratios, lower insulin resistance, higher androgen levels, including adrenal androgens, and more favourable lipid profiles. Overall, these findings add to the growing body of evidence supporting a genetic basis for PCOS as well as differences in genetic patterns relevant to PCOS BMI-subtype.
多囊卵巢综合征（PCOS）是一种复杂的多因素疾病，具有重要的遗传成分。然而，PCOS 的临床表现具有异质性，瘦型和肥胖型女性之间存在显著差异，这意味着不同的病理生理学表现出不同的身体质量指数（BMI）。我们对来自六个特征明确的队列的全基因组关联研究（GWAS）数据进行了荟萃分析，采用 BMI 分层的病例对照研究设计，旨在鉴定与瘦型和超重/肥胖型 PCOS 亚型相关的遗传变异。
该研究包括来自澳大利亚、爱沙尼亚、芬兰、荷兰和美国的个体研究中的 254588 名女性（5937 例病例和 248651 例对照），并根据三种 BMI 分层（瘦型、超重和肥胖型）进行了分离。对每个队列中的每个分层进行了全基因组关联分析，并使用 METAL 软件对每个 BMI 组的数据进行了荟萃分析。总研究人群的近一半（47%，n=119584）为瘦型 BMI（≤25kg/m）。鉴定到两个与瘦型 PCOS 相关的全基因组显著位点，由 DENND1A 内的 rs12000707 （P=1.55×10）和 XBP1 内的 rs2228260 （P=3.68×10）主导。通过基因分析突出了 LINC02905 与瘦型 PCOS 显著相关（P=1.76×10）。当分别分析超重或肥胖亚层时，没有观察到显著的位点，但当这些亚层合并时，由 DENND1A 内的 rs569675099 主导的关联信号达到全基因组显著水平（P=3.22×10），并鉴定到与 ERBB4 的基因关联（P=1.59×10）。在之前的 GWAS 中鉴定到的 28 个信号中的 19 个在瘦型亚层中具有一致的等位基因效应得到了复制。在超重和肥胖组中复制的信号较少，只有 4 个 SNP 在每个 BMI 亚层中得到了复制。
XBP1、LINC02905 和 ERBB4 基因座的遗传变异与特定 BMI 亚层的 PCOS 相关，而 DENND1A 则在多个亚层中表现出关联，为瘦型和超重/肥胖型 PCOS 女性之间的独特和共同遗传特征提供了证据。本研究表明，具有不同体重的 PCOS 女性不仅表型不同，而且遗传结构也存在差异；瘦型 PCOS 女性通常表现出升高的促性腺激素比值、较低的胰岛素抵抗、较高的雄激素水平，包括肾上腺雄激素，以及更有利的脂质谱。总的来说，这些发现增加了越来越多的证据支持 PCOS 的遗传基础以及与 PCOS BMI 亚型相关的遗传模式的差异。
