Genetic factors underlying insomnia and ovarian insufficiency

Abstract

Premature ovarian insufficiency (POI) is characterized by a loss of regular hormone production and egg release in women below the age of 40 years, which often leads to infertility, vaginal dryness and dysfunctional sleep. Acknowledging the common co-occurrence of insomnia and POI, we tested the overlap between POI and insomnia-associated genes, which were implicated in previous large-scale populational genetics efforts. Among the 27 overlapping genes, three pathways were found as enriched: DNA replication, homologous recombination and Fanconi anemia. We then describe biological mechanisms, which link these pathways to a dysfunctional regulation and response to oxidative stress. We propose that oxidative stress may correspond to one of the convergent cellular processes between ovarian malfunction and insomnia pathogenic etiology. This overlap might also be driven by cortisol release associated with dysregulated DNA repair mechanisms. Benefiting from the enormous advances in populational genetics studies, this study provides a novel outlook on the relationship between insomnia and POI. The shared genetic factors and critical biological nodes between these two comorbidities may lead to identification of putative pharmacological and therapeutical targets, which can leverage novel approaches to treat or alleviate their symptoms.

摘要

早发性卵巢功能不全是指女性在40岁以前失去正常的激素分泌和排卵, 这通常导致不孕、阴道干涩和睡眠障碍。考虑到失眠与POI的共存性, 我们测试了 POI 与失眠相关基因之间的重叠性, 这些基因在之前的大规模群体遗传学研究中被发现。在27个重叠基因中, 发现了三种途径富集: DNA复制、同源重组和范科尼贫血。然后, 我们描述了生物学机制, 将这些途径与氧化应激的功能失调调节和反应联系起来。我们认为, 氧化应激可能是卵巢功能失调与失眠病因之间的一个共同细胞过程。这种重叠也可能是由皮质醇释放引起的, 皮质醇释放与DNA修复机制失调有关。得益于人群遗传学研究的巨大进展, 这项研究为失眠和POI之间的关系提供了一个新的视角。这两种合并症之间共同的遗传因素和关键的生物节点可能会有助于潜在药理和治疗靶点的确定, 从而利用新方法来治疗或缓解其症状。

Keywords:

• Sleep
• insomnia
• premature ovarian insufficiency
• ovary
• DNA repair
• gene
• oxidative stress

Potential conflict of interest

No potential conflict of interest was reported by the authors.

Source of funding

This work was supported by Associação Fundo de Incentivo à Pesquisa (AFIP); Fundação de Amparo à Pesquisa do Estado de São Paulo [FAPESP, 2021/09089-0; recipient M.M.-O.]); Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, recipients M.L.A. and H.H.).