Causal Relationship Between Sleep Traits and Hypothalamic-Pituitary-Target Gland Axis Function: A Mendelian Randomization Study

Abstract

Background

In recent years, multiple observational studies have confirmed the association between sleep traits and various human physiopathological states. However, the causal relationship between sleep traits and hypothalamic-pituitary-target gland axis (HPTGA) function remains unknown.

Methods

We obtained summary statistics on sleep traits (insomnia, chronotype, and sleep duration (long and short)) from the UK Biobank database. Data related to the HPTGA functions were obtained from the publicly available database. Subsequently, a two-sample Mendelian randomization (MR) analysis was performed to investigate the causal relationship between different sleep traits and the HPTGA function. Reverse MR analysis was conducted to examine the direction of causality.

Results

The MR analysis results suggested that chronotype is associated with decreased levels of six hormones in HPTGA. Sleep duration was causally associated with decreased levels of free thyroxine and progesterone. Both long and short sleep durations are detrimental to the secretion of prolactin-releasing peptide, somatostatin, and plasma cortisol, while short sleep duration can promote progesterone secretion. After gender stratification, we found that female reproductive function is more susceptible to the influence of unfavorable sleep traits.

Conclusion

Our MR analysis indicated a significant causal association between chronotype and suppressed gonadal function in healthy adult humans, with no apparent gender-specific effect. Extreme sleep durations were also found to be detrimental to the maintenance of normal HPTGA secretion function. Compared to males, gonadal function in the female cohort is more susceptible to extreme sleep habits. Subsequent observational studies are urgently needed to confirm the underlying mechanisms.

Keywords:

• hypothalamo-hypophyseal-target gland axis
• sleep traits
• causal inference
• Mendelian randomization

Abbreviations

MR, Mendelian randomization; CRFBP, corticotropin-releasing factor-binding protein; PRL, prolactin; DHEA, dehydroepiandrosterone; TT, total testosterone; BT, bioavailable testosterone; FT4, free thyroxine; P4, progesterone; PrRP, prolactin-releasing peptide; SRIF, somatostatin; E2, estradiol; HPTGA, hypothalamic-pituitary-target gland axis; SNPs, single-nucleotide polymorphisms; TRH, thyrotropin-releasing hormone; GnRH, gonadotropin-releasing hormone; GH, growth hormone; LH, luteinizing hormone; FSH, follicle-stimulating hormone; TSH, thyroid stimulating hormone; ACTH, adrenocorticotropic hormone; TPO, thyroid peroxidase; Tg, thyroglobulin; NHSBT, England’s National Health Service Blood and Transplant; SHBG, sex hormone-binding globulin; ALD, IVs, aldosterone; instrumental variables; MAF, minor allele frequency; LD, linkage disequilibrium; ML, maximum likelihood; IVW, inverse variance weighted; HPO, hypothalamic-pituitary-ovarian; HPT, hypothalamic-pituitary-thyroid; HPA, hypothalamic‒pituitary‒adrenal.

Data Sharing Statement

The datasets analysed in this study are publicly available summary statistics. Genetic instruments can be obtained from the individual referenced papers.^19–21 All summary data of HPTGA can be downloaded from the following website: UK Biobank database (https://www.nealelab.is/uk-biobank), the IEU Open GWAS project (https://gwas.mrcieu.ac.uk/), the Thyroidomics Consortium (https://transfer.sysepi.medizin.uni-greifswald.de/thyroidomics/) and the Zenodo database (https://zenodo.org/).

Ethics Approval and Consent to Participate

All the contents of this study have been reviewed and approved by the Ethics Committee of the second affiliated hospital of Chongqing medical university and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Acknowledgments

All authors of this paper would like to extend their gratitude to all the participants involved in the GWAS cohorts included in this study, as well as to the IEU Open GWAS project, UK Biobank, Thyroidomics Consortium, Zenodo database, CORNET, and other research teams and researchers. We sincerely appreciate the GWAS summary statistics data provided by the aforementioned teams and individuals.

Disclosure

There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Additional information

Funding

This research was supported by the science and technology innovation project of Chongqing Municipal Science and Technology Commission (Number: cstc2015shmszx120054); Joint Key Projects of Chongqing Science and Technology Bureau and Health Care Commission (Number: 2022ZDXM004); Talent Program Project of Chongqing Science and Technology Bureau (Number: cstc2021ycjh-hgzxm0050).