Abstract
Premature ovarian insufficiency (POI) affects 1% of women and is a leading cause of infertility. It is often considered to be a monogenic disorder, with pathogenic variants in ~100 genes described in the literature. We sought to systematically evaluate the penetrance of variants in these genes using exome sequence data in 104,733 women from the UK Biobank, 2,231 (1.14%) of whom reported at natural menopause under the age of 40 years. We found limited evidence to support any previously reported autosomal dominant effect. For nearly all heterozygous effects on previously reported POI genes, we ruled out even modest penetrance, with 99.9% (13,699 out of 13,708) of all protein-truncating variants found in reproductively healthy women. We found evidence of haploinsufficiency effects in several genes, including TWNK (1.54 years earlier menopause, P = 1.59 × 10−6) and SOHLH2 (3.48 years earlier menopause, P = 1.03 × 10−4). Collectively, our results suggest that, for the vast majority of women, POI is not caused by autosomal dominant variants either in genes previously reported or currently evaluated in clinical diagnostic panels. Our findings, plus previous studies, suggest that most POI cases are likely oligogenic or polygenic in nature, which has important implications for future clinical genetic studies, and genetic counseling for families affected by POI.
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Data availability
We used publicly available individual-level genotype and phenotype data from the UK Biobank (https://biobank.ndph.ox.ac.uk/showcase/). Access to these data needs to be requested from the UK Biobank (https://www.ukbiobank.ac.uk/enable-your-research/apply-for-access). This research was conducted using the UK Biobank Resource under application 9905 (University of Cambridge) and 9072 and 871 (University of Exeter). POI genes were identified from the GEL Panel App (https://panelapp.genomicsengland.co.uk/panels/155/). Genes were annotated with pathogenicity constraint metrics from gnomAD v.2.1.1.
References
Wesevich, V., Kellen, A. N. & Pal, L. Recent advances in understanding primary ovarian insufficiency. F1000Res 9, F1000 Faculty Rev-1101 (2020).
Rudnicka, E. et al. Premature ovarian insufficiency—aetiopathology, epidemiology, and diagnostic evaluation. Prz. Menopauzalny 17, 105–108 (2018).
Coulam, C. B., Adamson, S. C. & Annegers, J. F. Incidence of premature ovarian failure. Obstet. Gynecol. 67, 604–606 (1986).
Golezar, S., Ramezani Tehrani, F., Khazaei, S., Ebadi, A. & Keshavarz, Z. The global prevalence of primary ovarian insufficiency and early menopause: a meta-analysis. Climacteric 22, 403–411 (2019).
Harlow, B. L. & Signorello, L. B. Factors associated with early menopause. Maturitas 35, 3–9 (2000).
Goswami, D. & Conway, G. S. Premature ovarian failure. Hum. Reprod. Update 11, 391–410 (2005).
Szeliga, A. et al. Autoimmune diseases in patients with premature ovarian insufficiency—our current state of knowledge. Int. J. Mol. Sci. 22, 2594 (2021).
Fortuño, C. & Labarta, E. Genetics of primary ovarian insufficiency: a review. J. Assist. Reprod. Genet. 31, 1573–1585 (2014).
Venturella, R. et al. The genetics of non-syndromic primary ovarian insufficiency: a systematic review. Int. J. Fertil. Steril. 13, 161–168 (2019).
Perry, J. R. et al. A genome-wide association study of early menopause and the combined impact of identified variants. Hum. Mol. Genet. 22, 1465–1472 (2013).
Ruth, K. S. et al. Genetic insights into biological mechanisms governing human ovarian ageing. Nature 596, 393–397 (2021).
Qin, Y. et al. ESR1, HK3 and BRSK1 gene variants are associated with both age at natural menopause and premature ovarian failure. Orphanet. J. Rare Dis. 7, 5 (2012).
van Kasteren, Y. M. et al. Familial idiopathic premature ovarian failure: an overrated and underestimated genetic disease? Hum. Reprod. 14, 2455–2459 (1999).
Pu, D., Xing, Y., Gao, Y., Gu, L. & Wu, J. Gene variation and premature ovarian failure: a meta-analysis. Eur. J. Obstet. Gynecol. Reprod. Biol. 182, 226–237 (2014).
Persani, L., Rossetti, R., Cacciatore, C. & Bonomi, M. Primary ovarian insufficiency: X chromosome defects and autoimmunity. J. Autoimmun. 33, 35–41 (2009).
Day, F. R. et al. Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair. Nat. Genet. 47, 1294–1303 (2015).
Liu, H. et al. Whole-exome sequencing in patients with premature ovarian insufficiency: early detection and early intervention. J. OVarian Res. 13, 114 (2020).
França, M. M. & Mendonca, B. B. Genetics of primary ovarian insufficiency in the next-generation sequencing era. J. Endocr. Soc. 4, bvz037 (2020).
Jin, H. et al. Identification of potential causal variants for premature ovarian failure by whole exome sequencing. BMC Med. Genomics 13, 159 (2020).
Patiño, L. C. et al. New mutations in non-syndromic primary ovarian insufficiency patients identified via whole-exome sequencing. Hum. Reprod. 32, 1512–1520 (2017).
Chapman, C., Cree, L. & Shelling, A. N. The genetics of premature ovarian failure: current perspectives. Int J. Women’s Health 7, 799–810 (2015).
Szustakowski, J. D. et al. Advancing human genetics research and drug discovery through exome sequencing of the UK Biobank. Nat. Genet. 53, 942–948 (2021).
Gardner, E. J. et al. Reduced reproductive success is associated with selective constraint on human genes. Nature 603, 858–863 (2022).
Karczewski, K. J. et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 581, 434–443 (2020).
Li, X. et al. Dynamic incorporation of multiple in silico functional annotations empowers rare variant association analysis of large whole-genome sequencing studies at scale. Nat. Genet. 52, 969–983 (2020).
Minikel, E. V. et al. Evaluating drug targets through human loss-of-function genetic variation. Nature 581, 459–464 (2020).
Stankovic, S. et al. Genetic susceptibility to earlier ovarian ageing increases de novo mutation rate in offspring. Preprint at medRxiv https://doi.org/10.1101/2022.06.23.22276698 (2022).
Korhonen, J. A., Gaspari, M. & Falkenberg, M. TWINKLE Has 5′ -> 3′ DNA helicase activity and is specifically stimulated by mitochondrial single-stranded DNA-binding protein. J. Biol. Chem. 278, 48627–48632 (2003).
Khan, I. et al. Biochemical characterization of the human mitochondrial replicative twinkle helicase: substrate specificity, DNA branch migration and ability to overcome blockades to DNA unwinding. J. Biol. Chem. 291, 14324–14339 (2016).
Bashamboo, A. & McElreavey, K. NR5A1/SF-1 and development and function of the ovary. Ann. Endocrinol. (Paris) 71, 177–182 (2010).
Choi, Y., Yuan, D. & Rajkovic, A. Germ cell-specific transcriptional regulator sohlh2 is essential for early mouse folliculogenesis and oocyte-specific gene expression. Biol. Reprod. 79, 1176–1182 (2008).
Cerván-Martín, M. et al. Intronic variation of the SOHLH2 gene confers risk to male reproductive impairment. Fertil. Steril. 114, 398–406 (2020).
Barros, F., Carvalho, F., Barros, A. & Dória, S. Premature ovarian insufficiency: clinical orientations for genetic testing and genetic counseling. Porto Biomed. J. 5, e62 (2020).
Stark, Z. et al. Scaling national and international improvement in virtual gene panel curation via a collaborative approach to discordance resolution. Am. J. Hum. Genet 108, 1551–1557 (2021).
Lerat, J. et al. An application of NGS for molecular investigations in Perrault syndrome: study of 14 families and review of the literature. Hum. Mutat. 37, 1354–1362 (2016).
Richards, S. et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet. Med. 17, 405–424 (2015).
Rouen, A. et al. Whole exome sequencing in a cohort of familial premature ovarian insufficiency cases reveals a broad array of pathogenic or likely pathogenic variants in 50% of families. Fertil. Steril. 117, 843–853 (2022).
Yang, X. et al. Gene variants identified by whole-exome sequencing in 33 French women with premature ovarian insufficiency. J. Assist. Reprod. Genet. 36, 39–45 (2019).
Ke, H. et al. Landscape of pathogenic mutations in premature ovarian insufficiency. Nat. Med. 29, 483–492 (2023).
Li, Z. et al. Validation of UK Biobank data for mental health outcomes: a pilot study using secondary care electronic health records. Int J. Med Inf. 160, 104704 (2022).
Fry, A. et al. Comparison of sociodemographic and health-related characteristics of UK Biobank participants with those of the general population. Am. J. Epidemiol. 186, 1026–1034 (2017).
Pirastu, N. et al. Genetic analyses identify widespread sex-differential participation bias. Nat. Genet. 53, 663–671 (2021).
Murray, A. et al. Population-based estimates of the prevalence of FMR1 expansion mutations in women with early menopause and primary ovarian insufficiency. Genet. Med. 16, 19–24 (2014).
Backman, J. D. et al. Exome sequencing and analysis of 454,787 UK Biobank participants. Nature 599, 628–634 (2021).
Sudlow, C. et al. UK Biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLoS Med. 12, e1001779 (2015).
McLaren, W. et al. The Ensembl variant effect predictor. Genome Biol. 17, 122 (2016).
Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).
Robinson, J. T., Thorvaldsdóttir, H., Wenger, A. M., Zehir, A. & Mesirov, J. P. Variant review with the integrative genomics viewer. Cancer Res. 77, e31–e34 (2017).
Robinson, J. T. et al. Integrative genomics viewer. Nat. Biotechnol. 29, 24–26 (2011).
Mbatchou, J. et al. Computationally efficient whole-genome regression for quantitative and binary traits. Nat. Genet. 53, 1097–1103 (2021).
Tyrrell, J. et al. Using genetics to understand the causal influence of higher BMI on depression. Int J. Epidemiol. 48, 834–848 (2019).
Loh, P. R. et al. Efficient Bayesian mixed-model analysis increases association power in large cohorts. Nat. Genet. 47, 284–290 (2015).
Bycroft, C. et al. The UK Biobank resource with deep phenotyping and genomic data. Nature 562, 203–209 (2018).
Gardner, E. J. et al. Damaging missense variants in IGF1R implicate a role for IGF-1 resistance in the aetiology of type 2 diabetes.Cell Genom. 2, 100208 (2022).
Seabold, S. & Perktold, J. Statsmodels: econometric and statistical modeling with Python. In Proc. 9th Python in Science Conference (eds van der Walt, S. & Millman, J.) (SCiPy, 2010).
Acknowledgements
This work was funded by the Medical Research Council (MRC) (Unit programs: MC_UU_12015/2, MC_UU_00006/2, MC_UU_12015/1, and MC_UU_00006/1). The views expressed are those of the author(s) and not necessarily those of the National Institute for Health and Care Research (NIHR) or the Department of Health and Social Care. The authors acknowledge the use of the University of Exeter High-Performance Computing facility in carrying out this work, funded by a MRC Clinical Research Infrastructure award (MRC Grant: MR/M008924/1). This study was supported by the NIHR Exeter Biomedical Research Centre. For the purpose of open access, the author has applied a Creative Commons Attribution (CC BY) license to any Author Accepted Manuscript version arising. S. Shekari was supported by the QUEX Institute (University of Exeter, UK and the University of Queensland, Australia). S. Stankovic is supported by the Clare Hall Ivan D. Jankovic PhD scholarship from the University of Cambridge. A.M., C.F.W. and M.N.W. are supported by the MRC (MR/T00200X/1). K.S.R. is supported by Cancer Research UK (grant number C18281/A29019). G.H. has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No. 875534. G.D.M. is supported by National Health and Medical Research Council Investigator grant (APP2009577). E.R.H. was supported by the European Research Council (724718-ReCAP), Novo Nordisk Foundation (NNF15COC0016662; NNF0066487), the Independent Research Foundation Denmark (0134-00299B) and a grant from the Danish National Research Foundation Centre (6110-00344B).
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All authors were involved in reviewing and editing the manuscript. The study was conceived by A. Murray and J.R.B.P. Lead analysts were S. Shekari and S. Stankovic, with additional analyses by E.J.G. and K.A.K. Exome sequencing pipelines were developed by E.J.G., G.H., R.N.B., A. Mörseburg, A.R.W., F.R.D., C.F.W., M.N.W., K.S.R., J.R.B.P. and A. Murray. Clinical interpretation was provided by G.D.M., E.R.H., J.B. J.K.P. and K.K.O.
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J.R.B.P. and E.J.G. hold shares in and are employees of Adrestia Therapeutics. The other authors declare no competing interests.
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Extended data
Extended Data Fig. 1
Bars to the right of the dotted red line represent those with menopause ≥40 years.
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Excel table with multiple sheets of additional data.
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Shekari, S., Stankovic, S., Gardner, E.J. et al. Penetrance of pathogenic genetic variants associated with premature ovarian insufficiency. Nat Med 29, 1692–1699 (2023). https://doi.org/10.1038/s41591-023-02405-5
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DOI: https://doi.org/10.1038/s41591-023-02405-5
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