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 natural menopause under the age of 40. In the largest study of POI to date, we found limited evidence to support any previously reported autosomal dominant effect. For nearly all heterozygous effects on previously reported POI genes we were able to rule out even modest penetrance, with 99.9% (13,699/13,708) of all identified protein truncating variants found in reproductively healthy women. We found evidence of novel 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. We suggest that the majority of POI cases are likely oligogenic or polygenic in nature, which has major implications for future clinical genetic studies, and genetic counselling for families affected by POI.

John Perry and Eugene Gardner hold shares in and are employees of Adrestia Therapeutics.

This work was funded by the Medical Research Council (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 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 National Institute for Health and Care Research 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. Saleh Shekari was supported by the QUEX Institute (University of Exeter, UK and the University of Queensland, Australia). Stasa Stankovic is supported by the Clare Hall Ivan D. Jankovic PhD scholarship from the University of Cambridge. Anna Murray, Caroline Wright and Michael Weedon are supported by the Medical Research Council (MR/T00200X/1). Katherine Ruth is supported by Cancer Research UK [grant number C18281/A29019]. Gareth Hawkes has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 875534. Gita Mishra is supported by National Health and Medical Research Council Investigator grant (APP2009577). Eva Hoffmann was supported by the ERC (724718-ReCAP), Novo Nordisk Foundation (NNF15COC0016662), the Independent Research Foundation Denmark (0134-00299B), and a grant from the Danish National Research Foundation Centre (6110-00344B).

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