Genome-wide analyses identify 25 infertility loci and relationships with reproductive traits across the allele frequency spectrum

Samvida S. Venkatesh; Laura B.L. Wittemans; Duncan S. Palmer; Nikolas A. Baya; Teresa Ferreira; Barney Hill; Frederik Heymann Lassen; Melody J. Parker; Saskia Reibe; Ahmed Elhakeem; Karina Banasik; Mie T. Bruun; Christian Erikstrup; Bitten Aagard Jensen; Anders Juul; Christina Mikkelsen; Henriette S. Nielsen; Sisse R. Ostrowski; Ole B. Pedersen; Palle Duun Rohde; Erik Sørensen; Henrik Ullum; David Westergaard; Asgeir Haraldsson; Hilma Holm; Ingileif Jonsdottir; Isleifur Olafsson; Thora Steingrimsdottir; Valgerdur Steinthorsdottir; Gudmar Thorleifsson; Jessica Figueredo; Minna K. Karjalainen; Anu Pasanen; Benjamin M. Jacobs; Georgios Kalantzis; Nikki Hubers; David A. van Heel; Georgi Hudjashov; Mari Nelis; Tõnu Esko; Lili Milani; Andres Metspalu; Reedik Mägi; Jaak Vilo; Sulev Reisberg; Sven Laur; Raivo Kolde; Bitten Aagard Jensen; Minna K. Karjalainen; Mette Nyegaard; Genes & Health Research Team; Estonian Biobank Research Team; Estonian Health Informatics Research Team; DBDS Genomic Consortium; FinnGen

doi:10.1038/s41588-025-02156-8

Genome-wide analyses identify 25 infertility loci and relationships with reproductive traits across the allele frequency spectrum

Samvida S. Venkatesh^*, Laura B.L. Wittemans, Duncan S. Palmer, Nikolas A. Baya, Teresa Ferreira, Barney Hill, Frederik Heymann Lassen, Melody J. Parker, Saskia Reibe, Ahmed Elhakeem, Karina Banasik, Mie T. Bruun, Christian Erikstrup, Bitten Aagard Jensen, Anders Juul, Christina Mikkelsen, Henriette S. Nielsen, Sisse R. Ostrowski, Ole B. Pedersen, Palle Duun RohdeErik Sørensen, Henrik Ullum, David Westergaard, Asgeir Haraldsson, Hilma Holm, Ingileif Jonsdottir, Isleifur Olafsson, Thora Steingrimsdottir, Valgerdur Steinthorsdottir, Gudmar Thorleifsson, Jessica Figueredo, Minna K. Karjalainen, Anu Pasanen, Benjamin M. Jacobs, Georgios Kalantzis, Nikki Hubers, David A. van Heel, Georgi Hudjashov, Mari Nelis, Tõnu Esko, Lili Milani, Andres Metspalu, Reedik Mägi, Jaak Vilo, Sulev Reisberg, Sven Laur, Raivo Kolde, Bitten Aagard Jensen, Minna K. Karjalainen, Mette Nyegaard, Genes & Health Research Team, Estonian Biobank Research Team, Estonian Health Informatics Research Team, DBDS Genomic Consortium, FinnGen

^*Corresponding author for this work

Research output: Contribution to journal › Journal article › Research › peer-review

Abstract

Genome-wide association studies (GWASs) may help inform the etiology of infertility. Here, we perform GWAS meta-analyses across seven cohorts in up to 42,629 cases and 740,619 controls and identify 25 genetic risk loci for male and female infertility. We additionally identify up to 269 genetic loci associated with follicle-stimulating hormone, luteinizing hormone, estradiol and testosterone through sex-specific GWAS meta-analyses (n = 6,095–246,862). Exome sequencing analyses reveal that women carrying testosterone-lowering rare variants in some genes are at risk of infertility. However, we find no local or genome-wide genetic correlation between female infertility and reproductive hormones. While infertility is genetically correlated with endometriosis and polycystic ovary syndrome, we find limited genetic overlap between infertility and obesity. Finally, we show that the evolutionary persistence of infertility-risk alleles may be explained by directional selection. Taken together, we provide a comprehensive view of the genetic determinants of infertility across multiple diagnostic criteria.

Original language	English
Article number	22
Journal	Nature Genetics
ISSN	1061-4036
DOIs	https://doi.org/10.1038/s41588-025-02156-8
Publication status	Accepted/In press - 2025

Bibliographical note

Publisher Copyright:
© The Author(s) 2025.

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10.1038/s41588-025-02156-8Licence: CC BY

Cite this

Venkatesh, S. S., Wittemans, L. B. L., Palmer, D. S., Baya, N. A., Ferreira, T., Hill, B., Lassen, F. H., Parker, M. J., Reibe, S., Elhakeem, A., Banasik, K., Bruun, M. T., Erikstrup, C., Aagard Jensen, B., Juul, A., Mikkelsen, C., Nielsen, H. S., Ostrowski, S. R., Pedersen, O. B., ... FinnGen (Accepted/In press). Genome-wide analyses identify 25 infertility loci and relationships with reproductive traits across the allele frequency spectrum. Nature Genetics, Article 22. https://doi.org/10.1038/s41588-025-02156-8

Venkatesh, SS, Wittemans, LBL, Palmer, DS, Baya, NA, Ferreira, T, Hill, B, Lassen, FH, Parker, MJ, Reibe, S, Elhakeem, A, Banasik, K, Bruun, MT, Erikstrup, C, Aagard Jensen, B, Juul, A , Mikkelsen, C , Nielsen, HS , Ostrowski, SR , Pedersen, OB, Rohde, PD, Sørensen, E, Ullum, H, Westergaard, D, Haraldsson, A, Holm, H, Jonsdottir, I, Olafsson, I, Steingrimsdottir, T, Steinthorsdottir, V, Thorleifsson, G, Figueredo, J, Karjalainen, MK, Pasanen, A, Jacobs, BM, Kalantzis, G, Hubers, N, van Heel, DA, Hudjashov, G, Nelis, M, Esko, T, Milani, L, Metspalu, A, Mägi, R, Vilo, J, Reisberg, S, Laur, S, Kolde, R, Jensen, BA, Karjalainen, MK, Nyegaard, M, Genes & Health Research Team, Estonian Biobank Research Team, Estonian Health Informatics Research Team, DBDS Genomic Consortium & FinnGen 2025, 'Genome-wide analyses identify 25 infertility loci and relationships with reproductive traits across the allele frequency spectrum', Nature Genetics. https://doi.org/10.1038/s41588-025-02156-8

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abstract = "Genome-wide association studies (GWASs) may help inform the etiology of infertility. Here, we perform GWAS meta-analyses across seven cohorts in up to 42,629 cases and 740,619 controls and identify 25 genetic risk loci for male and female infertility. We additionally identify up to 269 genetic loci associated with follicle-stimulating hormone, luteinizing hormone, estradiol and testosterone through sex-specific GWAS meta-analyses (n = 6,095–246,862). Exome sequencing analyses reveal that women carrying testosterone-lowering rare variants in some genes are at risk of infertility. However, we find no local or genome-wide genetic correlation between female infertility and reproductive hormones. While infertility is genetically correlated with endometriosis and polycystic ovary syndrome, we find limited genetic overlap between infertility and obesity. Finally, we show that the evolutionary persistence of infertility-risk alleles may be explained by directional selection. Taken together, we provide a comprehensive view of the genetic determinants of infertility across multiple diagnostic criteria.",

author = "Venkatesh, {Samvida S.} and Wittemans, {Laura B.L.} and Palmer, {Duncan S.} and Baya, {Nikolas A.} and Teresa Ferreira and Barney Hill and Lassen, {Frederik Heymann} and Parker, {Melody J.} and Saskia Reibe and Ahmed Elhakeem and Karina Banasik and Bruun, {Mie T.} and Christian Erikstrup and {Aagard Jensen}, Bitten and Anders Juul and Christina Mikkelsen and Nielsen, {Henriette S.} and Ostrowski, {Sisse R.} and Pedersen, {Ole B.} and Rohde, {Palle Duun} and Erik S{\o}rensen and Henrik Ullum and David Westergaard and Asgeir Haraldsson and Hilma Holm and Ingileif Jonsdottir and Isleifur Olafsson and Thora Steingrimsdottir and Valgerdur Steinthorsdottir and Gudmar Thorleifsson and Jessica Figueredo and Karjalainen, {Minna K.} and Anu Pasanen and Jacobs, {Benjamin M.} and Georgios Kalantzis and Nikki Hubers and {van Heel}, {David A.} and Georgi Hudjashov and Mari Nelis and T{\~o}nu Esko and Lili Milani and Andres Metspalu and Reedik M{\"a}gi and Jaak Vilo and Sulev Reisberg and Sven Laur and Raivo Kolde and Jensen, {Bitten Aagard} and Karjalainen, {Minna K.} and Mette Nyegaard and {Genes & Health Research Team} and {Estonian Biobank Research Team} and {Estonian Health Informatics Research Team} and {DBDS Genomic Consortium} and FinnGen",

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doi = "10.1038/s41588-025-02156-8",

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AU - Venkatesh, Samvida S.

AU - Wittemans, Laura B.L.

AU - Palmer, Duncan S.

AU - Baya, Nikolas A.

AU - Ferreira, Teresa

AU - Hill, Barney

AU - Lassen, Frederik Heymann

AU - Parker, Melody J.

AU - Reibe, Saskia

AU - Elhakeem, Ahmed

AU - Banasik, Karina

AU - Bruun, Mie T.

AU - Erikstrup, Christian

AU - Aagard Jensen, Bitten

AU - Juul, Anders

AU - Mikkelsen, Christina

AU - Nielsen, Henriette S.

AU - Ostrowski, Sisse R.

AU - Pedersen, Ole B.

AU - Rohde, Palle Duun

AU - Sørensen, Erik

AU - Ullum, Henrik

AU - Westergaard, David

AU - Haraldsson, Asgeir

AU - Holm, Hilma

AU - Jonsdottir, Ingileif

AU - Olafsson, Isleifur

AU - Steingrimsdottir, Thora

AU - Steinthorsdottir, Valgerdur

AU - Thorleifsson, Gudmar

AU - Figueredo, Jessica

AU - Karjalainen, Minna K.

AU - Pasanen, Anu

AU - Jacobs, Benjamin M.

AU - Kalantzis, Georgios

AU - Hubers, Nikki

AU - van Heel, David A.

AU - Hudjashov, Georgi

AU - Nelis, Mari

AU - Esko, Tõnu

AU - Milani, Lili

AU - Metspalu, Andres

AU - Mägi, Reedik

AU - Vilo, Jaak

AU - Reisberg, Sulev

AU - Laur, Sven

AU - Kolde, Raivo

AU - Jensen, Bitten Aagard

AU - Karjalainen, Minna K.

AU - Nyegaard, Mette

AU - Genes & Health Research Team

AU - Estonian Biobank Research Team

AU - Estonian Health Informatics Research Team

AU - DBDS Genomic Consortium

AU - FinnGen

PY - 2025

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N2 - Genome-wide association studies (GWASs) may help inform the etiology of infertility. Here, we perform GWAS meta-analyses across seven cohorts in up to 42,629 cases and 740,619 controls and identify 25 genetic risk loci for male and female infertility. We additionally identify up to 269 genetic loci associated with follicle-stimulating hormone, luteinizing hormone, estradiol and testosterone through sex-specific GWAS meta-analyses (n = 6,095–246,862). Exome sequencing analyses reveal that women carrying testosterone-lowering rare variants in some genes are at risk of infertility. However, we find no local or genome-wide genetic correlation between female infertility and reproductive hormones. While infertility is genetically correlated with endometriosis and polycystic ovary syndrome, we find limited genetic overlap between infertility and obesity. Finally, we show that the evolutionary persistence of infertility-risk alleles may be explained by directional selection. Taken together, we provide a comprehensive view of the genetic determinants of infertility across multiple diagnostic criteria.

AB - Genome-wide association studies (GWASs) may help inform the etiology of infertility. Here, we perform GWAS meta-analyses across seven cohorts in up to 42,629 cases and 740,619 controls and identify 25 genetic risk loci for male and female infertility. We additionally identify up to 269 genetic loci associated with follicle-stimulating hormone, luteinizing hormone, estradiol and testosterone through sex-specific GWAS meta-analyses (n = 6,095–246,862). Exome sequencing analyses reveal that women carrying testosterone-lowering rare variants in some genes are at risk of infertility. However, we find no local or genome-wide genetic correlation between female infertility and reproductive hormones. While infertility is genetically correlated with endometriosis and polycystic ovary syndrome, we find limited genetic overlap between infertility and obesity. Finally, we show that the evolutionary persistence of infertility-risk alleles may be explained by directional selection. Taken together, we provide a comprehensive view of the genetic determinants of infertility across multiple diagnostic criteria.

U2 - 10.1038/s41588-025-02156-8

DO - 10.1038/s41588-025-02156-8

M3 - Journal article

C2 - 40229599

AN - SCOPUS:105002614013

SN - 1061-4036

JO - Nature Genetics

JF - Nature Genetics

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ER -