TY - UNPB
T1 - Genome-wide analyses identify 21 infertility loci and over 400 reproductive hormone loci across the allele frequency spectrum
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 - Aagaard Jensen, Bitten
AU - Juul, Anders
AU - Mikkelsen, Christina
AU - Nielsen, Henriette S.
AU - Ostrowsk, Sisse R.
AU - Pedersen, Ole B.
AU - Rohde, Palle Duun
AU - Sorensen, 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 - Hubers, Nikki
AU - Genes & Health Research Team
AU - Estonian Biobank Research Team
AU - Estonian Health Informatics Research Team
AU - DBDS Genomic Consortium
AU - FinnGen
AU - Lippincott, Margaret
AU - Fraser, Abigail
AU - Lawlor, Deborah A.
AU - Timpson, Nicholas J.
AU - Nyegaard, Mette
AU - Stefansson, Kari
AU - Magi, Reedik
AU - Laivuor, Hannele
AU - van Heel, David A.
AU - Boomsma, Dorret I.
AU - Balasubramanian, Ravikumar
AU - Seminara, Stephanie B.
AU - Chan, Yee-Ming
AU - Laisk, Triin
AU - Lindgren, Cecilia M.
PY - 2024/3/20
Y1 - 2024/3/20
N2 - Genome-wide association studies (GWASs) may help inform treatments for infertility, whose causes remain unknown in many cases. Here we present GWAS meta-analyses across six cohorts for male and female infertility in up to 41,200 cases and 687,005 controls. We identified 21 genetic risk loci for infertility (
P ≤5E-08), of which 12 have not been reported for any reproductive condition. We found positive genetic correlations between endometriosis and all-cause female infertility (
r
g =0.585,
P =8.98E-14), and between polycystic ovary syndrome and anovulatory infertility (
r
g =0.403,
P =2.16E-03). The evolutionary persistence of female infertility-risk alleles in
EBAG9 may be explained by recent directional selection. We additionally identified up to 269 genetic loci associated with follicle-stimulating hormone (FSH), luteinising hormone, oestradiol, and testosterone through sex-specific GWAS meta-analyses (N=6,095-246,862). While hormone-associated variants near
FSHB and
ARL14EP colocalised with signals for anovulatory infertility, we found no
r
g between female infertility and reproductive hormones (
P >0.05). Exome sequencing analyses in the UK Biobank (N=197,340) revealed that women carrying testosterone-lowering rare variants in
GPC2 were at higher risk of infertility (OR=2.63,
P =1.25E-03). Taken together, our results suggest that while individual genes associated with hormone regulation may be relevant for fertility, there is limited genetic evidence for correlation between reproductive hormones and infertility at the population level. We provide the first comprehensive view of the genetic architecture of infertility across multiple diagnostic criteria in men and women, and characterise its relationship to other health conditions.
AB - Genome-wide association studies (GWASs) may help inform treatments for infertility, whose causes remain unknown in many cases. Here we present GWAS meta-analyses across six cohorts for male and female infertility in up to 41,200 cases and 687,005 controls. We identified 21 genetic risk loci for infertility (
P ≤5E-08), of which 12 have not been reported for any reproductive condition. We found positive genetic correlations between endometriosis and all-cause female infertility (
r
g =0.585,
P =8.98E-14), and between polycystic ovary syndrome and anovulatory infertility (
r
g =0.403,
P =2.16E-03). The evolutionary persistence of female infertility-risk alleles in
EBAG9 may be explained by recent directional selection. We additionally identified up to 269 genetic loci associated with follicle-stimulating hormone (FSH), luteinising hormone, oestradiol, and testosterone through sex-specific GWAS meta-analyses (N=6,095-246,862). While hormone-associated variants near
FSHB and
ARL14EP colocalised with signals for anovulatory infertility, we found no
r
g between female infertility and reproductive hormones (
P >0.05). Exome sequencing analyses in the UK Biobank (N=197,340) revealed that women carrying testosterone-lowering rare variants in
GPC2 were at higher risk of infertility (OR=2.63,
P =1.25E-03). Taken together, our results suggest that while individual genes associated with hormone regulation may be relevant for fertility, there is limited genetic evidence for correlation between reproductive hormones and infertility at the population level. We provide the first comprehensive view of the genetic architecture of infertility across multiple diagnostic criteria in men and women, and characterise its relationship to other health conditions.
KW - genetic and genomic medicine
U2 - 10.1101/2024.03.19.24304530
DO - 10.1101/2024.03.19.24304530
M3 - Preprint
C2 - 38562841
BT - Genome-wide analyses identify 21 infertility loci and over 400 reproductive hormone loci across the allele frequency spectrum
PB - medRxiv
ER -