Homozygosity for a stop-gain variant in CCDC201 causes primary ovarian insufficiency
Age at menopause (AOM) has a substantial impact on fertility and disease risk. While many loci with variants that associate with AOM have been identified through genome-wide association studies (GWAS) under an additive model, other genetic models are rarely considered 1 . Here through GWAS meta-anal...
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Published in | Nature genetics Vol. 56; no. 9; pp. 1804 - 1810 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
New York
Nature Publishing Group US
01.09.2024
Nature Publishing Group |
Subjects | |
Online Access | Get full text |
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Summary: | Age at menopause (AOM) has a substantial impact on fertility and disease risk. While many loci with variants that associate with AOM have been identified through genome-wide association studies (GWAS) under an additive model, other genetic models are rarely considered
1
. Here through GWAS meta-analysis under the recessive model of 174,329 postmenopausal women from Iceland, Denmark, the United Kingdom (UK; UK Biobank) and Norway, we study low-frequency variants with a large effect on AOM. We discovered that women homozygous for the stop-gain variant
rs117316434
(A) in
CCDC201
(p.(Arg162Ter), minor allele frequency ~1%) reached menopause 9 years earlier than other women (
P
= 1.3 × 10
−15
). The genotype is present in one in 10,000 northern European women and leads to primary ovarian insufficiency in close to half of them. Consequently, homozygotes have fewer children, and the age at last childbirth is 5 years earlier (
P
= 3.8 × 10
−5
). The
CCDC201
gene was only found in humans in 2022 and is highly expressed in oocytes. Homozygosity for
CCDC201
loss-of-function has a substantial impact on female reproductive health, and homozygotes would benefit from reproductive counseling and treatment for symptoms of early menopause.
Genome-wide analysis of age at menopause under a recessive model identifies a stop-gain variant in
CCDC201
associated with primary ovarian insufficiency. This homozygous genotype is present in 1 in 10,000 women of northern European ancestry. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 1061-4036 1546-1718 1546-1718 |
DOI: | 10.1038/s41588-024-01885-6 |