CCDC201 停止-增益变异的同基因遗传会导致原发性卵巢功能不全。

IF 31.7 1区 生物学 Q1 GENETICS & HEREDITY Nature genetics Pub Date : 2024-08-27 DOI:10.1038/s41588-024-01885-6
Asmundur Oddsson, Valgerdur Steinthorsdottir, Gudjon R. Oskarsson, Unnur Styrkarsdottir, Kristjan H. S. Moore, Salvor Isberg, Gisli H. Halldorsson, Gardar Sveinbjornsson, David Westergaard, Henriette Svarre Nielsen, Run Fridriksdottir, Brynjar O. Jensson, Gudny A. Arnadottir, Hakon Jonsson, Arni Sturluson, Audunn S. Snaebjarnarson, Ole A. Andreassen, G. Bragi Walters, Mette Nyegaard, Christian Erikstrup, Thora Steingrimsdottir, Rolv T. Lie, Pall Melsted, Ingileif Jonsdottir, Bjarni V. Halldorsson, Gudmar Thorleifsson, Jona Saemundsdottir, Olafur Th. Magnusson, DBDS Genomic Consortium, Karina Banasik, Erik Sorensen, Gisli Masson, Ole Birger Pedersen, Laufey Tryggvadottir, Jan Haavik, Sisse Rye Ostrowski, Hreinn Stefansson, Hilma Holm, Thorunn Rafnar, Daniel F. Gudbjartsson, Patrick Sulem, Kari Stefansson
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摘要

绝经年龄(AOM)对生育和疾病风险有很大影响。虽然在加性模型下通过全基因组关联研究(GWAS)发现了许多与绝经年龄相关的变异位点,但很少考虑其他遗传模型1。在此,我们通过对来自冰岛、丹麦、英国(UK;UK Biobank)和挪威的 174 329 名绝经后妇女进行隐性模型下的 GWAS 元分析,研究了对 AOM 影响较大的低频变异。我们发现,CCDC201(p.(Arg162Ter),小等位基因频率约为 1%)中的停止-增益变异 rs117316434 (A)的同源女性比其他女性提前 9 年绝经(P = 1.3 × 10-15)。北欧每 10,000 名妇女中就有一人存在这种基因型,其中近一半会导致原发性卵巢功能不全。因此,同型基因携带者生育的子女较少,末次生育年龄提前 5 年(P = 3.8 × 10-5)。CCDC201 基因于 2022 年才在人类中发现,在卵母细胞中高度表达。CCDC201功能缺失的同基因遗传对女性生殖健康有很大影响,同基因遗传者将受益于生殖咨询和更年期提前症状的治疗。
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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 considered1. 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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来源期刊
Nature genetics
Nature genetics 生物-遗传学
CiteScore
43.00
自引率
2.60%
发文量
241
审稿时长
3 months
期刊介绍: Nature Genetics publishes the very highest quality research in genetics. It encompasses genetic and functional genomic studies on human and plant traits and on other model organisms. Current emphasis is on the genetic basis for common and complex diseases and on the functional mechanism, architecture and evolution of gene networks, studied by experimental perturbation. Integrative genetic topics comprise, but are not limited to: -Genes in the pathology of human disease -Molecular analysis of simple and complex genetic traits -Cancer genetics -Agricultural genomics -Developmental genetics -Regulatory variation in gene expression -Strategies and technologies for extracting function from genomic data -Pharmacological genomics -Genome evolution
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