Genome-wide analyses identify 21 infertility loci and over 400 reproductive hormone loci across the allele frequency spectrum

Venkatesh, Samvida S.; Wittemans, Laura B. L.; Palmer, Duncan S.; Baya, Nikolas A.; Ferreira, Teresa; Hill, Barney; Lassen, Frederik Heymann; Parker, Melody J.; Reibe, Saskia; Elhakeem, Ahmed; Banasik, Karina; Bruun, Mie T.; Erikstrup, Christian; Jensen, Bitten A.; Juul, Anders; Mikkelsen, Christina; Nielsen, Henriette S.; Ostrowski, Sisse R.; Pedersen, Ole B.; Rohde, Palle D.; Sorensen, Erik; Ullum, Henrik; Westergaard, David; Haraldsson, Asgeir; Holm, Hilma; Jonsdottir, Ingileif; Olafsson, Isleifur; Steingrimsdottir, Thora; Steinthorsdottir, Valgerdur; Thorleifsson, Gudmar; Figueredo, Jessica; Karjalainen, Minna K.; Pasanen, Anu; Jacobs, Benjamin M.; Hubers, Nikki; ,; ,; ,; ,; ,; Lippincott, Margaret; Fraser, Abigail; Lawlor, Deborah A.; Timpson, Nicholas J.; Nyegaard, Mette; Stefansson, Kari; Magi, Reedik; Laivuori, Hannele; van Heel, David A.; Boomsma, Dorret I.; Balasubramanian, Ravikumar; Seminara, Stephanie B.; Chan, Yee-Ming; Laisk, Triin; Lindgren, Cecilia M.

doi:10.1101/2024.03.19.24304530

Cited by 5 publications

References 183 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

Inherited infertility - mapping loci associated with impaired female reproduction

Ruotsalainen,

Karjalainen,

Kurki

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

Female infertility is a common and complex health problem affecting millions of women worldwide. While multiple factors can contribute to this condition, the underlying cause remains elusive in up to 15-30% of cases. In our large genome-wide association study (GWAS) of 22,849 women with infertility and 198,989 controls from the Finnish population cohort FinnGen, we unveil a unique landscape of genetic factors associated with the disease. Our recessive analysis identified a low-frequency stop-gained mutation inTBPL2(p.Arg331Ter; minor allele frequency (MAF) = 1.2%) with an impact comparable to highly penetrant monogenic mutations (OR = 650, p = 4.1 ×10-25). While previous studies have linked the homologous gene to anovulation and sterility in knockout mice, the severe consequence of the p.Arg331Ter mutation was evidenced by homozygous carriers having significantly fewer offspring (average of 0.16) compared to women belonging to the other genotype groups (average of 1.75 offspring, p = 1.4×10-15). Notably, all homozygous women who had given birth had received infertility therapy. Moreover, our age-stratified analyses identified three additional genome-wide significant loci. Two loci were associated with early-onset disease (infertility diagnosed before age 30), located nearCHEK2and within the major histocompatibility complex (MHC)-region. The third locus, associated with late-onset disease, had its lead SNP located in an intron of a lncRNA gene. Taken together, our data highlight the significance of rare recessive alleles in shaping female infertility risk. The results further provide evidence supporting specific age-dependent mechanisms underlying this complex disorder.

show abstract

Inherited infertility - mapping loci associated with impaired female reproduction

Ruotsalainen,

Karjalainen,

Kurki

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

Genome-wide analysis identifies 66 variants underlying anatomical variation in human neuroendocrine structures and reveals links to testosterone

Currant,

Arthofer,

Ferreira

et al. 2024

Preprint

View full text Add to dashboard Cite

The hypothalamus, pituitary gland and olfactory bulbs are neuroanatom-ical structures key to the regulation of the endocrine system. Variation in their anatomy can affect the function of the reproductive system. To investigate this relationship, we extracted four largely unexplored phenotypes from 34,834 individuals within UK Biobank by quantifying the volume of the hypothalamus, pituitary gland and olfactory bulbs using multi-modal magnetic resonance imaging. Genome-wide associ-ation studies of these phenotypes identified 66 independent common genetic associations with endocrine-related neuroanatomical volumes (P <5×10−8), five of which had a prior association to testos-terone levels, representing enrichment of testosterone-associated SNPs over random chance (P-value =9.89×10−12). Exome-wide rare variant burden analysis identifiedSTAB1as being significantly associ-ated with hypothalamus volume (P= 3.78×10−7), with known associations to brain iron levels. Common variants associated with hypothalamic grey matter volume were also found to be associated with iron metabolism, in which testosterone plays a key role. These results provide initial evidence of common and rare genetic effects on both anatomical variation in neuroendocrine structures and their func-tion in hormone production and regulation. Variants associated with pituitary gland volume were enriched for gene expression specific to theca cells, responsible for testosterone production in ovaries, suggest-ing shared underlying genetic variation affecting both neuroanatomical and gonadal endocrine tissues. Cell-type expression enrichment analysis across hypothalamic cell types identified tanycytes to be associated (P= 1.69×10−3) with olfactory bulb volume associated genetic variants, a cell type involved in release of gonadotropin-releasing hormone into the bloodstream. Voxel-wise analysis highlighted associations between the variants associated with pituitary gland volume and areas of intracranial venous drainage involved in hormonal release into the blood circulation. Together, our results suggest a shared role of genetics impacting both the anatomy and function of neuroendocrine structures within the repro-ductive system in their production and release of reproductive hormones.

show abstract

From Biobanking to Personalized Medicine: the journey of the Estonian Biobank

Milani,

Alver,

Laur

et al. 2024

Preprint

View full text Add to dashboard Cite

Large biobanks have set a new standard for research and innovation in human genomics and implementation of personalised medicine. The Estonian Biobank was founded a quarter of a century ago, and its biological specimens, clinical, health, omics, and lifestyle data have been included in over 800 publications to date. What makes the biobank unique internationally is its translational focus, with active efforts to conduct clinical studies based on genetic findings, and to explore the effects of return of results on participants. In this review we provide an overview of the Estonian Biobank, highlight its strengths for studying the effects of genetic variation and quantitative phenotypes on health-related traits, development of methods and frameworks for bringing genomics into the clinic, and its role as a driving force for implementing personalized medicine on a national level and beyond.

show abstract

Genome-wide analyses identify 21 infertility loci and over 400 reproductive hormone loci across the allele frequency spectrum

Cited by 5 publications

References 183 publications

Inherited infertility - mapping loci associated with impaired female reproduction

Inherited infertility - mapping loci associated with impaired female reproduction

Genome-wide analysis identifies 66 variants underlying anatomical variation in human neuroendocrine structures and reveals links to testosterone

From Biobanking to Personalized Medicine: the journey of the Estonian Biobank

Contact Info

Product

Resources

About