Abstract
Infertility in men and women is a complex genetic trait with shared biological bases between the sexes. Here, we perform a series of rare variant analyses across 73,185 women and men to identify genes that contribute to primary gonadal dysfunction. We report CSMD1, a complement regulatory protein on chromosome 8p23, as a strong candidate locus in both sexes. We show that CSMD1 is enriched at the germ-cell/somatic-cell interface in both male and female gonads. Csmd1-knockout males show increased rates of infertility with significantly increased complement C3 protein deposition in the testes, accompanied by severe histological degeneration. Knockout females show significant reduction in ovarian quality and breeding success, as well as mammary branching impairment. Double knockout of Csmd1 and C3 causes non-additive reduction in breeding success, suggesting that CSMD1 and the complement pathway play an important role in the normal postnatal development of the gonads in both sexes.
Highlights
Infertility in men and women is a complex genetic trait with shared biological bases between the sexes
We used a rare variant association approach to search for genes that modulate both male and female gonadal function, and identified the complement regulator CUB and Sushi multiple domains 1 (CSMD1) to be reproducibly associated across multiple patient cohorts and different classes of genetic variation
We found that multiple types of genetic perturbations of CSMD1 associate with infertility traits in humans, most notably deletions within introns 1–3 of the gene
Summary
Infertility in men and women is a complex genetic trait with shared biological bases between the sexes. Only roughly 1000 oocytes survive the sojourn to menopause, representing colossal germ cell loss not attributable to ovulation[9]. Primary gonadal dysfunction — which manifests as early idiopathic menopause in women and oligo-/azoo-spermia in men — is a subset of the infertility phenotype that is tractable for human genetic analysis and has a prevalence of at least 1% in adult males and females[11,12]. We incorporate array and exome sequencing data from a large cohort of early idiopathic menopause from the Women’s Health Initiative[24] to search for novel, shared factors required for normal gonadal function in both sexes, identifying an association with the gene CSMD1 in male and female gonadal dysfunction, and replicate our findings with samples from the UK Biobank[25]. Our findings highlight the value of human genetic analysis as an entry point into surprising and previously unappreciated pathways in disease processes — in this case, a novel connection between of complement-related processes and gonadal function
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