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Common and rare genetic variants predisposing females to unexplained recurrent pregnancy loss

Author

Listed:
  • Kyuto Sonehara

    (the University of Tokyo
    Osaka University Graduate School of Medicine
    RIKEN Center for Integrative Medical Sciences)

  • Yoshitaka Yano

    (Nagoya City University Graduate School of Medical Sciences)

  • Tatsuhiko Naito

    (Osaka University Graduate School of Medicine
    RIKEN Center for Integrative Medical Sciences)

  • Shinobu Goto

    (Nagoya City University Graduate School of Medical Sciences)

  • Hiroyuki Yoshihara

    (Nagoya City University Graduate School of Medical Sciences)

  • Takahiro Otani

    (Nagoya City University Graduate School of Medical Sciences)

  • Fumiko Ozawa

    (Nagoya City University Graduate School of Medical Sciences)

  • Tamao Kitaori

    (Nagoya City University Graduate School of Medical Sciences)

  • Koichi Matsuda

    (The University of Tokyo
    the University of Tokyo)

  • Takashi Nishiyama

    (Nagoya City University Graduate School of Medical Sciences)

  • Yukinori Okada

    (the University of Tokyo
    Osaka University Graduate School of Medicine
    RIKEN Center for Integrative Medical Sciences
    Osaka University)

  • Mayumi Sugiura-Ogasawara

    (Nagoya City University Graduate School of Medical Sciences)

Abstract

Recurrent pregnancy loss (RPL) is a major reproductive health issue with multifactorial causes, affecting 2.6% of all pregnancies worldwide. Nearly half of the RPL cases lack clinically identifiable causes (e.g., antiphospholipid syndrome, uterine anomalies, and parental chromosomal abnormalities), referred to as unexplained RPL (uRPL). Here, we perform a genome-wide association study focusing on uRPL in 1,728 cases and 24,315 female controls of Japanese ancestry. We detect significant associations in the major histocompatibility complex (MHC) region at 6p21 (lead variant=rs9263738; P = 1.4 × 10−10; odds ratio [OR] = 1.51 [95% CI: 1.33–1.72]; risk allele frequency = 0.871). The MHC associations are fine-mapped to the classical HLA alleles, HLA-C*12:02, HLA-B*52:01, and HLA-DRB1*15:02 (P = 1.1 × 10−10, 1.5 × 10−10, and 1.2 × 10−9, respectively), which constitute a population-specific common long-range haplotype with a protective effect (P = 2.8 × 10−10; OR = 0.65 [95% CI: 0.57–0.75]; haplotype frequency=0.108). Genome-wide copy-number variation (CNV) calling demonstrates rare predicted loss-of-function (pLoF) variants of the cadherin-11 gene (CDH11) conferring the risk of uRPL (P = 1.3 × 10−4; OR = 3.29 [95% CI: 1.78–5.76]). Our study highlights the importance of reproductive immunology and rare variants in the uRPL etiology.

Suggested Citation

  • Kyuto Sonehara & Yoshitaka Yano & Tatsuhiko Naito & Shinobu Goto & Hiroyuki Yoshihara & Takahiro Otani & Fumiko Ozawa & Tamao Kitaori & Koichi Matsuda & Takashi Nishiyama & Yukinori Okada & Mayumi Sug, 2024. "Common and rare genetic variants predisposing females to unexplained recurrent pregnancy loss," Nature Communications, Nature, vol. 15(1), pages 1-9, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49993-5
    DOI: 10.1038/s41467-024-49993-5
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    References listed on IDEAS

    as
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