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

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. Here, the authors perform a genome-wide association study for recurrent pregnancy loss without apparent clinical causes and identify a protective HLA haplotype. They also show that rare predicted loss-of-function variants in CDH11 are associated with risk of recurrent pregnancy loss. [ABSTRACT FROM AUTHOR]