Identification of premature ovarian failure‐associated genes using linkage disequilibrium‐based genome‐wide association study

Premature ovarian failure (POF) as known to be a heterogeneous and polygenic disorder is the cessation of menstrual cycle before the age of 40. It was characterized by primary amenorrhea (absent menarche) and secondary amenorrhea (lack of gonadotrophin stimulation). Even though there were many of reports, physiological mechanism and genes contributed to POF still are in mist. To identify genes considered to be associated with POF, genome‐wide association study (GWAS) based on linkage disequilibrium (LD) mapping was performed with 24 patients with POF and their 24 matched controls. In the present study, about 100 genes were identified to be associated with POF. Among them, two genes revealed the best strong association with POF, which were laminin, gamma 1 (LAMC1) and branched chain alpha‐keto acid dehydrogenase, E1‐beta subunit (BCKDHB) genes. Through the LD analysis, complete LD (|D’|=1,γ 2 ≠ 1) block was formed throughout LAMC1 gene, and the same block was formed focused on exon 10 including alternative splicing site in BCKDHB gene. Haplotypes reconstructed from each blocks showed significant association with POF after statistical correction by multiple testing. The results in our study suggest that these genes may contribute to increase the risk for POF. With regard to the concepts of LD, it is suggested that causal variants may exist in POF‐susceptible haplotypes. We hope that our findings propose a new direction in this field.