Targeted resequencing sheds light on the etiology of unexplained female infertilty

Abstract

Approximately 15% of couples experiencing difficulty conceiving are diagnosed with idiopathic infertility. Genetic polymorphisms could shed light on many of these currently unexplained cases by revealing disruptions to oocyte quality or uterine receptivity that may exist on a subcellular level. To assess the role of single nucleotide variants (SNVs) in female infertility, we conducted an investigation surveying over 200 genomic loci predicted to be associated with female infertility among a cohort of patients with unexplained infertility. Retrospective cohort of female patients with unexplained infertility. Genomic DNA extracted from blood samples was obtained from 32 patients undergoing non-donor in-vitro fertilization (IVF) cycles at a large academic medical center. Based on literature review, ∼200 loci (spanning 250Mb) relating to female fertility were selected. Selected loci were targeted using a custom NimbleGen Sequence Capture Array, followed by paired-end Illumina HiSeq 2000 sequencing. Principal component analysis was used to correct for population stratification. Samples from the 1000 Genomes Project were used as controls. Among sites with read depths ≥20×, a total of ∼80,000 SNVs were detected, representing 0.3% of targeted sites. Removing singletons, this fraction was reduced to 0.2%. ∼500 SNVs are predicted to affect protein function. In comparison to the 1000 Genomes Project, ∼150 of these SNVs appear to be unique to the unexplained infertility cohort (P<.001, Logistic regression adjusted for population structure). Our preliminary survey of genetic variation among patients diagnosed with unexplained infertility revealed a number of potential genetic biomarkers associated with infertility. Based on these promising results, we are currently investigating female infertility-associated genetic variation through whole genome sequence analysis and in a larger validation cohort.