Normal hearing function genetics: have you heard all about it? An integrated approach of genome-wide association studies and transcriptome-wide association studies in three Italian cohorts.

Introduction: Deepening the genetic mechanisms underlying Normal Hearing Function (NHF) has proven challenging, despite extensive efforts through Genome-Wide Association Studies (GWAS). Methods: NHF was described as a set of nine quantitative traits (i.e., hearing thresholds at 0.25, 0.5, 1, 2, 4, and 8 kHz, and three pure-tone averages of thresholds at low, medium, and high frequencies). For each trait, GWAS analyses were performed on the Moli-sani cohort (n = 1,209); then, replication analyses were conducted on Carlantino (CAR, n = 261) and Val Borbera (VBI, n = 425) cohorts. Expression levels of the most significantly associated genes were assessed employing single-nucleus RNA sequencing data (snRNA-seq) on human fetal and adult inner ear tissues. Finally, for all nine NHF traits, Transcriptome-Wide Association Studies (TWAS) were performed, combining GWAS summary statistics and pre-computed gene expression weights in 12 brain tissues. Results: GWAS on the Discovery cohort allowed the detection of 667 SNPs spanning 327 protein coding genes at a Conclusion: This study took advantage of three Italian cohorts, deeply characterized from a genetic and audiological point of view. Bioinformatics and biostatistics analyses allowed the identification of three novel candidate genes, namely,