A Single-cell Transcriptome-wide Association Study Reveals Susceptibility Genes for Age-related Hearing Loss

Abstract Age-related hearing loss (ARHL) is the most common type of hearing loss. Genetic factors are considered to play important roles in the development of ARHL. To identify novel susceptibility genes and cell types relevant to ARHL, we performed a two-stage single-cell transcriptome-wide association study (scTWAS) on ARHL in 96,372 cases and 141,590 controls of European descent. In the discovery stage, we identified 1034 gene–cell pairs that showed suggestive associations with ARHL (P < 1.0 × 10−5), representing 450 genes across various cell types. These genes were enriched in multiple pathways, including the immune-related, estrogen signaling, and oxidative damage response pathways. Besides, we provided prominent genetic evidence for putative drug repurposing, highlighting several genes as potential targets, including NR3C2, CHRM4 and SHBG. Further, we validated the significant association of 41 genes with ARHL in the replication stage of scTWAS, including previously reported genes such as HLA-DRA, as well as novel candidates such as TNF, ZC3HAV1, and SLC44A4. Among these novel candidates, several are highly biologically plausible in the development of ARHL. In conclusion, this scTWAS broadens our understanding of the genetic susceptibility to ARHL, which might be helpful in developing new strategies for the treatment and prevention of ARHL.