Transcriptome-wide association study identifies novel susceptibility genes contributing to hearing impairment

Abstract Hearing impairment (HI) is a growing public health issue of global concern, which may lead to decreased work efficiency, social withdrawal and depression. However, the knowledge of the genetic basis of HI is limited. We conducted a transcriptome-wide association study (TWAS) on risk of HI by combining an European cohort (578 cases and 583 controls) with a Chinese cohort (89 cases and 209 controls). We identified that 46 genes show transcriptome-wide significant associations with the HI risk in the meta-analyses of the European and the Chinese cohorts (all P < 3.96 ×10− 6). Of these 46 candidate genes, four genes (ARL6IP6, TMEM127, TOMM7 and JAM3) showed nominal evidence of association in both cohorts (all P < 0.05). Among these four genes, two ones (ARL6IP6 and TMEM127) revealed strong, colocalized, and potentially causal associations with HI. Pathway enrichment analyses showed that the ciliary landscape (P = 5.55 × 10− 4), cholesterol biosynthesis (P = 7.09 × 10− 3), glycerophospholipid metabolism (P = 9.65 × 10− 3) and IL-4 (P = 1.11 × 10− 2) signaling pathways are significantly associated with HI. Our findings identified several novel susceptibility genes contributing to HI, and emphasized the power of TWAS in identifying putatively causal genes for common diseases.