GWAS Identifies 44 Independent Associated Genomic Loci for Self-Reported Adult Hearing Difficulty in UK Biobank

Abstract

Age-related hearing impairment (ARHI) is the most common sensory impairment in the aging population; a third of individuals are affected by disabling hearing loss by the age of 65. It causes social isolation and depression and has recently been identified as a risk factor for dementia. The genetic risk factors and underlying pathology of ARHI are largely unknown, meaning that targets for new therapies remain elusive, yet heritability estimates range between 35% and 55%. We performed genome-wide association studies (GWASs) for two self-reported hearing phenotypes, using more than 250,000 UK Biobank (UKBB) volunteers aged between 40 and 69 years. Forty-four independent genome-wide significant loci (p < 5E-08) were identified, considerably increasing the number of established trait loci. Thirty-four loci are novel associations with hearing loss of any form, and only one of the ten known hearing loci has a previously reported association with an ARHI-related trait. Gene sets from these loci are enriched in auditory processes such as synaptic activities, nervous system processes, inner ear morphology, and cognition, while genetic correlation analysis revealed strong positive correlations with multiple personality and psychological traits for the first time. Immunohistochemistry for protein localization in adult mouse cochlea implicate metabolic, sensory, and neuronal functions for NID2, CLRN2, and ARHGEF28. These results provide insight into the genetic landscape underlying ARHI, opening up novel therapeutic targets for further investigation. In a wider context, our study also highlights the viability of using self-report phenotypes for genetic discovery in very large samples when deep phenotyping is unavailable.

Figure 1

Workflow Schematic for Discovery and Validation of Associated Loci N, sample size; QC, quality control; PC, principal components; MAF, minor allele frequency; INFO, quality metric, combination of imputation score and dosage confidence.

Figure 2

Manhattan Plots Displaying GWAS Results for Hearing Difficulty and Hearing Aid Use Phenotypes Shown are (A) hearing difficulty and (B) hearing aid use. The Manhattan plots display the p values of all SNPs tested in discovery analysis. The threshold for genome wide significance (p < 5 × 10⁻⁸) is indicated by a red dotted line. Loci that reached genome-wide significance in both phenotypes are annotated with gene symbol.

Figure 3

Heatmap of the Enriched Functional Terms for Genes Mapped to Lead SNP at Suggestive Level (HDiff Analysis) via ToppGene Suite Genes and functional terms were grouped using clustering of the strength of the enrichment of genes for respective functional terms. Functional terms include GO Biological Process, GO Molecular Function, GO Cellular Component, Mouse Phenotype, Pathway, and Disease.

Figure 4

Cochlear Expression of Three Putative Hearing Genes Identified in HDiff and HAid GWASs (A–D) Locus zoom plots of associated loci, generated with HDiff summary statistics. Four associated loci are plotted which have lead SNPs in or in proximity to ARHGEF28 (A and B), NID2 (C), and CLRN2 (D). Purple indicates lead independent SNP generated from GCTA-COJO conditional analysis. Coloring of remaining SNPs is based on linkage disequilibrium (LD) with the lead SNP. The genes within the region are annotated, and the direction of the transcripts is shown by arrows. Two independent regions were identified within the ARHGEF28 locus; both are shown. (E–H) Immunofluorescence images of adult mouse cochlea, spiral ganglion neurons (E) and organ of Corti (F–H). Vibratome sections stained with the three proteins of interest in mouse inner ear; DAPI (blue) and Phalloidin (magenta) were also used for staining of actin and nuclei, respectively. (E) Anti-ARHGEF28 (green) staining is observed in the neuronal cell bodies and axons. (F) Anti-ARHGEF28 (green) staining is mainly observed in outer and inner hair cells. (G) Anti-NID2 (green) staining is observed lining blood vessels and the epithelial lining of the inner spiral sulcus. (H) Anti-CLRN2 (green) staining is observed in outer and inner hair cells, in addition to the stria vascularis. The scale bar in (G) represents 100 μm. The scale is consistent for all images in this figure.