Salt-inducible kinase 3, SIK3, is a new gene associated with hearing

Abstract

Hearing function is known to be heritable, but few significant and reproducible associations of genetic variants have been identified to date in the adult population. In this study, genome-wide association results of hearing function from the G-EAR consortium and TwinsUK were used for meta-analysis. Hearing ability in eight population samples of Northern and Southern European ancestry (n = 4591) and the Silk Road (n = 348) was measured using pure-tone audiometry and summarized using principal component (PC) analysis. Genome-wide association analyses for PC1–3 were conducted separately in each sample assuming an additive model adjusted for age, sex and relatedness of subjects. Meta-analysis was performed using 2.3 million single-nucleotide polymorphisms (SNPs) tested against each of the three PCs of hearing ability in 4939 individuals. A single SNP lying in intron 6 of the salt-inducible kinase 3 (SIK3) gene was found to be associated with hearing PC2 (P = 3.7×10−8) and further supported by whole-genome sequence in a subset. To determine the relevance of this gene in the ear, expression of the Sik3 protein was studied in mouse cochlea of different ages. Sik3 was expressed in murine hair cells during early development and in cells of the spiral ganglion during early development and adulthood. Our results suggest a developmental role of Sik3 in hearing and may be required for the maintenance of adult auditory function.

Age-Related Hearing Loss

“…Since the first successful genome-wide association study (GWAS) conducted in age-related macular degeneration was published in 2005 (Klein et al 2005), much hope was raised that this cohort-based approach rather than family-based analysis could reveal the genetic susceptibilities underlying common complex diseases including ARHL. Several GWAS into adult hearing status or ARHL have now been published (summarized in Table 1) (Friedman et al 2009;Van Laer et al 2010;Girotto et al 2011;Nolan et al 2013;Wolber et al 2014;Fransen et al 2015;Vuckovic et al 2015;Hoffmann et al 2016), and although many candidates have been linked to ARHL a lack of genome-wide findings that are significant and a poor replication of findings across these studies has limited their impact. One interpretation of these studies is that the heritability of ARHL has been overestimated or, alternatively, that there are thousands of rare variants in the population of small effect on ARHL risk, which would be impossible to detect by GWAS (Fransen et al 2015).…”

“…These have included pathway analysis to identify enrichment of genes from pathogenic pathways, prioritizing hits in known deafness genes, investigation of gene function in mutant mouse models, and metaanalysis of data across cohorts. These methods have helped strengthen evidence for ESRRG, encoding estrogen-related receptor γ (Nolan et al 2013) (mouse model), PCDH20 encoding protocadherin 20 (Vuckovic et al 2015), SLC28A3 encoding the nucleoside transporter, solute carrier family 28 member 3 (Vuckovic et al 2015), and SIK3 encoding salt-inducible kinase 3 (Wolber et al 2014) (all meta-analysis) as having a role in adult hearing loss. However, given the known heterogeneity involved in congenital deafness (Bowl et al 2017), the expectation is that variants in hundreds of genes contribute to ARHL.…”

Genome-wide association study identifies 44 independent genomic loci for self-reported adult hearing difficulty in the UK Biobank cohort

“…ARHI is expected to be a highly genetically heterogeneous trait given that over 150 genetic loci have been identified in non-syndromic hereditary hearing loss alone (https://hereditaryhearingloss.org/). Previous GWAS of ARHI have identified a small number of promising candidate genes, though there has been poor replication of findings to date, possibly reflecting varied phenotyping approaches and limited sample sizes [14][15][16][17][18][19][20][21][22][23][24] .…”

Genetics of age‐related hearing loss

“…Under the common trait-common variant hypothesis, likely thousands of genetic risk loci contribute to the development and progression of ARHL and this genetic complexity reflects the complexity of the anatomical, and in turn cellular and molecular make up of the auditory system. Heritability estimates for ARHL are moderate, with estimates ranging from 30% to 70% (Bedin et al, 2009;Bogo et al, 2015;Christensen, Frederiksen, & Hoffman, 2001;Hendrickx et al, 2013;Momi, Wolber, Fabiane, MacGregor, & Williams, 2015;Viljanen et al, 2007), with variability likely to be due to the different phenotyping methods, limited sample sizes and differing sample demographics-particularly age-of ARHL genetic studies (Duijvestijn, Anteunis, Hendriks, & Manni, 1999;Fransen et al, 2015;Friedman et al, 2009;Girotto et al, 2011;Hoffmann et al, 2016;Luo et al, 2013;Newman et al, 2012;Nolan et al, 2013;Van Laer et al, 2010;Vuckovic et al, 2015;Wolber et al, 2014).…”