The revolution in genetic association studies as a result of the International HapMap and Human Genome Projects has finally come of age in hearing research. Since the Wellcome Trust Case Control Consortium (WTCCC) reported in 2007 the genetic variants underlying previously intractable diseases such as rheumatoid arthritis,1 the number of insights into the genetic architecture of common complex traits has risen exponentially.2 Deeper understanding of the genetics of traits like bone mineral density, which predisposes someone to osteoporotic fracture, has revealed new biological pathways and provided molecular targets for the development of new therapeutic agents3—now used in clinical practice.
In assessing genome-wide association studies (GWAS), it has become apparent that rigorous clinical ascertainment of cases to strict epidemiological standards is not necessarily required. At first, accuracy in phenotyping was considered key to successful association studies. With the advent of citizen science and companies such as 23andMe, it became clear that methodical and painstaking trait assessment was not essential. Myopia associations reported for refractive error measurement,4 for example, were similar to those discovered using self-reported age at “doctor's diagnosis of near-sightedness.”5 That each study replicated many of the others’ discovery variants showed the phenotyping dogma to have been misplaced.
Our team's research interest lies in the genetics of age-related hearing impairment (ARHI), which is moderately to highly heritable depending on traits. The ARHI research journey has considerable parallels with that for myopia. The gold-standard measure of hearing ability is pure-tone audiometry, which requires specialist equipment and highly trained personnel. It is therefore costly and unsuitable for the large-scale sample collection required by GWAS. We showed in the TwinsUK cohort that the web-based speech-in-noise test was a useful surrogate for the pure-tone audiogram in association studies because it shared genetic predisposition.7 This allowed its rollout to thousands of participants who were invited to test their hearing ability online using personal computers at home. In this test, which is a modified version of the original telephone test,8 a voice is heard articulating monosyllable digits in triplets (such as eight, six, four) against a rising background of hissing radio interference. Each ear is tested in turn.
Self-reported hearing complaints determined using a simple questionnaire can provide suitable ARHI phenotypes for GWAS and may be applied on a large scale. Our work and those of others have highlighted the usefulness of questionnaires on hearing ability (under review with the European Journal of Human Genetics): Genetic correlation between questions and hearing tests is high, up to 0.8, showing that questionnaires will be a useful tool in gene finding.9 This is in keeping with myopia and the other large GWAS on ARHI that examined U.S. health records of audiogram-based diagnoses.10 We found no smoking gun—no single variant had a large effect. It is now very evident that ARHI is a highly polygenic trait with multiple predisposing variants having effect sizes in the odds ratio range of 1.01 to 1.2. Of the 44 variants we associated with hearing difficulty, only a quarter were at known hearing loci and the remaining 33 were novel trait associations. That our work replicated the three variants identified by the GERA health records study shows that questionnaires are detecting the same variants identified through pure-tone audiometry. Further work will reveal new pathways and mechanisms in ARHI. An association identified at HLA-DQA1 in the MCH class II region hints at autoimmune disease—a locus that is also associated with rheumatic fever and celiac disease.
Could pure-tone audiometry capture an aspect of the ARHI phenotype that is not reported in a questionnaire? False-positive associations are a major issue in candidate gene studies and clearly documented in bone mineral density, in which only nine of 150 proven candidate gene associations were replicated in a well-powered GWAS.11 Of interest, our ARHI GWAS failed similarly to replicate a number of audiometry-based associations previously thought secure, such as GRM712,13 and SIK3.14
Much remains to be done, not least to determine where besides the cochlea the encoded proteins are acting. Some of the difficulties in ARHI lie in the brain pathways that stream signal from noise, and this work may shed light on the biology underlying that process.
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1. Wellcome Trust Case Control C: Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature
2. Visscher Peter M, Brown Matthew A, McCarthy Mark I, Yang J: Five Years of GWAS Discovery. The American Journal of Human Genetics
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6. Viljanen A, Kaprio J, Pyykko I, Sorri M, Kauppinen M, Koskenvuo M, Rantanen T: Genetic and environmental influences on hearing at different frequencies separately for the better and worse hearing ear in older women. Int J Audiol
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8. Smits C, Kapteyn TS, Houtgast T: Development and validation of an automatic speech-in-noise screening test by telephone. Int J Audiol
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11. Richards JB, Kavvoura FK, Rivadeneira F, Styrkarsdottir U, Estrada K, Halldorsson BV, Hsu YH, Zillikens MC, Wilson SG, Mullin BH et al: Collaborative meta-analysis: associations of 150 candidate genes with osteoporosis and osteoporotic fracture. Ann Intern Med
12. Friedman RA, Van Laer L, Huentelman MJ, Sheth SS, Van Eyken E, Corneveaux JJ, Tembe WD, Halperin RF, Thorburn AQ, Thys S et al: GRM7 variants confer susceptibility to age-related hearing impairment. Hum Mol Genet
13. Van Laer L, Huyghe JR, Hannula S, Van Eyken E, Stephan DA, Maki-Torkko E, Aikio P, Fransen E, Lysholm-Bernacchi A, Sorri M et al: A genome-wide association study for age-related hearing impairment in the Saami. Eur J Hum Genet
14. Wolber LE, Girotto G, Buniello A, Vuckovic D, Pirastu N, Lorente-Canovas B, Rudan I, Hayward C, Polasek O, Ciullo M et al: Salt-inducible kinase 3, SIK3, is a new gene associated with hearing. Hum Mol Genet