Genes and lifestyle in normal hearing function and age-related hearing loss

The auditory system is a complex machinery, constituted by many molecules involving hair cells, cochlear neurons, the stria vascularis, and combinations thereof. The analysis of complex genetic traits/diseases such as normal hearing function and Age-Related Hearing Loss has long been an enigma of genetic biology, whether in the animal or in medical sciences. In particular, Age-Related Hearing Loss is the most prevalent sensory impairment in the elderly affecting 30% of people aged over 60. The disease is not directly life threatening but it contributes to loss of autonomy and is associated with anxiety, depression, and cognitive decline largely compromising the quality of life. Until now, only few genes are known to contribute to variability of normal hearing function and Age-Related Hearing Loss. In both cases interactions between lifestyle and environmental determinants as well as several molecular and cellular basis and pathways should be taken into account. The main aim of the thesis is the understanding of the molecular bases of variation of normal hearing function and Age-Related Hearing Loss using: a) Genome Wide Association Studies to identify new genes/loci, b) immunohistochemistry to evaluate their expression in the mouse cochlea and c) epidemiological studies to identify environmental/lifestyle factors. Genome-Wide Association studies and the following Meta-analysis have been carried out on 3815 people coming from isolated villages located in Italy, Croatia, Caucasus and central Asia recruited within the International Consortium G-EAR leading to the identification of 3 loci (rs614171 on chromosome 13, rs3786724 on chromosome 19, rs11711388 on chromosome 3) with p-value?1*10-8, 26 loci with p-value ?1*10-7 and many others with high p-value. 23 genes have been then chosen for evaluation using expression studies in wildtype mice by immunohistochemistry and confocal microscopy. Five of them (Arsg, Slc16a6, Dclk1, Gabrg3, Csmd1) display strikingly specific expression in the cochlea and additional eight (Ptprd, Grm8, 7 Kiaa056/GlyBP, Evi5, Irg1, Rimbp2, Ank2, Cdh13) show expression in multiple cell types of the cochlea. As regards environmental/lifestyle factors, the epidemiological analysis revealed that coffee consumption (coffee yes vs. no) and coffee intake (cups/day) displayed a significant association with better hearing function in four out of ten populations investigated. In particular, coffee drinking was associated at low and high frequencies (lowest p-value=0.006) while the intake only at high frequency (lowest p-value=0.003). Moreover, a statistical significant association between ARHL and education level was detected (lowest p-value=0.0003) confirming previously reported data.