Hearing difficulty is linked to Alzheimer’s disease by common genetic vulnerability, not shared genetic architecture

Age-related hearing loss was recently established as the largest modifiable risk factor for Alzheimer’s disease (AD), however, the reasons for this link remain unclear. We investigate shared underlying genetic associations using results from recent large genome-wide association studies (GWAS) on adult hearing difficulty and AD. Genetic correlation and Mendelian randomization (MR) analysis do not support a genetic correlation between the disorders, but suggest a direct causal link from AD genetic risk to hearing difficulty, driven by APOE. Systematic MR analyses on the effect of other traits revealed shared effects of glutamine, gamma-glutamylglutamine, and citrate levels on reduced risk of both hearing difficulty and AD. In addition, pathway analysis on GWAS risk variants suggests shared function in neuronal signalling pathways as well as etiology of diabetes and cardiovascular disease. However, after multiple testing corrections, neither analysis led to statistically significant associations. Altogether, our genetic-driven analysis suggests hearing difficulty and AD are linked by a shared vulnerability in molecular pathways rather than by a shared genetic architecture

Ketamine Restores Thalamic-Prefrontal Cortex Functional Connectivity in a Mouse Model of Neurodevelopmental Disorder-Associated 2p16.3 Deletion

2p16.3 deletions, involving heterozygous NEUREXIN1 (NRXN1) deletion, dramatically increase the risk of developing neurodevelopmental disorders, including autism and schizophrenia. We have little understanding of how NRXN1 heterozygosity increases the risk of developing these disorders, particularly in terms of the impact on brain and neurotransmitter system function and brain network connectivity. Thus, here we characterize cerebral metabolism and functional brain network connectivity in Nrxn1α heterozygous mice (Nrxn1α+/− mice), and assess the impact of ketamine and dextro-amphetamine on cerebral metabolism in these animals. We show that heterozygous Nrxn1α deletion alters cerebral metabolism in neural systems implicated in autism and schizophrenia including the thalamus, mesolimbic system, and select cortical regions. Nrxn1α heterozygosity also reduces the efficiency of functional brain networks, through lost thalamic “rich club” and prefrontal cortex (PFC) hub connectivity and through reduced thalamic-PFC and thalamic “rich club” regional interconnectivity. Subanesthetic ketamine administration normalizes the thalamic hypermetabolism and partially normalizes thalamic disconnectivity present in Nrxn1α+/− mice, while cerebral metabolic responses to dextro-amphetamine are unaltered. The data provide new insight into the systems-level impact of heterozygous Nrxn1α deletion and how this increases the risk of developing neurodevelopmental disorders. The data also suggest that the thalamic dysfunction induced by heterozygous Nrxn1α deletion may be NMDA receptor-dependent

Differential regulation of mammalian and avian ATOH1 by E2F1 and its implication for hair cell regeneration in the inner ear

The mammalian inner ear has a limited capacity to regenerate its mechanosensory hair cells. This lack of regenerative capacity underlies the high incidence of age-related hearing loss in humans. In contrast, non-mammalian vertebrates can form new hair cells when damage occurs, a mechanism that depends on re-activation of expression of the pro-hair cell transcription factor Atoh1. Here, we show that members of the E2F transcription factor family, known to play a key role in cell cycle progression, regulate the expression of Atoh1. E2F1 activates chicken Atoh1 by directly interacting with a cis-regulatory region distal to the avian Atoh1 gene. E2F does not activate mouse Atoh1 gene expression, since this regulatory element is absent in mammals. We also show that E2F1 expression changes dynamically in the chicken auditory epithelium during ototoxic damage and hair cell regeneration. Therefore, we propose a model in which the mitotic regeneration of non-mammalian hair cells is due to E2F1-mediated activation of Atoh1 expression, a mechanism which has been lost in mammals

Disruption of SorCS2 reveals differences in the regulation of stereociliary bundle formation between hair cell types in the inner ear

Behavioural anomalies suggesting an inner ear disorder were observed in a colony of transgenic mice. Affected animals were profoundly deaf. Severe hair bundle defects were identified in all outer and inner hair cells (OHC, IHC) in the cochlea and in hair cells of vestibular macular organs, but hair cells in cristae were essentially unaffected. Evidence suggested the disorder was likely due to gene disruption by a randomly inserted transgene construct. Whole-genome sequencing identified interruption of the SorCS2 (Sortilin-related VPS-10 domain containing protein) locus. Real-time-qPCR demonstrated disrupted expression of SorCS2 RNA in cochlear tissue from affected mice and this was confirmed bySorCS2 immuno-labelling. In all affected hair cells, stereocilia were shorter than normal, but abnormalities of bundle morphology and organisation differed between hair cell types. Bundles on OHC were grossly misshapen with significantly fewer stereocilia than normal. However, stereocilia were organised in rows of increasing height. Bundles on IHC contained significantly more stereocilia than normal with some longer stereocilia towards the centre, or with minimal height differentials. In early postnatal mice, kinocilia (primary cilia) of IHC and of OHC were initially located towards the lateral edge of the hair cell surface but often became surrounded by stereocilia as bundle shape and apical surface contour changed. In macular organs the kinocilium was positioned in the centre of the cell surface throughout maturation. There was disruption of the signalling pathway controlling intrinsic hair cell apical asymmetry. LGN and Gαi3 were largely absent, and atypical Protein Kinase C (aPKC) lost its asymmetric distribution. The results suggest that SorCS2 plays a role upstream of the intrinsic polarity pathway and that there are differences between hair cell types in the deployment of the machinery that generates a precisely organised hair bundle

Genome-wide association study suggests that variation at the RCOR1 locus is associated with tinnitus in UK Biobank

Tinnitus is a prevalent condition in which perception of sound occurs without an external stimulus. It is often associated with pre-existing hearing loss or noise-induced damage to the auditory system. In some individuals it occurs frequently or even continuously and leads to considerable distress and difficulty sleeping. There is little knowledge of the molecular mechanisms involved in tinnitus which has hindered the development of treatments. Evidence suggests that tinnitus has a heritable component although previous genetic studies have not established specific risk factors. From a total of 172,608 UK Biobank participants who answered questions on tinnitus we performed a case-control genome-wide association study for self-reported tinnitus. Final sample size used in association analysis was N = 91,424. Three variants in close proximity to the RCOR1 gene reached genome wide significance: rs4906228 (p = 1.7E-08), rs4900545 (p = 1.8E-08) and 14:103042287_CT_C (p = 3.50E-08). RCOR1 encodes REST Corepressor 1, a component of a co-repressor complex involved in repressing neuronal gene expression in non-neuronal cells. Eleven other independent genetic loci reached a suggestive significance threshold of p < 1E-06

Age-Related Hearing Loss

Age-related hearing loss (ARHL) is the most prevalent sensory deficit in the elderly. This progressive hearing impairment leads to social isolation and is also associated with comorbidities, such as frailty, falls, and late-onset depression. Moreover, there is a growing evidence linking it with cognitive decline and increased risk of dementia. Given the large social and welfare burden that results from ARHL, and because ARHL is potentially a modifiable risk factor for dementia, there is an urgent need for therapeutic interventions to ameliorate age-related auditory decline. However, a prerequisite for design of therapies is knowledge of the underlying molecular mechanisms. Currently, our understanding of ARHL is very limited. Here, we review recent findings from research into ARHL from both human and animal studies and discuss future prospects for advances in our understanding of genetic susceptibility, pathology, and potential therapeutic approaches in ARHL

Evidence of distinct RELN and TGFB1 genetic associations in familial and non-familial otosclerosis in a British population

Otosclerosis is a common form of hearing loss which typically presents in young adults. The disease has a familial, monogenic form and a non-familial form with a more complex aetiology. A previous genome wide association study identified evidence that variants within RELN are associated with the condition. Other genes in which an association has been reported include BMP2, COL1A1, FGF2, PPP2R5B and TGFB1. However, follow up studies have often failed to replicate initial positive results. The aim of this study was to establish if an association exists between eight single nucleotide polymorphisms (SNPs) in these six previously implicated genes and otosclerosis in a British case-control cohort (n = 748). Evidence of an association between rs1800472 in TGFB1 and otosclerosis was found (p = 0.034), this association was strongest amongst non-familial cases (p = 0.011). No evidence of an association was detected with variants in COL1A1, FGF2, BMP2, and PPP2R5B. No association between variation in RELN and otosclerosis was observed in the whole cohort. However, a significant association (p = 0.0057) was detected between one RELN SNP (rs39399) and otosclerosis in familial patients. Additionally, we identify expression of one RELN transcript in 51 of 81 human stapes tested, clarifying previous conflicting data as to whether RELN is expressed in the affected tissue. Our findings strengthen the association of TGFB1 (rs1800472) with otosclerosis and support a relationship between RELN and familial otosclerosis only, which may explain previous variable replications

Self-reported hearing loss questions provide a good measure for genetic studies: a polygenic risk score analysis from UK Biobank

Age-related hearing impairment (ARHI) is very common in older adults and has major impact on quality of life. The heritability of ARHI has been estimated to be around 50%. The present study aimed to estimate heritability and environmental contributions to liability of ARHI and the extent to which a polygenic risk score (PRS) derived from a recent genome-wide association study of questionnaire items regarding hearing loss using the UK Biobank is predictive of hearing loss in other samples. We examined (1) a sample from TwinsUK who have had hearing ability measured by pure-tone audiogram and the speech-to-noise ratio test as well as questionnaire measures that are comparable with the UK Biobank questionnaire items and (2) European and non-European samples from the UK Biobank which were not part of the original GWAS. Results indicated that the questionnaire items were over 50% heritable in TwinsUK and comparable with the objective hearing measures. In addition, we found very high genetic correlation (0.30–0.84) between the questionnaire responses and objective hearing measures in the TwinsUK sample. Finally, PRS computed from weighted UK Biobank GWAS results were predictive of both questionnaire and objective measures of hearing loss in the TwinsUK sample, as well as questionnaire-measured hearing loss in Europeans but not non-European subpopulations. These results demonstrate the utility of questionnaire-based methods in genetic association studies of hearing loss in adults and highlight the differences in genetic predisposition to ARHI by ethnic background

Long-term effects of chronic light pollution on seasonal functions of European blackbirds (turdus merula)

Light pollution is known to affect important biological functions of wild animals, including daily and annual cycles. However, knowledge about long-term effects of chronic exposure to artificial light at night is still very limited. Here we present data on reproductive physiology, molt and locomotor activity during two-year cycles of European blackbirds (Turdus merula) exposed to either dark nights or 0.3 lux at night. As expected, control birds kept under dark nights exhibited two regular testicular and testosterone cycles during the two-year experiment. Control urban birds developed testes faster than their control rural conspecifics. Conversely, while in the first year blackbirds exposed to light at night showed a normal but earlier gonadal cycle compared to control birds, during the second year the reproductive system did not develop at all: both testicular size and testosterone concentration were at baseline levels in all birds. In addition, molt sequence in light-treated birds was more irregular than in control birds in both years. Analysis of locomotor activity showed that birds were still synchronized to the underlying light-dark cycle. We suggest that the lack of reproductive activity and irregular molt progression were possibly the results of i) birds being stuck in a photorefractory state and/or ii) chronic stress. Our data show that chronic low intensities of light at night can dramatically affect the reproductive system. Future studies are needed in order to investigate if and how urban animals avoid such negative impact and to elucidate the physiological mechanisms behind these profound long-term effects of artificial light at night. Finally we call for collaboration between scientists and policy makers to limit the impact of light pollution on animals and ecosystems

Mutations and altered expression of SERPINF1 in patients with familial otosclerosis

Otosclerosis is a relatively common heterogenous condition, characterized by abnormal bone remodelling in the otic capsule leading to fixation of the stapedial footplate and an associated conductive hearing loss. Although familial linkage and candidate gene association studies have been performed in recent years, little progress has been made in identifying disease-causing genes. Here, we used whole-exome sequencing in four families exhibiting dominantly inherited otosclerosis to identify 23 candidate variants (reduced to 9 after segregation analysis) for further investigation in a secondary cohort of 84 familial cases. Multiple mutations were found in the SERPINF1 (Serpin Peptidase Inhibitor, Clade F) gene which encodes PEDF (pigment epithelium-derived factor), a potent inhibitor of angiogenesis and known regulator of bone density. Six rare heterozygous SERPINF1 variants were found in seven patients in our familial otosclerosis cohort; three are missense mutations predicted to be deleterious to protein function. The other three variants are all located in the 5'-untranslated region (UTR) of an alternative spliced transcript SERPINF1-012 RNA-seq analysis demonstrated that this is the major SERPINF1 transcript in human stapes bone. Analysis of stapes from two patients with the 5'-UTR mutations showed that they had reduced expression of SERPINF1-012 All three 5'-UTR mutations are predicted to occur within transcription factor binding sites and reporter gene assays confirmed that they affect gene expression levels. Furthermore, RT-qPCR analysis of stapes bone cDNA showed that SERPINF1-012 expression is reduced in otosclerosis patients with and without SERPINF1 mutations, suggesting that it may be a common pathogenic pathway in the disease