Genome-wide association meta-analysis identifies 48 risk variants and highlights the role of the stria vascularis in hearing loss

Hearing loss is one of the top contributors to years lived with disability and is a risk factor for dementia. Molecular evidence on the cellular origins of hearing loss in humans is growing. Here, we performed a genome-wide association meta-analysis of clinically diagnosed and self-reported hearing impairment on 723,266 individuals and identified 48 significant loci, 10 of which are novel. A large proportion of associations comprised missense variants, half of which lie within known familial hearing loss loci. We used single-cell RNA-sequencing data from mouse cochlea and brain and mapped common-variant genomic results to spindle, root, and basal cells from the stria vascularis, a structure in the cochlea necessary for normal hearing. Our findings indicate the importance of the stria vascularis in the mechanism of hearing impairment, providing future paths for developing targets for therapeutic intervention in hearing loss

nfluence of antidepressants on glucose homeostasis : effects and mechanisms

Depression has shown to be a common morbidity in patients with diabetes mellitus and comorbid depression in diabetes mellitus patients is frequently treated with antidepressants. It has been postulated that antidepressants may interfere with glucose homeostasis and that the interference of antidepressants with glucose homeostasis, at least partly, depends on the complex pharmacology of antidepressants. If antidepressants indeed interfere with glucose homeostasis, glycaemic control could be further complicated, which is a limiting factor to prevent, or delay long-term microvascular complications. There are two main objectives in this thesis. The first objective is to investigate the relative risk of hyper- and hypoglycaemia or other metabolic changes associated with antidepressant use. The second objective is to elucidate the mechanism behind antidepressant related disturbances in glucose homeostasis from a pharmacological perspective and to find out which patients are at risk. The first part of this thesis (Chapter 2) focuses on the receptor binding profiles of antidepressants in relation to adverse drug reaction profiles of antidepressants. We presented a novel model to classify antidepressants based on their binding properties of most common receptor- and transporter sites for a better understanding of receptor-mediated pharmacological action of antidepressants. In addition, we evaluated the pharmacological classification with the traditional classification of antidepressants through an analysis of type A and type B adverse drug reaction (ADR) categories. We found that the pharmacological classification of antidepressants may be helpful to predict type A ADR profiles of antidepressants. In Chapter 3, we used this pharmacological classification to elucidate the mechanism of antidepressant-related disturbances in glucose homeostasis from a pharmacological perspective. Chapter 3 focuses on the association between antidepressant use and interference with glucose homeostasis. The studies in Chapter 3 show that antidepressants interfere with glucose homeostasis and that the antidepressants are associated with both hyper- and hypoglycaemia. In several studies, we observed a statistical significant association between antidepressant use and effects on glucose homeostasis. In other studies, we observed a statistically non-significant association. However, direction of effects of antidepressants on glucose homeostasis was consistent in all studies. We showed that antidepressants with common binding affinity for the norepineprine transporter, histamine 1 receptor and serotonin 2C receptor are associated to hyperglycaemic effects and may contribute to deterioration of diabetes mellitus. Antidepressants with selective binding affinity for the serotonin transporter may have hypoglycaemic effects and may have insulin sparing effects in patients with diabetes. In conclusion, the findings from the studies in this thesis justify the conclusion that antidepressants may disturb glucose homeostasis. The risk of severe antidepressant-related disturbances in glucose homeostasis may be small, but even so the fact that depression and diabetes mellitus are common diseases and they often co-occur, even a small risk has major impact on population level. It is important that patients, physicians and pharmacists are informed about the effects of antidepressants on glucose homeostasis so that they can use this information for better prescribing and use of antidepressants