Unravelling the genetic bases of the sense of smell: clinical and molecular characterisation of a large cohort of COVID-19 patients with persistent olfactory dysfunction

Despite olfaction plays an essential role in modulating human behaviour and survival, its dysregulations are often underestimated. However, the recent COVID-19 pandemic has risen considerable awareness towards a very common smell alteration, namely post-viral olfactory dysfunction (PVOD). As there are remarkable differences in the development of this disorder between people affected even by the same strain of SARS-CoV-2, it is believed that host genetic factors are involved in its etiopathogenesis. In this light, the goal of this study was to explore the molecular bases of COVID-19-related PVOD through the analysis of Whole Genome Sequencing (WGS) data of 153 deeply characterised subjects presenting the condition. To achieve this aim, a detailed personal anamnesis was collected and orthonasal olfactory function was evaluated through the extended Sniffin’ Sticks test (Threshold – Identification - Discrimination scores - TDI). All coding variants in a manually curated shortlist of 298 genes involved in antiviral response regulation were extracted from WGS data. For each gene and for each individual, a gene score, defined as the ratio of the number of homozygous alternative variants within the gene to its length, was calculated. The association between the gene score and TDI results was tested with linear regression models. Overall, 475 biallelic variants in 177 genes were extracted and exploited to calculate the gene score, with the following statistically significant results: • ACE2 increased gene score is associated with a worsen olfactory performance in females (combined TDI p-value = 0.03; Discrimination subtest p-value = 0.03). • IFI44 increased gene score is associated with a better smell function in males (Discrimination subtest p-value = 0.01). • NDUFAF4 increased gene score is associated with a better olfactory performance in males (Discrimination subtest p-value = 0.004). Considering the physiological role of the proteins encoded by these genes and literature data, it can be hypothesised that a reduced expression of ACE2 may be associated with a protracted and severe inflammatory response in the olfactory epithelium, thus worsening patients’ smell abilities. Conversely, an increased gene score in IFI44 and NDUFAF4 might be associated with a decreased inflammatory response, thus correlating with a better olfactory performance. In conclusion, this study identified new host genetic factors that may play a pivotal role in determining the interindividual variability of COVID-19-related PVOD, thus shedding light on the genetic architecture of long-lasting smell loss and opening new possibilities to better clarify the molecular mechanisms underlying the complex physiology of the olfactory system.