The UGT2A1/UGT2A2 locus is associated with COVID-19-related loss of smell or taste.

Using online surveys, we collected data regarding COVID-19-related loss of smell or taste from 69,841 individuals. We performed a multi-ancestry genome-wide association study and identified a genome-wide significant locus in the vicinity of the UGT2A1 and UGT2A2 genes. Both genes are expressed in the olfactory epithelium and play a role in metabolizing odorants. These findings provide a genetic link to the biological mechanisms underlying COVID-19-related loss of smell or taste.

Integrating pheromonal and spatial information in the amygdalo-hippocampal network.

Vomeronasal information is critical in mice for territorial behavior. Consequently, learning the territorial spatial structure should incorporate the vomeronasal signals indicating individual identity into the hippocampal cognitive map. In this work we show in mice that navigating a virtual environment induces synchronic activity, with causality in both directionalities, between the vomeronasal amygdala and the dorsal CA1 of the hippocampus in the theta frequency range. The detection of urine stimuli induces synaptic plasticity in the vomeronasal pathway and the dorsal hippocampus, even in animals with experimentally induced anosmia. In the dorsal hippocampus, this plasticity is associated with the overexpression of pAKT and pGSK3ß. An amygdalo-entorhino-hippocampal circuit likely underlies this effect of pheromonal information on hippocampal learning. This circuit likely constitutes the neural substrate of territorial behavior in mice, and it allows the integration of social and spatial information.

Effect of the rs2890498 polymorphism of the OBPIIa gene on the human ability to smell single molecules.

Most odors of foods and drinks are mixtures of molecules. By means of the coupled Gas Chromatography-Olfactometry (GC-O) technique, single components of flavor mixtures can be separated, identified and verbally evaluated by subjects. The number of single molecules smelled by subjects during GC-O analysis (i.e., the number of odor-active compounds) was previously found to be linearly correlated with odor Threshold (T) score. Using the "Sniffin' Sticks" test, the same subjects were classified as normosmic or hyposmic. Hydrophobic odorants are captured and transported through the mucus layer by the odorant binding proteins (OBPs), particularly expressed in the olfactory cleft and associated with the olfactory function. In this study, subjects were genotyped for the rs2590498 (A/G) polymorphism of the OBPIIa gene, whose major allele A is associated with a higher olfactory sensitivity as compared to the minor allele G. One-way ANOVA showed a significant effect of the genotype of the OBPIIa locus on the: a) T score; b) number of odor-active compounds smelled; c) intensity perceived when sniffing the complex odor of banana. In conclusion, the threshold olfactory performance, but also the individual ability to smell single molecules, can be attributed, partly at least, to the rs2590498 polymorphism of the OBPIIa gene.

Congenital Hypogonadotropic Hypogonadism with Anosmia and Gorlin Features Caused by a PTCH1 Mutation Reveals a New Candidate Gene for Kallmann Syndrome.

BACKGROUND: Two loci (CHD7 and SOX10) underlying Kallmann syndrome (KS) were discovered through clinical and genetic analysis of CHARGE and Waardenburg syndromes, conditions that include congenital anosmia caused by olfactory bulb (CA/OBs) defects and congenital hypogonadotropic hypogonadism (CHH). We hypothesized that other candidate genes for KS could be discovered by analyzing rare syndromes presenting with these signs. Study Design, Size, Duration: We first investigated a family with Gorlin-Goltz syndrome (GGS) in which affected members exhibited clinical signs suggesting KS. Participants/Materials, Methods: Proband and family members underwent detailed clinical assessment. The proband received detailed neuroendocrine evaluation. Genetic analyses included sequencing the PTCH1 gene at diagnosis, followed by exome analyses of causative or candidate KS/CHH genes, in order to exclude contribution to the phenotypes of additional mutations. Exome analyses in additional 124 patients with KS/CHH probands with no additional GGS signs. RESULTS: The proband exhibited CA, absent OBs on magnetic resonance imaging, and had CHH with unilateral cryptorchidism, consistent with KS. Pulsatile Gonadotropin-releasing hormone (GnRH) therapy normalized serum gonadotropins and increased testosterone levels, supporting GnRH deficiency. Genetic studies revealed 3 affected family members harbor a novel mutation of PTCH1 (c.838G> T; p.Glu280*). This unreported nonsense deleterious mutation results in either a putative truncated Ptch1 protein or in an absence of translated Ptch1 protein related to nonsense mediated messenger RNA decay. This heterozygous mutation cosegregates in the pedigree with GGS and CA with OBs aplasia/hypoplasia and with CHH in the proband suggesting a genetic linkage and an autosomal dominant mode of inheritance. No pathogenic rare variants in other KS/CHH genes cosegregated with these phenotypes. In additional 124 KS/CHH patients, 3 additional heterozygous, rare missense variants were found and predicted in silico to be damaging: p.Ser1203Arg, p.Arg1192Ser, and p.Ile108Met. CONCLUSION: This family suggests that the 2 main signs of KS can be included in GGS associated with PTCH1 mutations. Our data combined with mice models suggest that PTCH1 could be a novel candidate gene for KS/CHH and reinforce the role of the Hedgehog signaling pathway in pathophysiology of KS and GnRH neuron migration.

Further delineation of a recognizable type of syndromic short stature caused by biallelic SEMA3A loss-of-function variants.

The semaphorin protein family is a diverse set of extracellular signaling proteins that perform fundamental roles in the development and operation of numerous biological systems, notably the nervous, musculoskeletal, cardiovascular, endocrine, and reproductive systems. Recently, recessive loss-of-function (LoF) variants in SEMA3A (semaphorin 3A) have been shown to result in a recognizable syndrome characterized by short stature, skeletal abnormalities, congenital heart defects, and variable additional anomalies. Here, we describe the clinical and molecular characterization of a female patient presenting with skeletal dysplasia, hypogonadotropic hypogonadism (HH), and anosmia who harbors a nonsense variant c.1633C>T (p.Arg555*) and a deletion of exons 15, 16, and 17 in SEMA3A in the compound heterozygous state. These variants were identified through next-generation sequencing analysis of a panel of 26 genes known to be associated with HH/Kallmann syndrome. Our findings further substantiate the notion that biallelic LoF SEMA3A variants cause a syndromic form of short stature and expand the phenotypic spectrum associated with this condition to include features of Kallmann syndrome.

Individual Differences in Thresholds and Consumer Preferences for Rotundone Added to Red Wine.

Rotundone is an aromatic compound found in the skin of some grapes (e.g., Shiraz, Noiret) that contributes peppery notes to wines made with these varieties. There may be a specific anosmia for rotundone, as some individuals are unable to detect it even at high concentrations, despite otherwise normal olfaction. This may affect perception of and preference for rotundone-containing wines. Here, we report rotundone detection thresholds (orthonasal n = 56; retronasal n = 53) and rejection thresholds (n = 86) in red wine for a convenience sample of non-expert consumers in Pennsylvania. Focus groups were conducted to better understand consumer attitudes and preferences for rotundone. Ortho- and retronasal detection thresholds were nearly identical (140 v. 146 ng/L). Roughly 40% of our sample was anosmic to rotundone, extending evidence for a specific anosmia to a North American cohort. As ortho- and retronasal thresholds were extremely similar, future work on rotundone can rely on orthonasal assessment. In our participants, added rotundone was generally disliked, and in focus groups, the concept of a 'peppery' wine was not appealing. Winemakers need to carefully consider biological and attitudinal segmentation when making and marketing peppery wines. Further work is needed to identify the genetic basis for this anosmia.

Co­expression of peripheral olfactory receptors with SARS­CoV­2 infection mediators: Potential implications beyond loss of smell as a COVID­19 symptom.

Severe acute respiratory syndrome (SARS) coronavirus­2 (SARS­CoV­2) enters into human host cells via mechanisms facilitated mostly by angiotensin­converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2). New loss of smell (anosmia/hyposmia) is now recognized as a COVID­19 related symptom, which may be caused by SARS­CoV­2 infection and damage of the olfactory receptor (OR) cells in the nasal neuro­epithelium and/or central involvement of the olfactory bulb. ORs are also expressed peripherally (e.g., in tissues of the gastrointestinal and respiratory systems) and it is possible that their local functions could also be impaired by SARS­CoV­2 infection of these tissues. Using Gene Expression Profiling Interactive Analysis, The Cancer Genome Atlas, Genotype­Tissue Expression, cBioPortal and Shiny Methylation Analysis Resource Tool, we highlight the expression of peripheral ORs in both healthy and malignant tissues, and describe their co­expression with key mediators of SARS­CoV­2 infection, such as ACE2 and TMPRSS2, as well as cathepsin L (CTSL; another cellular protease mediating SARS­CoV­2 infection of host cells). A wide expression profile of peripheral ORs was noted, particularly in tissues such as the prostate, testis, thyroid, brain, liver, kidney and bladder, as well as tissues with known involvement in cardio­metabolic disease (e.g., the adipose tissue, pancreas and heart). Among these, OR51E2, in particular, was significantly upregulated in prostate adenocarcinoma (PRAD) and co­expressed primarily with TMPRSS2. Functional networks of this OR were further analysed using the GeneMANIA interactive tool, showing that OR51E2 interacts with a plethora of genes related to the prostate. Further in vitro and clinical studies are clearly required to elucidate the role of ORs, both at the olfactory level and the periphery, in the context of COVID­19.