RESUMEN
Population isolates such as those in Finland benefit genetic research because deleterious alleles are often concentrated on a small number of low-frequency variants (0.1% ≤ minor allele frequency < 5%). These variants survived the founding bottleneck rather than being distributed over a large number of ultrarare variants. Although this effect is well established in Mendelian genetics, its value in common disease genetics is less explored1,2. FinnGen aims to study the genome and national health register data of 500,000 Finnish individuals. Given the relatively high median age of participants (63 years) and the substantial fraction of hospital-based recruitment, FinnGen is enriched for disease end points. Here we analyse data from 224,737 participants from FinnGen and study 15 diseases that have previously been investigated in large genome-wide association studies (GWASs). We also include meta-analyses of biobank data from Estonia and the United Kingdom. We identified 30 new associations, primarily low-frequency variants, enriched in the Finnish population. A GWAS of 1,932 diseases also identified 2,733 genome-wide significant associations (893 phenome-wide significant (PWS), P < 2.6 × 10-11) at 2,496 (771 PWS) independent loci with 807 (247 PWS) end points. Among these, fine-mapping implicated 148 (73 PWS) coding variants associated with 83 (42 PWS) end points. Moreover, 91 (47 PWS) had an allele frequency of <5% in non-Finnish European individuals, of which 62 (32 PWS) were enriched by more than twofold in Finland. These findings demonstrate the power of bottlenecked populations to find entry points into the biology of common diseases through low-frequency, high impact variants.
Asunto(s)
Enfermedad , Frecuencia de los Genes , Fenotipo , Humanos , Persona de Mediana Edad , Enfermedad/genética , Estonia , Finlandia , Frecuencia de los Genes/genética , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Metaanálisis como Asunto , Reino Unido , Población Blanca/genéticaRESUMEN
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.
Asunto(s)
Sordera , Pérdida Auditiva , Animales , Cóclea , Estudio de Asociación del Genoma Completo , Pérdida Auditiva/genética , Humanos , Ratones , Estría VascularRESUMEN
INTRODUCTION: Well-differentiated thyroid cancer is among the most common types of endocrine cancer. Despite its increasing prevalence, the prognosis of thyroid cancer is rather good, with a five-year survival rate ranging between 80% and 90%, depending on the histological type. Not only the post-treatment complications and the side effects of the lifelong medication but also the possibility of a recurrence may have a negative impact on the patient's quality of life (QoL). OBJECTIVE: The aim of this study is to investigate the impact of total thyroidectomy on the QoL of patients with well-differentiated thyroid carcinoma. METHODS: A prospective study was performed in patients who underwent total thyroidectomy due to well-differentiated thyroid carcinoma in the Otolaryngology-Head and Neck Surgery Department at the University Hospital of Larissa, Greece. The QoL was evaluated based on the "Quality of Life (Thyroid Version)" questionnaire. RESULTS: One hundred patients participated in the study, with a mean age of 51.24±15.33 years. Of these, 63 (63%) were females and 37 (37%) were males. Social concerns, physical well-being, and psychological well-being presented a gradual positive alteration during the first 12 months after the surgery, with psychological well-being reporting the most significant progress of 15.3%. However, spiritual well-being appeared to decline over time. The younger patients progressively improved their physical, psychological, and mental well-being; however, the older patients showed an amelioration of their social skills. Female patients reported higher levels of spiritual well-being, whereas males developed better social skills. CONCLUSIONS: In the long term, total thyroidectomy can ameliorate patients' physical status, psychological well-being, and social concerns. However, it might have a negative effect on their mental health during the first 12 months postoperatively. In addition, QoL is directly influenced by demographic characteristics such as age and gender.
RESUMEN
To evaluate the genetics of chronic nonsuppurative otitis media (OM). We performed a genome-wide association study of 429,599 individuals included in the FinnGen study using three different case definitions: combined chronic nonsuppurative OM (7034 cases) (included serous and mucous chronic OM), mucous chronic OM (5953 cases), and secretory chronic OM (1689 cases). Individuals without otitis media were used as controls (417,745 controls). We used immunohistochemistry (IHC) of the murine middle ear to evaluate the expression of annexin A13. Four loci were significantly associated (p < 1.7 × 10-8) with nonsuppurative OM. Three out of the four association signals included missense variants in genes that may play a role in otitis media pathobiology. According to our subtype-specific analyses, one novel locus, located near ANXA13, was associated with secretory OM. Three loci (near TNFRSF13B, GAS2L2, and TBX1) were associated with mucous OM. Immunohistochemistry of murine middle ear samples revealed annexin A13 expression at the apical pole of the Eustachian tube epithelium as well as variable intensity of the secretory cells of the glandular structure in proximity to the Eustachian tube. We demonstrated that secretory and mucous OM have distinct and shared genetic associations. The association of GAS2L2 with ciliary epithelium function and the pathogenesis of dysfunctional mucosa in mucous OM is suggested. The abundant expression of annexin A13 in the Eustachian tube epithelium, along with its role in apical transport for the binding and transfer of phospholipids, indicates the role of annexin A13 and phospholipids in Eustachian tube dysfunction.
Asunto(s)
Anexinas , Estudio de Asociación del Genoma Completo , Otitis Media , Animales , Anexinas/genética , Anexinas/metabolismo , Humanos , Ratones , Otitis Media/genética , Otitis Media/metabolismo , Otitis Media/patología , Femenino , Masculino , Oído Medio/metabolismo , Oído Medio/patología , Polimorfismo de Nucleótido Simple , Predisposición Genética a la Enfermedad , Trompa Auditiva/patología , Trompa Auditiva/metabolismoRESUMEN
Nocardia is regarded as an opportunistic pathogen primarily affecting the respiratory system, whereas Nocardia farcinica is the species of the Nocardia family that is most frequently blamed for central nervous system impairment. The authors present the first case of mastoiditis caused by Nocardia farcinica, accompanied by intracranial complications. An immunocompetent 74-year-old woman who reported a three-week left ear discharge and a two-week facial nerve palsy was referred to our department. MRI revealed mastoiditis and epidural abscess. The bacterial cultures obtained during the surgical management of the patient confirmed the presence of Nocardia farcinica. Targeted antibiotic therapy was subsequently administrated, gradually resulting in favourable outcomes. Nocardia species provoke a disseminated infection that emerges not only among the immunosuppressed individuals but can also affect the healthy population. The nonspecific clinical manifestations in addition to the difficulties identifying the pathogen, remain obstacles to a punctual diagnosis. However, the combination of surgical debridement and antibiotic treatment with trimethoprim and sulfamethoxazole is considered the most appropriate management, leading to propitious results.
RESUMEN
Our aim was to evaluate the effects of balloon sinuplasty on the size of the ostium in the maxillary sinuses in patients with chronic rhinosinusitis from cone beam computer tomography (CBCT) scans of the sinus. This is a blinded retrospective trial in patients who had undergone balloon sinuplasty of the maxillary sinus. CBCT scans were taken and SNOT-22 Quality of Life questionnaire completed before and 12 months after the operation. The size of the maxillary ostium was measured from the CBCT scans three-dimensionally. The association of changes in the SNOT-22 scores of the ostium was analysed. We discovered that the balloon sinuplasty increased the size of the maxillary ostium in all dimensions. The changes were statistically significant (p<0.05) in the axial diameter and the ostium area. The number of patent ostia increased after the intervention. The association between SNOT-22 score and ostium patency were statistically significant before the operation. Our conclusion is that the threedimensional measuring technique provides a reliable method to evaluate ostium dimensions. Balloon sinuplasty increased the size of the maxillary ostium and the result was maintained for 12 months after the operation.
Asunto(s)
Tomografía Computarizada de Haz Cónico/métodos , Seno Maxilar/cirugía , Sinusitis/cirugía , Adulto , Dilatación , Femenino , Humanos , Imagenología Tridimensional , Masculino , Calidad de Vida , Estudios Retrospectivos , Sinusitis/fisiopatologíaRESUMEN
The bone encasing the inner ear, known as the otic capsule, is unique because it remodels little postnatally compared to other bones in the body. Previous studies established that osteoprotegerin (OPG) in the inner ear inhibits otic capsule remodeling. OPG acts as a decoy receptor of receptor activator of nuclear factor κB ligand (RANKL) to disrupt the interaction between RANKL and RANK, the primary regulators of bone metabolism. Here we studied the expression and function of RANK and RANKL in the murine cochlea. Using a combination of in situ hybridization, real-time quantitative RT-PCR, and western blot, we demonstrate that Rankl and Rank genes and their protein products are expressed in the intracochlear soft tissues and the otic capsule in a developmentally regulated manner. Using a culture of neonatal murine cochlear neurons, we show that the interaction between RANK and RANKL inhibits neurite outgrowth in these neurons, and is associated with upregulation of NOGO-A expression. Taken together, our results suggest that, in addition to regulating otic capsule bone remodeling, RANK and RANKL expressed by intracochlear soft tissues may also regulate spiral ganglion neuron function by affecting neurite outgrowth.