Age-related hearing loss (ARHL) is the most common sensory disorder in the elderly. Although not directly life threatening, it contributes to loss of autonomy and is associated with anxiety, depression and cognitive decline. To search for genetic risk factors underlying ARHL, a large whole-genome sequencing (WGS) approach has been carried out in a cohort of 212 cases and controls, both older than 50 years to select genes characterized by a burden of variants specific to cases or controls.Accordingly, the total variation load per gene was compared and two groups were detected: 375 genes more variable in cases and 371 more variable in controls. In both cases, Gene Ontology analysis showed that the largest enrichment for biological processes (fold > 5, p-value = 0.042) was the “sensory perception of sound”, suggesting cumulative genetic effects were involved. Replication confirmed 141 genes, while additional analysis based on natural selection led to a prioritization of 21 genes. The majority of them (20 out of 21) showed positive expression in mouse cochlea cDNA and were associated with two functional pathways. Among them, two genes were previously associated with hearing (CSMD1 and PTRPD) and resequenced in a large Italian cohort of ARHL patients (N = 389). Results led to the identification of six coding variants not detected in cases so far, suggesting a possible protective role, which requires investigation. In conclusion, we show that this multistep strategy (WGS, selection, expression, pathway analysis and targeted re-sequencing) can provide major insights into the molecular characterization of complex diseases such as ARHL.

Whole-genome sequencing reveals new insights into age-related hearing loss: cumulative effects, pleiotropy and the role of selection / D. Vuckovic, M. Mezzavilla, M. Cocca, A. Morgan, M. Brumat, E. Catamo, M.P. Concas, G. Biino, A. Franzè, U. Ambrosetti, M. Pirastu, P. Gasparini, G. Girotto. - In: EUROPEAN JOURNAL OF HUMAN GENETICS. - ISSN 1018-4813. - (2018). [Epub ahead of print]

Whole-genome sequencing reveals new insights into age-related hearing loss: cumulative effects, pleiotropy and the role of selection

U. Ambrosetti;
2018

Abstract

Age-related hearing loss (ARHL) is the most common sensory disorder in the elderly. Although not directly life threatening, it contributes to loss of autonomy and is associated with anxiety, depression and cognitive decline. To search for genetic risk factors underlying ARHL, a large whole-genome sequencing (WGS) approach has been carried out in a cohort of 212 cases and controls, both older than 50 years to select genes characterized by a burden of variants specific to cases or controls.Accordingly, the total variation load per gene was compared and two groups were detected: 375 genes more variable in cases and 371 more variable in controls. In both cases, Gene Ontology analysis showed that the largest enrichment for biological processes (fold > 5, p-value = 0.042) was the “sensory perception of sound”, suggesting cumulative genetic effects were involved. Replication confirmed 141 genes, while additional analysis based on natural selection led to a prioritization of 21 genes. The majority of them (20 out of 21) showed positive expression in mouse cochlea cDNA and were associated with two functional pathways. Among them, two genes were previously associated with hearing (CSMD1 and PTRPD) and resequenced in a large Italian cohort of ARHL patients (N = 389). Results led to the identification of six coding variants not detected in cases so far, suggesting a possible protective role, which requires investigation. In conclusion, we show that this multistep strategy (WGS, selection, expression, pathway analysis and targeted re-sequencing) can provide major insights into the molecular characterization of complex diseases such as ARHL.
Settore MED/03 - Genetica Medica
Settore MED/32 - Audiologia
30-apr-2018
Article (author)
File in questo prodotto:
File Dimensione Formato  
Vuckovic D et al 2018 (IF = 4.287).pdf

accesso aperto

Descrizione: Articolo principale
Tipologia: Publisher's version/PDF
Dimensione 2.79 MB
Formato Adobe PDF
2.79 MB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/574877
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 18
  • ???jsp.display-item.citation.isi??? 17
social impact