Genome-wide association analysis identifies a susceptibility locus for sporadic vestibular schwannoma at 9p21

Katherine Sadler, John Bowes, Charles Rowlands, Cristina Perez-Becerril, C. Mwee van der Meer, Andrew Thomas King, Scott A Rutherford, Omar Pathmanaban, Charlotte Hammerbeck-ward, Simon K W Lloyd, Simon Freeman, Ricky Williams, Cathal John Hannan, Daniel Lewis, Stephen Eyre, D Gareth Evans, Miriam J Smith

Research output: Contribution to journalArticlepeer-review


Vestibular schwannomas are benign nerve sheath tumours that arise on the vestibulocochlear nerves. Vestibular schwannomas are known to occur in the context of tumour predisposition syndromes NF2-related and LZTR1-related schwannomatosis. However, the majority of vestibular schwannomas present sporadically without identification of germline pathogenic variants.
To identify novel genetic associations with risk of vestibular schwannoma development, we conducted a genome-wide association study in a cohort of 911 sporadic vestibular schwannoma cases collated from the neurofibromatosis type 2 genetic testing service in the North West of England, UK and 5,500 control samples from the UK Biobank resource.
One risk locus reached genome-wide significance in our association analysis (9p21.3, rs1556516, P = 1.47e-13, odds ratio = 0.67, allele frequency = 0.52). 9p21.3 is a genome-wide association study association hotspot, and a number of genes are localised to this region, CDKN2B-AS1 and CDKN2A/B, also referred to as the INK4 locus.
Dysregulation of gene products within the INK4 locus have been associated with multiple pathologies and the genes in this region have been observed to directly impact the expression of one another. Recurrent associations of the INK4 locus with components of well described oncogenic pathways provides compelling evidence that the 9p21.3 region is truly associated with risk of vestibular schwannoma tumourigenesis.
Original languageEnglish
Publication statusPublished - 22 Dec 2022


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