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

Authors :
Sadler KV
Bowes J
Rowlands CF
Perez-Becerril C
van der Meer CM
King AT
Rutherford SA
Pathmanaban ON
Hammerbeck-Ward C
Lloyd SKW
Freeman SR
Williams R
Hannan CJ
Lewis D
Eyre S
Evans DG
Smith MJ
Source :
Brain : a journal of neurology [Brain] 2023 Jul 03; Vol. 146 (7), pp. 2861-2868.
Publication Year :
2023

Abstract

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 5500 control samples from the UK Biobank resource. One risk locus reached genome-wide significance in our association analysis (9p21.3, rs1556516, P = 1.47 × 10-13, odds ratio = 0.67, allele frequency = 0.52). 9p21.3 is a genome-wide association study association hotspot, and a number of genes are localized to this region, notably 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 tumorigenesis.<br /> (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Details

Language :
English
ISSN :
1460-2156
Volume :
146
Issue :
7
Database :
MEDLINE
Journal :
Brain : a journal of neurology
Publication Type :
Academic Journal
Accession number :
36546557
Full Text :
https://doi.org/10.1093/brain/awac478