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. 2023 Jul 3;146(7):2861-2868.
doi: 10.1093/brain/awac478.

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

Katherine V Sadler  1   2 , John Bowes  3 , Charlie F Rowlands  4 , Cristina Perez-Becerril  1   2 , C Mwee van der Meer  2 , Andrew T King  5 , Scott A Rutherford  5 , Omar N Pathmanaban  5 , Charlotte Hammerbeck-Ward  5 , Simon K W Lloyd  6   7 , Simon R Freeman  6 , Ricky Williams  8 , Cathal John Hannan  5   9 , Daniel Lewis  5 , Steve Eyre  10 , D Gareth Evans  1   2 , Miriam J Smith  1   2
Affiliations

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

Katherine V Sadler et al. Brain. .

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.

Keywords: GWAS; NF2; VS; sporadic VS; vestibular schwannoma.

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Conflict of interest statement

The authors report no competing interests.

Figures

Figure 1
Figure 1
Manhattan plot of MAF > 1% SNP P-values in the GWAS combined cohort across the autosomes. The dashed red line represents P-value = 5 × 10−8.
Figure 2
Figure 2
Kaplan–Meier survival curve of age at VS presentation in GWAS cohort of sporadic VS patients by genotype group at SNP rs1556516.
Figure 3
Figure 3
Kaplan–Meier survival curve of age at VS presentation in NF2-related schwannomatosis patients by genotype group at SNP rs1537371.
See this image and copyright information in PMC

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