Genome-wide association analysis identifies a meningioma risk locus at 11p15.5

Abstract

Background: Meningiomas are adult brain tumors originating in the meningeal coverings of the brain and spinal cord, with significant heritable basis. Genome-wide association studies (GWAS) have previously identified only a single risk locus for meningioma, at 10p12.31.

Methods: To identify a susceptibility locus for meningioma, we conducted a meta-analysis of 2 GWAS, imputed using a merged reference panel from the 1000 Genomes Project and UK10K data, with validation in 2 independent sample series totaling 2138 cases and 12081 controls.

Results: We identified a new susceptibility locus for meningioma at 11p15.5 (rs2686876, odds ratio = 1.44, P = 9.86 × 10-9). A number of genes localize to the region of linkage disequilibrium encompassing rs2686876, including RIC8A, which plays a central role in the development of neural crest-derived structures, such as the meninges.

Conclusions: This finding advances our understanding of the genetic basis of meningioma development and provides additional support for a polygenic model of meningioma.

Fig. 1

Manhattan plot of association P-values. Shown are the genome-wide P-values (2-sided) of >9 million successfully imputed SNPs in 1606 cases and 9823 controls. Text labeled in red is about previously identified risk loci and text labeled in blue is about newly identified risk loci. Imputation of rs7124615 was not supported by sequencing and this SNP is therefore not represented.

Fig. 2

Forest plot of effect size and direction for the SNP from the newly reported locus associated with meningioma risk.

Fig. 3

Regional plot of the 11p15.5 association. Plot (drawn using visPig) shows association results of both genotyped (triangles) and imputed (circles) SNPs in the GWAS samples and recombination rates; −log₁₀P-values (y-axis) of the SNPs are shown according to their chromosomal positions (x-axis). The sentinel SNP is shown as a large circle and is labeled by its rsID. The color intensity of each symbol reflects the extent of linkage disequilibrium with the top genotyped SNP, white (r² = 0) through to dark red (r² = 1.0). Genetic recombination rates, estimated using 1000 Genomes Project samples, are shown with a light blue line. Physical positions are based on National Center for Biotechnology Information (NCBI) build 37 of the human genome. Also shown are the chromatin-state segmentation tracks for 127 cell types and tissues from ENCODE and the Roadmap Epigenomics Consortium, generated using ChromHMM and the Wash U Epigenome Browser, and the positions of genes and transcripts mapping to the region of association. ANO9 is located 128 kb centromeric of the plotted region.