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. 2020 Nov 26;22(11):1602-1613.
doi: 10.1093/neuonc/noaa117.

Adult diffuse glioma GWAS by molecular subtype identifies variants in D2HGDH and FAM20C

Jeanette E Eckel-Passow  1 , Kristen L Drucker  1 , Thomas M Kollmeyer  2 , Matt L Kosel  1 , Paul A Decker  1 , Annette M Molinaro  3   4 , Terri Rice  3 , Corinne E Praska  2 , Lauren Clark  2 , Alissa Caron  2 , Alexej Abyzov  1 , Anthony Batzler  1 , Jun S Song  5 , Melike Pekmezci  6 , Helen M Hansen  3 , Lucie S McCoy  3 , Paige M Bracci  1 , Joseph Wiemels  4 , John K Wiencke  3   4   7 , Stephen Francis  3   4 , Terry C Burns  8 , Caterina Giannini  2 , Daniel H Lachance  2   9 , Margaret Wrensch  3   4   7 , Robert B Jenkins  2
Affiliations

Adult diffuse glioma GWAS by molecular subtype identifies variants in D2HGDH and FAM20C

Jeanette E Eckel-Passow et al. Neuro Oncol. .

Abstract

Background: Twenty-five germline variants are associated with adult diffuse glioma, and some of these variants have been shown to be associated with particular subtypes of glioma. We hypothesized that additional germline variants could be identified if a genome-wide association study (GWAS) were performed by molecular subtype.

Methods: A total of 1320 glioma cases and 1889 controls were used in the discovery set and 799 glioma cases and 808 controls in the validation set. Glioma cases were classified into molecular subtypes based on combinations of isocitrate dehydrogenase (IDH) mutation, telomerase reverse transcriptase (TERT) promoter mutation, and 1p/19q codeletion. Logistic regression was applied to the discovery and validation sets to test for associations of variants with each of the subtypes. A meta-analysis was subsequently performed using a genome-wide P-value threshold of 5 × 10-8.

Results: Nine variants in or near D-2-hydroxyglutarate dehydrogenase (D2HGDH) on chromosome 2 were genome-wide significant in IDH-mutated glioma (most significant was rs5839764, meta P = 2.82 × 10-10). Further stratifying by 1p/19q codeletion status, one variant in D2HGDH was genome-wide significant in IDH-mutated non-codeleted glioma (rs1106639, meta P = 4.96 × 10-8). Further stratifying by TERT mutation, one variant near FAM20C (family with sequence similarity 20, member C) on chromosome 7 was genome-wide significant in gliomas that have IDH mutation, TERT mutation, and 1p/19q codeletion (rs111976262, meta P = 9.56 × 10-9). Thirty-six variants in or near GMEB2 on chromosome 20 near regulator of telomere elongation helicase 1 (RTEL1) were genome-wide significant in IDH wild-type glioma (most significant was rs4809313, meta P = 2.60 × 10-10).

Conclusions: Performing a GWAS by molecular subtype identified 2 new regions and a candidate independent region near RTEL1, which were associated with specific glioma molecular subtypes.

Keywords: GWAS glioma; allergy; glioblastoma; molecular subtype.

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Figures

Fig. 1
Fig. 1
Manhattan plot for (A) IDH-mutated glioma, (B) IDH mutated non-codeleted glioma, (C) Triple-positive glioma, and (D) IDH wild-type glioma. Results from the discovery set are shown and genes that passed genome-wide significance (P < 5 × 10−8) in the meta analysis are annotated.
Fig. 2
Fig. 2
D2HGDH functional analyses. (A) Genomic region for 200 kb surrounding rs5839764 is shown. The heatmap shows DNA states predicted by the ChromHMM algorithm in the dorsolateral prefrontal cortex (DPC) and hippocampus (Hippo) in brains from normal donors. The locus zoom plot shows the P-values from the meta-analysis for all variants in the region and the recombination rate. DNA-DNA interactions were measured by Hi-C analysis in the dorsolateral prefrontal cortex, hippocampus, and H1-derived neural progenitor cells; each blue line denotes an interaction. (B) eQTL was examined using GTEx for rs71430382, the second most significant variant (Supplementary Table 2), as no data were available in GTEx for rs5839764. Significant eQTL were observed in frontal cortex (top), cortex (middle), and hippocampus (bottom).
Fig. 3
Fig. 3
GMEB2 functional analyses. Genomic region for 200 kb surrounding rs4809313 is shown. The heatmap shows DNA states predicted by the ChromHMM algorithm in the dorsolateral prefrontal cortex (DPC) and hippocampus (Hippo) in brains from normal donors. The locus zoom plot shows the P-values from the meta-analysis for all variants in the region and the recombination rate. DNA-DNA interactions were measured by Hi-C analysis in the dorsolateral prefrontal cortex, hippocampus, and H1-derived neural progenitor cells; each blue line denotes an interaction.
Fig. 4
Fig. 4
FAM20C functional analyses. Genomic region for 200 kb surrounding rs111976262 is shown. The heatmap shows DNA states predicted by the ChromHMM algorithm in the dorsolateral prefrontal cortex (DPC) and hippocampus (Hippo) in brains from normal donors. The locus zoom plot shows the P-values from the meta-analysis for all variants in the region and the recombination rate. DNA-DNA interactions were measured by Hi-C analysis in the dorsolateral prefrontal cortex, hippocampus, and H1-derived neural progenitor cells; each blue line denotes an interaction.
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