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

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 x 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 x 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 x 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 x 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 x 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. Importance of the Study Twenty-five germline variants have been associated with adult diffuse glioma, and some of these variants have subsequently been shown to be associated with particular subtypes of glioma. By performing a GWAS by molecular subtype, we identified 2 new regions that are associated with specific molecular subtypes of glioma. Variants in D2HGDH on chromosome 2 were associated with IDH-mutated glioma. A variant near FAM20C on chromosome 7 was associated with gliomas that have IDH mutation, TERT mutation, and 1p/19q codeletion. One of the regions, D2HGDH, is a region that is also associated with allergy and asthma. The identification of additional novel germline variants will help to further understand the etiology of adult diffuse glioma.