INTRODUCTION Medulloblastoma is a malignant embryonal tumor of the cerebellum that occurs predominantly in children. To find germline genetic variants associated with medulloblastoma risk, we conducted a genome-wide association study (GWAS) including 244 medulloblastoma cases and 247 control subjects from Sweden and Denmark. METHODS Genotyping was performed using Illumina BeadChips, and untyped variants were imputed using IMPUTE2. RESULTS Fifty-nine variants in 11 loci were associated with increased medulloblastoma risk (p < 1 × 10-5), but none were statistically significant after adjusting for multiple testing (p < 5 × 10-8). Thirteen of these variants were genotyped, whereas 46 were imputed. Genotyped variants were further investigated in a validation study comprising 249 medulloblastoma cases and 629 control subjects. In the validation study, rs78021424 (18p11.23, PTPRM) was associated with medulloblastoma risk with OR in the same direction as in the discovery cohort (ORT = 1.59, pvalidation = 0.02). We also selected seven medulloblastoma predisposition genes for investigation using a candidate gene approach: APC, BRCA2, PALB2, PTCH1, SUFU, TP53, and GPR161. The strongest evidence for association was found for rs201458864 (PALB2, ORT = 3.76, p = 3.2 × 10-4) and rs79036813 (PTCH1, ORA = 0.42, p = 2.6 × 10-3). CONCLUSION The results of this study, including a novel potential medulloblastoma risk loci at 18p11.23, are suggestive but need further validation in independent cohorts.

中文翻译：

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髓母细胞瘤的全基因组关联研究。

简介 髓母细胞瘤是一种主要发生于儿童的小脑恶性胚胎肿瘤。为了寻找与髓母细胞瘤风险相关的种系遗传变异，我们进行了一项全基因组关联研究 (GWAS)，包括来自瑞典和丹麦的 244 例髓母细胞瘤病例和 247 名对照受试者。方法使用 Illumina BeadChips 进行基因分型，并使用 IMPUTE2 估算未分型的变异。结果 11 个位点的 59 个变异与髓母细胞瘤风险增加相关 (p < 1 × 10-5)，但在调整多重测试后，没有一个具有统计学意义 (p < 5 × 10-8)。其中 13 个变体进行了基因分型，而 46 个变体进行了估算。在一项包含 249 名髓母细胞瘤病例和 629 名对照受试者的验证研究中进一步研究了基因分型变异。在验证研究中，rs78021424（18p11.23，PTPRM）与髓母细胞瘤风险相关，OR 方向与发现队列中的方向相同（ORT = 1.59，pvalidation = 0.02）。我们还使用候选基因方法选择了七个髓母细胞瘤易感基因进行研究：APC、BRCA2、PALB2、PTCH1、SUFU、TP53 和 GPR161。最有力的关联证据是 rs201458864 (PALB2，ORT = 3.76，p = 3.2 × 10-4) 和 rs79036813 (PTCH1，ORA = 0.42，p = 2.6 × 10-3)。结论 这项研究的结果，包括位于 18p11.23 的一个新的潜在髓母细胞瘤风险位点，具有启发性，但需要在独立队列中进一步验证。