With mounting interest in translating genome-wide association study (GWAS) hits from large meta-analyses (meta-GWAS) in diverse clinical settings, evaluating their generalizability in target populations is crucial. Here, we consider long-term survivors of childhood cancers from the St. Jude Lifetime Cohort Study, and we show the limited generalizability of 1,376 robust SNP associations reported in the general population across 12 complex anthropometric and cardiometabolic phenotypes (n = 2,231; observed-to-expected replication ratio = 0.70, p = 6.2 × 10⁻⁸). An examination of five comparable phenotypes in a second independent cohort of survivors from the Childhood Cancer Survivor Study corroborated the overall limited generalizability of meta-GWAS hits to survivors (n = 4,212; observed-to-expected replication ratio = 0.55, p = 5.6 × 10⁻¹⁵). Finally, in direct comparisons of survivor samples against independent equivalently powered general population samples from the UK Biobank, we consistently observed lower meta-GWAS hit replication rates and poorer polygenic risk score predictive performance in survivor samples for multiple phenotypes. As a possible explanation, we found that meta-GWAS hits were less likely to be replicated in survivors who had been exposed to cancer therapies that are associated with phenotype risk. Examination of complementary DNA methylation data in a subset of survivors revealed that treatment-related methylation patterns at genomic sites linked to meta-GWAS hits may disrupt established genetic signals in survivors.

随着对从不同临床环境中的大型荟萃分析 (meta-GWAS) 转化全基因组关联研究 (GWAS) 的兴趣越来越大，评估它们在目标人群中的普遍性至关重要。在这里，我们考虑了来自 St. Jude 终生队列研究的儿童癌症的长期幸存者，并且我们展示了在 12 种复杂的人体测量和心脏代谢表型（n = 2,231；观察到 -与预期的复制比率 = 0.70，p = 6.2 × 10 ^-8). 对来自儿童癌症幸存者研究的第二个独立幸存者队列中的五个可比表型的检查证实了元 GWAS 命中对幸存者的总体普遍性有限（n = 4,212；观察到预期的复制比 = 0.55，p = 5.6 × 10 ^-15). 最后，在将幸存者样本与来自英国生物银行的独立等效一般人群样本进行直接比较时，我们始终观察到较低的 meta-GWAS 命中复制率和幸存者样本中多种表型的较差多基因风险评分预测性能。作为一种可能的解释，我们发现元 GWAS 命中不太可能在接受过与表型风险相关的癌症治疗的幸存者中复制。对一部分幸存者的互补 DNA 甲基化数据的检查表明，与 meta-GWAS 命中相关的基因组位点的治疗相关甲基化模式可能会破坏幸存者中已建立的遗传信号。