Generalizability of "GWAS Hits" in Clinical Populations: Lessons from Childhood Cancer Survivors

Am J Hum Genet. 2020 Oct 1;107(4):636-653. doi: 10.1016/j.ajhg.2020.08.014. Epub 2020 Sep 17.


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.

Keywords: DNA methylation; cardiovascular disease; chemotherapy; childhood cancer survivor; genome-wide association study; metabolic disease; polygenic risk score; polygenic risk score generalizability; radiation therapy; replication.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anthropometry / methods
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Cancer Survivors*
  • Child
  • Cohort Studies
  • DNA Methylation
  • Epigenesis, Genetic*
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Genes, Neoplasm*
  • Genome-Wide Association Study
  • Genotype
  • Humans
  • Hypothalamic Neoplasms / diagnosis
  • Hypothalamic Neoplasms / genetics*
  • Hypothalamic Neoplasms / pathology
  • Hypothalamic Neoplasms / therapy
  • Male
  • Meta-Analysis as Topic
  • Metabolome / genetics
  • Multifactorial Inheritance
  • Phenotype
  • Predictive Value of Tests
  • Risk Assessment