Genome-wide association studies identify novel genetic loci for epigenetic age acceleration among survivors of childhood cancer

Abstract

Background: Increased epigenetic age acceleration (EAA) in survivors of childhood cancer is associated with specific treatment exposures, unfavorable health behaviors, and presence of certain chronic health conditions. To better understand inter-individual variability, we investigated the genetic basis underlying EAA.

Methods: Genome-wide association studies of EAA based on multiple epigenetic clocks (Hannum, Horvath, PhenoAge, and GrimAge) were performed. MethylationEPIC BeadChip array and whole-genome sequencing data were generated with blood-derived DNA from participants in the St. Jude Lifetime Cohort Study (discovery: 2138 pre-existing and 502 newly generated data, all survivors; exploratory: 282 community controls). Linear regression models were fit for each epigenetic age against the allelic dose of each genetic variant, adjusting for age at sampling, sex, and cancer treatment exposures. Fixed-effects meta-analysis was used to combine summary statistics from two discovery data sets. LD (Linkage disequilibrium) score regression was used to estimate single-nucleotide polymorphism (SNP)-based heritability.

Results: For EAA-Horvath, a genome-wide significant association was mapped to the SELP gene with the strongest SNP rs732314 (meta-GWAS: β=0.57, P=3.30×10^-11). Moreover, the stratified analysis of the association between rs732314 and EAA-Horvath showed a substantial heterogeneity between children and adults (meta-GWAS: β=0.97 vs. 0.51, I²=73.1%) as well as between survivors with and without chest/abdominal/pelvic-RT exposure (β=0.64 vs. 0.31, I²=66.3%). For EAA-Hannum, an association was mapped to the HLA locus with the strongest SNP rs28366133 (meta-GWAS: β=0.78, P=3.78×10^-11). There was no genome-wide significant hit for EAA-PhenoAge or EAA-GrimAge. Interestingly, among community controls, rs732314 was associated with EAA-Horvath (β=1.09, P=5.43×10^-5), whereas rs28366133 was not associated with EAA-Hannum (β=0.21, P=0.49). The estimated heritability was 0.33 (SE=0.20) for EAA-Horvath and 0.17 (SE=0.23) for EAA-Hannum, but close to zero for EAA-PhenoAge and EAA-GrimAge.

Conclusions: We identified novel genetic variants in the SELP gene and HLA region associated with EAA-Horvath and EAA-Hannum, respectively, among survivors of childhood cancer. The new genetic variants in combination with other replicated known variants can facilitate the identification of survivors at higher risk in developing accelerated aging and potentially inform drug targets for future intervention strategies among vulnerable survivors.

Keywords: Childhood cancer; Epigenetic age acceleration; Genome-wide association study; HLA; SELP; Survivorship.

Fig. 1

Pairwise correlations of four epigenetic age (A) and epigenetic age acceleration (B). Abbreviations: epigenetic age (EA) and epigenetic age acceleration (EAA). Pair-wise Pearson correlation coefficients were shown with P< 0.001 denoted as ***

Fig. 2

Manhattan plots of genome-wide association study (GWAS) for epigenetic age acceleration (EAA)-Horvath (A) and EAA-Hannum (B). ^aEach dot represents the test result for one SNP. ^bX-axis is the genomic location along each chromosome, and Y-axis is -log10 of P value. ^cThe red horizontal line corresponds to the P value of 5×10^-8

Fig. 3

Regional plots for genetic associations between SELP locus and epigenetic age acceleration (EAA)-Horvath (A), HLA locus, and EAA-Hannum (B). ^aEach dot represents the test result for one SNP. ^bX-axis is the genomic location along each chromosome, and Y-axis is -log10 of P value. ^cThe red horizontal line corresponds to the P value of 5×10^-8. ^dSNP depicted in diamond is the index SNP for the region, and all other SNPs were depicted as circles and their correlations (i.e., pair-wise linkage disequilibrium) with the index SNP was warm/cool color-coded