Examining the Impact of Imputation Errors on Fine-Mapping Using DNA Methylation QTL as a Model Trait.
Genetic variants disrupting DNA methylation at CpG dinucleotides (CpG-SNP) provide a set of known causal variants to serve as models to test fine-mapping methodology. We use 1716 CpG-SNPs to test three fine-mapping approaches (Bayesian imputation-based association mapping, Bayesian sparse linear mixed model, and the J-test), assessing the impact of imputation errors and the choice of reference panel by using both whole-genome sequence (WGS), and genotype array data on the same individuals (n = 1166). The choice of imputation reference panel had a strong effect on imputation accuracy, with the 1000 Genomes Project Phase 3 (1000G) reference panel (n = 2504 from 26 populations) giving a mean nonreference discordance rate between imputed and sequenced genotypes of 3.2% compared to 1.6% when using the Haplotype Reference Consortium (HRC) reference panel (n = 32,470 Europeans). These imputation errors had an impact on whether the CpG-SNP was included in the 95% credible set, with a difference of ∼23% and ∼7% between the WGS and the 1000G and HRC imputed datasets, respectively. All of the fine-mapping methods failed to reach the expected 95% coverage of the CpG-SNP. This is attributed to secondary cis genetic effects that are unable to be statistically separated from the CpG-SNP, and through a masking mechanism where the effect of the methylation disrupting allele at the CpG-SNP is hidden by the effect of a nearby SNP that has strong linkage disequilibrium with the CpG-SNP. The reduced accuracy in fine-mapping a known causal variant in a low-level biological trait with imputed genetic data has implications for the study of higher-order complex traits and disease.
['Chundru|V Kartik|VK|0000-0002-6348-5565', 'Marioni|Riccardo E|RE|0000-0003-4430-4260', 'Prendergast|James G D|JGD|0000-0001-8916-018X', 'Vallerga|Costanza L|CL|0000-0001-9493-6800', 'Lin|Tian|T|', 'Beveridge|Allan J|AJ|', '|||', 'Gratten|Jacob|J|0000-0003-1293-409X', 'Hume|David A|DA|0000-0002-2615-1478', 'Deary|Ian J|IJ|0000-0002-1733-263X', 'Wray|Naomi R|NR|0000-0001-7421-3357', 'Visscher|Peter M|PM|0000-0002-2143-8760', 'McRae|Allan F|AF|0000-0001-5286-5485']
D018899:CpG Islands D019175:DNA Methylation D055106:Genome-Wide Association Study D006801:Humans D020641:Polymorphism, Single Nucleotide D040641:Quantitative Trait Loci D019655:Quantitative Trait, Heritable D012015:Reference Standards D015203:Reproducibility of Results D000073336:Whole Genome Sequencing
imputation fine-mapping CpG-SNPs DNA-methylation