Epigenome-wide association studies(EWAS)are susceptible to widespread confounding caused by population structure and genetic relatedness.Nevertheless,kinship estimation is challenging in EWAS without genotyping data.H...Epigenome-wide association studies(EWAS)are susceptible to widespread confounding caused by population structure and genetic relatedness.Nevertheless,kinship estimation is challenging in EWAS without genotyping data.Here,we proposed MethylGenotyper,a method that for the first time enables accurate genotyping at thousands of single nucleotide polymorphisms(SNPs)directly from commercial DNA methylation microarrays.We modeled the intensities of methylation probes near SNPs with a mixture of three beta distributions corresponding to different genotypes and estimated parameters with an expectation-maximization algorithm.We conducted extensive simulations to demonstrate the performance of the method.When applying MethylGenotyper to the Infinium EPIC array data of 4662 Chinese samples,we obtained genotypes at 4319 SNPs with a concordance rate of 98.26%,enabling the identification of 255 pairs of close relatedness.Furthermore,we showed that MethylGenotyper allows for the estimation of both population structure and cryptic relatedness among 702 Australians of diverse ancestry.We also implemented MethylGenotyper in a publicly available R package(https://github.com/Yi-Jiang/MethylGenotyper)to facilitate future large-scale EWAS.展开更多
基金supported by grants from the National Natural Science Foundation of China(Grant Nos.82325044 and 82021005)the China Postdoctoral Science Foundation(Grant No.2021M701318)+2 种基金the Natural Science Fund for Distinguished Young Scholars of Hubei Province,China(Grant No.2022CFA046)the Fundamental Research Funds for the Central Universities,China(Grant Nos.2019kfyXJJS036 and 2023BR030 of HUST)funded by the National Health and Medical Research Council in Australia(Grant Nos.GNT1161706 and GNT1151854).
文摘Epigenome-wide association studies(EWAS)are susceptible to widespread confounding caused by population structure and genetic relatedness.Nevertheless,kinship estimation is challenging in EWAS without genotyping data.Here,we proposed MethylGenotyper,a method that for the first time enables accurate genotyping at thousands of single nucleotide polymorphisms(SNPs)directly from commercial DNA methylation microarrays.We modeled the intensities of methylation probes near SNPs with a mixture of three beta distributions corresponding to different genotypes and estimated parameters with an expectation-maximization algorithm.We conducted extensive simulations to demonstrate the performance of the method.When applying MethylGenotyper to the Infinium EPIC array data of 4662 Chinese samples,we obtained genotypes at 4319 SNPs with a concordance rate of 98.26%,enabling the identification of 255 pairs of close relatedness.Furthermore,we showed that MethylGenotyper allows for the estimation of both population structure and cryptic relatedness among 702 Australians of diverse ancestry.We also implemented MethylGenotyper in a publicly available R package(https://github.com/Yi-Jiang/MethylGenotyper)to facilitate future large-scale EWAS.
