Abstract
BackgroundThe influence of genetics on variation in DNA methylation (DNAme) is well documented. Yet confounding from population stratification is often unaccounted for in DNAme association studies. Existing approaches to address confounding by population stratification using DNAme data may not generalize to populations or tissues outside those in which they were developed. To aid future placental DNAme studies in assessing population stratification, we developed an ethnicity classifier, PlaNET (Placental DNAme Elastic Net Ethnicity Tool), using five cohorts with Infinium Human Methylation 450k BeadChip array (HM450k) data from placental samples that is also compatible with the newer EPIC platform.ResultsData from 509 placental samples were used to develop PlaNET and show that it accurately predicts (accuracy = 0.938, kappa = 0.823) major classes of self-reported ethnicity/race (African: n = 58, Asian: n = 53, Caucasian: n = 389), and produces ethnicity probabilities that are highly correlated with genetic ancestry inferred from genome-wide SNP arrays (> 2.5 million SNP) and ancestry informative markers (n = 50 SNPs). PlaNET’s ethnicity classification relies on 1860 HM450K microarray sites, and over half of these were linked to nearby genetic polymorphisms (n = 955). Our placental-optimized method outperforms existing approaches in assessing population stratification in placental samples from individuals of Asian, African, and Caucasian ethnicities.ConclusionPlaNET provides an improved approach to address population stratification in placental DNAme association studies. The method can be applied to predict ethnicity as a discrete or continuous variable and will be especially useful when self-reported ethnicity information is missing and genotyping markers are unavailable.
Highlights
Epigenome-wide association studies (EWAS) have shown that a substantial amount of variation in DNA methylation (DNAme) exists between human populations [1,2,3,4,5,6,7]
In this study we developed placental elastic net ethnicity classifier (PlaNET) (Placental DNAme Elastic Net Ethnicity Tool), an ethnicity classifier, using DNAme and genotyping data measured on the Human Methylation 450k Beadchip array (HM450K) array in multiple cohorts of placentas from North America
We searched for placental HM450K data on the Gene Expression Omnibus [27] that contained more than one ethnicity group and made sample-specific ethnicity information available (Table 2)
Summary
Epigenome-wide association studies (EWAS) have shown that a substantial amount of variation in DNA methylation (DNAme) exists between human populations [1,2,3,4,5,6,7]. If left unaccounted for, populationassociated variation can interfere with the discovery of DNAme alterations associated with disease or environment. This type of confounding, often referred to as population stratification, can be addressed by inferring. In EWAS, confounding from population stratification is most often addressed using self-reported ethnicity/race to stratify study samples across the phenotype of interest. To aid future placental DNAme studies in assessing population stratification, we developed an ethnicity classifier, PlaNET (Placental DNAme Elastic Net Ethnicity Tool), using five cohorts with Infinium Human Methylation 450k BeadChip array (HM450k) data from placental samples that is compatible with the newer EPIC platform
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