A GWAS assessment of the contribution of genomic imprinting to the variation of body mass index in mice

Abstract

BackgroundGenomic imprinting is an epigenetic mechanism that can lead to differential gene expression depending on the parent-of-origin of a received allele. While most studies on imprinting address its underlying molecular mechanisms or attempt at discovering genomic regions that might be subject to imprinting, few have focused on the amount of phenotypic variation contributed by such epigenetic process. In this report, we give a brief review of a one-locus imprinting model in a quantitative genetics framework, and provide a decomposition of the genetic variance according to this model. Analytical deductions from the proposed imprinting model indicated a non-negligible contribution of imprinting to genetic variation of complex traits. Also, we performed a whole-genome scan analysis on mouse body mass index (BMI) aiming at revealing potential consequences when existing imprinting effects are ignored in genetic analysis.Results10,021 SNP markers were used to perform a whole-genome single marker regression on mouse BMI using an additive and an imprinting model. Markers significant for imprinting indicated that BMI is subject to imprinting. Marked variance changed from 1.218 ×10−4 to 1.842 ×10−4 when imprinting was considered in the analysis, implying that one third of marked variance would be lost if existing imprinting effects were not accounted for. When both marker and pedigree information were used, estimated heritability increased from 0.176 to 0.195 when imprinting was considered.ConclusionsWhen a complex trait is subject to imprinting, using an additive model that ignores this phenomenon may result in an underestimate of additive variability, potentially leading to wrong inferences about the underlying genetic architecture of that trait. This could be a possible factor explaining part of the missing heritability commonly observed in genome-wide association studies (GWAS).

Invited review: Genome-wide association analysis for quantitative traits in livestock – a selective review of statistical models and experimental designs

“…Trait-associated SNPs with imprinting effects can be detected by linkage analysis and GWASs. Models to do such analyses are presented in Mantey et al (2005) and Hu et al (2015).…”

Evolutionary Quantitative Genetics of Genomic Imprinting

“…Our model cleanly separates imprinting from the standard (additive and dominance) genetic effects, providing for a clear understanding of how imprinting contributes to both nonheritable and heritable variation and, hence, evolutionary processes. While a similar formulation of genetic effects has been used by others to partition variation (de Koning et al 2002;Shete and Amos 2002;Mantey et al 2005;Álvarez-Castro 2014;Hu et al 2015), these studies have not examined the consequences of imprinting for evolution. A previous study has evaluated how imprinting impacts the responses to selection (Santure and Spencer 2011), but because it is built on a nonorthogonal model of genetic effects it did not allow the effects of imprinting and dominance to be disentangled.…”

“…It has previously been shown that, with imprinting, the mean genotypic (and phenotypic, assuming no environmental effect on phenotype) value for the population ( w) is equivalent to that under standard Mendelian expression (de Koning et al 2002;Spencer 2002;Hu et al 2015):…”

“…In the classic quantitative genetic model, alleles coming from mothers and fathers are equivalent, and hence parent-oforigin of alleles is ignored when calculating components of variation. However, imprinting creates an epigenetic difference between the effects of the maternally and paternally inherited alleles (de Koning et al 2002;Spencer 2002;Hu et al 2015), which can contribute a component of trait variation. To understand how this parent-of-origin dependent effect contributes heritable and nonheritable components of variation and resemblance of relatives, we start by deriving the effects of alleles coming from mothers and fathers.…”

“…In practice, components of quantitative genetic variation (e.g., V A and V D ) are typically estimated by measuring the phenotypic resemblance of different types of relatives (Falconer and Mackay 1996). It is important to understand how these are changed by imprinting, because components of variance may be over or underestimated if imprinting is ignored (Hu et al 2015). The phenotypic resemblances of relatives (parent-offspring, and full and half-siblings) for a locus with imprinting are summarized in Table 2.…”