Underestimation of Heritability across the Molecular Layers of the Gene Expression Process

Abstract

We investigated the extent of the heritability underestimation for molecules from an infinitesimal model in mixed model analysis. To this end, we estimated the heritability of transcription, ribosome occupancy, and translation in lymphoblastoid cell lines from Yoruba individuals. Upon considering all genome-wide nucleotide variants, a considerable underestimation in heritability was observed for mRNA transcription (−0.52), ribosome occupancy (−0.48), and protein abundance (−0.47). We employed a mixed model with an optimal number of nucleotide variants, which maximized heritability, and identified two novel expression quantitative trait loci (eQTLs; p < 1.0 × 10−5): rs11016815 on chromosome 10 that influences the transcription of SCP2, a trans-eGene on chromosome 1—whose expression increases in response to MGMT downregulation-induced apoptosis, the cis-eGene of rs11016815—and rs1041872 on chromosome 11 that influences the ribosome occupancy of CCDC25 on chromosome 8 and whose cis-eGene encodes ZNF215, a transcription factor that potentially regulates the translation speed of CCDC25. Our results suggest that an optimal number of nucleotide variants should be used in a mixed model analysis to accurately estimate heritability and identify eQTLs. Moreover, a heterogeneous covariance structure based on gene identity and the molecular layers of the gene expression process should be constructed to better explain polygenic effects and reduce errors in identifying eQTLs.