UCSF

Approximately 8% of the human genome is comprised of endogenous retroviral insertions (ERVs) originating from historic retroviral integration into germ cells. The function of ERVs as regulators of gene expression is well established. Less well studied are insertional polymorphisms of ERVs and their contribution to the heritability of complex phenotypes. The most recent integration of ERV, HERV-K, is expressed in a range of complex human conditions from cancer to neurologic diseases. Using an in-house computational pipeline and whole-genome sequencing data from the diverse 1,000 Genomes Phase 3 population (n = 2,504), we identified 46 polymorphic HERV-K insertions that are tagged by adjacent single nucleotide polymorphisms (SNPs). To test the potential role of polymorphic HERV-K in the heritability of complex diseases, existing databases were queried for enrichment of established relationships between the HERV-K insertion-associated SNPs (hiSNPs), and tissue specific gene expression and disease phenotypes. Overall, hiSNPs for the 46 polymorphic HERV-K sites were statistically enriched (p < 1.0E^-16) for eQTLs across 44 human tissues. Fifteen of the 46 HERV-K insertions had hiSNPs annotated in the EMBL-EBI GWAS Catalog and cumulatively associated with >100 phenotypes. Experimental factor ontology enrichment analysis suggests that polymorphic HERV-K specifically contribute to neurologic and immunologic disease phenotypes, including traits related to intra cranial volume (FDR 2.00E-09), Parkinson's disease (FDR 1.80E-09), and autoimmune diseases (FDR 1.80E-09). These results provide strong candidates for context-specific study of polymorphic HERV-K insertions in disease-related traits, serving as a roadmap for future studies of the heritability of complex disease.