Expanded map of genomic imprinting reveals insight into human disease

Genomic imprinting involves parent-of-origin effect (POE) of regulatory element activity, often measured through methylation of CpG (5-mC) dinucleotides. While a dozen clinical syndromes are linked to defective imprinting, the extent this epigenetic phenomenon is linked to phenotypic variation and disease susceptibility remains undetermined. We show long-read HiFi genome sequencing for single-molecular profiling of 5-mC, together with pedigree-based phasing in early developmental tissue, provides critical insight into previously uncharted loci in the human genome. Using this approach in 75 samples from 25 trios, we develop a 10-fold enhanced map of human imprinting during development. While the majority of POE was maternal (90%), germ cell hypermethylation was confirmed at most loci (72%) showing signature of paternal imprinting. Integrating summary statistics from large GWAS finds enrichment of common (birthweight) and rare (congenital anomalies) disease loci in newly identified imprinting regions. Accessing pedigree-based rare disease cohorts, we show preponderance of paternal inheritance of pathogenic variants mapping to autosomal dominant OMIM genes with a maternal POE-bin identifying two genes (BNC2, DNMT1) as novel candidate imprinting disorder loci. Our enhanced human map of POE of 5-mC significantly extends the current imprintome and uncovers previously under-appreciated genes and variants that appear crucial for human development and disease.