ArticleAmerican journal of human genetics2019
Disease Heritability Enrichment of Regulatory Elements Is Concentrated in Elements with Ancient Sequence Age and Conserved Function across Species.
Article in American journal of human genetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 64 papers, 1 of them a synthesis that pooled it.
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Who cites it
64 citing papers in PubMed, 1 synthesis or guideline pooled it, 103 citations in OpenAlex.
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- Evolution of CTCF binding sites in the human genome.Molecular biology and evolution · 2026Article
- Improved heritability partitioning and enrichment analyses using summary statistics with graphREML.Nature genetics · 2026Article
- Mapping the genetic architecture of human cortical expansion and its links to neuropsychiatric disorders.bioRxiv : the preprint server for biology · 2026Article
- Fine-mapping candidate neuropsychiatric regulatory variants using cell type-aware comparative genomics.bioRxiv : the preprint server for biology · 2026Article
- Shared genetic and neuroimmune architecture links type 1 diabetes with neurocognitive traits.Nature communications · 2026Article
- Genetic Signal Augmentation of Childhood-Onset and Treatment-Resistant Major Depression Reveals Distinct Biological Disorders.medRxiv : the preprint server for health sciences · 2026Article
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- Comprehensive Multi-omics Analysis of Regulatory Variants for Body Weight in Cattle.Genomics, proteomics & bioinformatics · 2025Article
- Aggregation of recount3 RNA-seq data improves inference of consensus and tissue-specific gene coexpression networks.Genome research · 2025Article
- Identification of replicative aging and inflammatory aging signatures via whole-genome CRISPRi screens.Genome biology · 2025Article
- Improved multiancestry fine-mapping identifies cis-regulatory variants underlying molecular traits and disease risk.Nature genetics · 2025Article
- The Importance of Regulatory Network Structure for Complex Trait Heritability and Evolution.Molecular biology and evolution · 2025Article
- Decoding DNA sequence-driven evolution of the human brain epigenome at cellular resolution.Nature communications · 2025Article
- Investigating the Shared Genetic Architecture Between Leukocyte Telomere Length and Prostate Cancer.The world journal of men's health · 2025Article
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- Evolutionary divergence in CTCF-mediated chromatin topology drives transcriptional innovation in humans.Nature communications · 2025Article
4 more citing papers are in PubMed but not listed here.
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Authors and funding
5 authors at 1 institution in 1 country.
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Abstract
Regulatory elements, e.g., enhancers and promoters, have been widely reported to be enriched for disease and complex trait heritability. We investigated how this enrichment varies with the age of the underlying genome sequence, the conservation of regulatory function across species, and the target gene of the regulatory element. We estimated heritability enrichment by applying stratified LD score regression to summary statistics from 41 independent diseases and complex traits (average N = 320K) and meta-analyzing results across traits. Enrichment of human putative enhancers and promoters was larger in elements with older sequence age, assessed via alignment with other species irrespective of conserved functionality: putative enhancer elements with ancient sequence age (older than the split between marsupial and placental mammals) were 8.8× enriched (versus 2.5× for all putative enhancers; p = 3e-14), and promoter elements with ancient sequence age were 13.5× enriched (versus 5.1× for all promoters; p = 5e-16). Enrichment of human putative enhancers and promoters was also larger in elements whose regulatory function was conserved across species, e.g., human putative enhancers that were enhancers in ≥5 of 9 other mammals were 4.6× enriched (p = 5e-12 versus all putative enhancers). Enrichment of human promoters was larger in promoters of loss-of-function intolerant genes: 12.0× enrichment (p = 8e-15 versus all promoters). The mean value of several measures of negative selection within these genomic annotations mirrored all of these findings. Notably, the annotations with these excess heritability enrichments were jointly significant conditional on each other and on our baseline-LD model, which includes a broad set of coding, conserved, regulatory, and LD-related annotations.
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