Genetic effects of sequence-conserved enhancer-like elements on human complex traits.

Data integration Enhancer Fine mapping Gene prioritization Genome-wide association study Heritability Sequence conservation Tissue specificity

Journal

Genome biology

ISSN: 1474-760X

Titre abrégé: Genome Biol

Pays: England

ID NLM: 100960660

Informations de publication

Date de publication:
02 Jan 2024

Historique:

received: 02 09 2022

accepted: 08 12 2023

medline: 4 1 2024

pubmed: 4 1 2024

entrez: 3 1 2024

Statut: epublish

Résumé

The vast majority of findings from human genome-wide association studies (GWAS) map to non-coding sequences, complicating their mechanistic interpretations and clinical translations. Non-coding sequences that are evolutionarily conserved and biochemically active could offer clues to the mechanisms underpinning GWAS discoveries. However, genetic effects of such sequences have not been systematically examined across a wide range of human tissues and traits, hampering progress to fully understand regulatory causes of human complex traits. Here we develop a simple yet effective strategy to identify functional elements exhibiting high levels of human-mouse sequence conservation and enhancer-like biochemical activity, which scales well to 313 epigenomic datasets across 106 human tissues and cell types. Combined with 468 GWAS of European (EUR) and East Asian (EAS) ancestries, these elements show tissue-specific enrichments of heritability and causal variants for many traits, which are significantly stronger than enrichments based on enhancers without sequence conservation. These elements also help prioritize candidate genes that are functionally relevant to body mass index (BMI) and schizophrenia but were not reported in previous GWAS with large sample sizes. Our findings provide a comprehensive assessment of how sequence-conserved enhancer-like elements affect complex traits in diverse tissues and demonstrate a generalizable strategy of integrating evolutionary and biochemical data to elucidate human disease genetics.

Sections du résumé

BACKGROUND BACKGROUND

RESULTS RESULTS

Here we develop a simple yet effective strategy to identify functional elements exhibiting high levels of human-mouse sequence conservation and enhancer-like biochemical activity, which scales well to 313 epigenomic datasets across 106 human tissues and cell types. Combined with 468 GWAS of European (EUR) and East Asian (EAS) ancestries, these elements show tissue-specific enrichments of heritability and causal variants for many traits, which are significantly stronger than enrichments based on enhancers without sequence conservation. These elements also help prioritize candidate genes that are functionally relevant to body mass index (BMI) and schizophrenia but were not reported in previous GWAS with large sample sizes.

CONCLUSIONS CONCLUSIONS

Our findings provide a comprehensive assessment of how sequence-conserved enhancer-like elements affect complex traits in diverse tissues and demonstrate a generalizable strategy of integrating evolutionary and biochemical data to elucidate human disease genetics.

Identifiants

DOI: 10.1186/s13059-023-03142-1 PMID: 38167462

pubmed: 38167462

doi: 10.1186/s13059-023-03142-1

pii: 10.1186/s13059-023-03142-1

doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

Pagination

Subventions

Organisme : NIH HHS

ID : P50HG007735

Pays : United States

Organisme : NIH HHS

ID : R01HG010359

Pays : United States

Informations de copyright

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