Leveraging mouse chromatin data for heritability enrichment informs common disease architecture and reveals cortical layer contributions to schizophrenia

Paul W. Hook, Andrew S. McCallion

Research output: Contribution to journalArticle

Abstract

Genome-wide association studies have implicated thousands of noncoding variants across common human phenotypes. However, they cannot directly inform the cellular context in which disease-associated variants act. Here, we use open chromatin profiles from discrete mouse cell populations to address this challenge. We applied stratified linkage disequilibrium score regression and evaluated heritability enrichment in 64 genome-wide association studies, emphasizing schizophrenia. We provide evidence that mouse-derived human open chromatin profiles can serve as powerful proxies for difficult to obtain human cell populations, facilitating the illumination of common disease heritability enrichment across an array of human phenotypes. We demonstrate that signatures from discrete subpopulations of cortical excitatory and inhibitory neurons are significantly enriched for schizophrenia heritability with maximal enrichment in cortical layerVexcitatory neurons. We also show that differences between schizophrenia and bipolar disorder are concentrated in excitatory neurons in cortical layers II-III, IV, and V, as well as the dentate gyrus. Finally, we leverage these data to fine-map variants in 177 schizophrenia loci nominating variants in 104/177. We integrate these data with transcription factor binding site, chromatin interaction, and validated enhancer data, placing variants in the cellular context where they may modulate risk.

Original languageEnglish (US)
Pages (from-to)528-539
Number of pages12
JournalGenome research
Volume30
Issue number4
DOIs
StatePublished - Apr 2020

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Fingerprint Dive into the research topics of 'Leveraging mouse chromatin data for heritability enrichment informs common disease architecture and reveals cortical layer contributions to schizophrenia'. Together they form a unique fingerprint.

  • Cite this