NEW YORK – By tracking enhancer expression, an Icahn School of Medicine at Mount Sinai-led team has uncovered ties between neuropsychiatric disease heritability, tissue- or cell-type-specific enhancers, and the genes they regulate.
"Identification of risk variants for neuropsychiatric diseases within enhancers underscores the importance of understanding population-level variation in enhancer function in the human brain," senior and corresponding author Panos Roussos, a researcher affiliated with the Icahn School of Medicine at Mount Sinai's Center for Disease Neurogenomics and other institutes and departments at Mount Sinai, and his colleagues wrote, pointing to the potential importance of understanding how enhancers are expressed and regulated to better understand such conditions.
As they reported in Nature Genetics on Monday, the investigators used machine learning to assess multiomic datasets spanning cell-sorted neuronal and non-neuronal cell types found in postmortem brain samples from 10 neuropsychiatric disease-free individuals, focusing on five brain regions. Based on RNA sequencing, chromatin immunoprecipitation sequencing, ATAC-seq, and other data, they unearthed 30,795 candidate transcribed enhancers in neuronal cells, along with 23,265 more candidate transcribed enhancers in non-neuronal cell types.
By digging into almost 1,400 RNA-seq datasets representing postmortem brain samples from another 774 individuals with or without schizophrenia, meanwhile, the team was able to start teasing apart the extent to which enhancer expression varies from one individual to the next across the full cohort and within schizophrenia-affected individuals.
Together with their expression quantitative trait locus profiling analysis, which included eQTLs influencing the expression of enhancer-regulated genes and enhancers themselves, the investigators' data highlighted the influence that enhancers and the genes they target can have on neuropsychiatric disease risk and heritability.
"We found that [transcribed enhancers] and [transcribed enhancer]-linked genes are strongly associated with neuropsychiatric disease, and that [transcribed enhancers] mediate neuropsychiatric trait heritability in a manner that is complementary to gene expression," the authors reported.
Moreover, the researchers explained, they were able to get a more refined view of neuropsychiatric disease-associated loci by incorporating information on gene eQTLs and enhancer eQTLs into a schizophrenia transcriptome-wide association study based on a published genome-wide association study.
"We built expression models for 10,669 unique genes and 8,702 unique enhancers from the two brain regions, which markedly increased transcriptome coverage for TWAS compared with previous human brain studies in [schizophrenia]," the researchers added.
The team noted that more than two dozen loci tagged both enhancers and genes, for example, while still other loci tagged enhancers alone — results they explored further with fine-mapping and other analyses.
"Overall, the consideration of population variation in enhancer expression provides insights into the regulatory mechanisms of gene expression and complex traits," the authors wrote, noting that "further integration of our enhancer expression framework with cell-type-specific, spatial-specific, and temporal-specific human brain multiomic data has the potential to provide additional insights into the molecular mechanisms of neuropsychiatric diseases."