Abstract
Genome-wide association studies have identified over 100 robust risk loci for schizophrenia with thousands of variants mediating genetic heritability, the majority of which reside in non-coding regions. Analytical approaches have shown this heritability is strongly enriched at variants within regulatory elements identified from human post-mortem brain tissue. However, bulk post-mortem brain tissue has a heterogeneous cell composition, making biological interpretations difficult. We sought to refine the cell types mediating schizophrenia heritability by separating neuronal and glial signals using data from: (1) NeuN-sorted post-mortem brain and (2) cell culture systems. Schizophrenia heritability was partitioned using linkage disequilbrium (LD) score regression. Variants within genomic regions marked by H3K4me3 (marker of active promoters) from NeuN-positive (neuronal) and NeuN-negative (non-neuronal) cells explained a significant amount of schizophrenia heritability (P = 1.38 × 10−10 and P = 7.97 × 10−10). However, variants located in H3K4me3 sites specific to NeuN-positive (neuronal) cells were enriched (P = 3.13 × 10−4), while those specific to NeuN-negative (non-neuronal) cells were not (P = 0.470). Data from cell culture systems mimicked this pattern of association. We show the previously observed enrichment of heritability from variants at brain H3K4me3 sites is mediated by both neuronal and non-neuronal brain cell types. However, only neuronal cell populations showed a unique contribution driven by cell-type specific regulatory elements. Cell culture systems recapitulate disease relevant gene-regulatory landscapes, validating them as a tool for future investigation of genetic mechanisms underlying schizophrenia. Identifying the cell types in which risk variants operate will greatly increase our understanding of schizophrenia pathobiology and aid in the development of novel model systems and therapies.
Highlights
Genome-wide association studies (GWAS) have successfully identified genetic loci mediating human diseases and phenotypes
Our analysis sought to investigate the relative contribution of two major brain cell types, neurons and glia, to genetic risk mechanisms for schizophrenia
Using measurements of genome-wide partitioned heritability, we find that both neurons and glia are potential mediators of genetic risk for schizophrenia
Summary
Genome-wide association studies (GWAS) have successfully identified genetic loci mediating human diseases and phenotypes. More than 100 genome-wide significant loci have been identified[1]. Causal variants will disrupt the function of non-coding regulatory elements in cell types relevant to disease. The heritability of complex diseases is governed by thousands of variants across the genome, it is enriched at regulatory elements from specific cell types[4]. These measurements of partitioned heritability, as well as other enrichment analyses[5], can provide powerful insights into the tissue and cell types underlying pathobiology, which are important for establishing valid disease models and assays of gene function
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