Abstract
Recent genome-wide association studies have identified numerous loci associated with neuropsychiatric disorders. The majority of these are in non-coding regions, and are commonly assigned to the nearest gene along the genome. However, this approach neglects the three-dimensional organisation of the genome, and the fact that the genome contains arrays of extremely conserved non-coding elements termed genomic regulatory blocks (GRBs), which can be utilized to detect genes under long-range developmental regulation. Here we review a GRB-based approach to assign loci in non-coding regions to potential target genes, and apply it to reanalyse the results of one of the largest schizophrenia GWAS (SWG PGC, 2014). We further apply this approach to GWAS data from two related neuropsychiatric disorders—autism spectrum disorder and bipolar disorder—to show that it is applicable to developmental disorders in general. We find that disease-associated SNPs are overrepresented in GRBs and that the GRB model is a powerful tool for linking these SNPs to their correct target genes under long-range regulation. Our analysis identifies novel genes not previously implicated in schizophrenia and corroborates a number of predicted targets from the original study. The results are available as an online resource in which the genomic context and the strength of enhancer–promoter associations can be browsed for each schizophrenia-associated SNP.
Highlights
The primary aim of genome-wide association studies (GWAS) and other genetic association studies is arguably to serve as the first step in elucidation of the biological mechanisms responsible for the onset of disease, which will eventually lead to their translation into clinical practice
While the rest of our analysis focuses exclusively on schizophrenia-associated variants, two additional recent datasets of single-nucleotide polymorphism (SNP) associated with other neurodevelopmental phenotypes, i.e. autism spectrum disorder (ASD) [84] and bipolar disorder (BD) [85], were checked for overrepresentation in genomic regulatory blocks (Fig. 2)
NCAM1 has previously been implicated in a number of neuropsychiatric disorders, including schizophrenia [61], and our analysis identifies NCAM1 as another plausible target, despite not being categorized as a genomic regulatory blocks (GRBs) target
Summary
The primary aim of genome-wide association studies (GWAS) and other genetic association studies is arguably to serve as the first step in elucidation of the biological mechanisms responsible for the onset of disease, which will eventually lead to their translation into clinical practice. The concordance of putative enhancers in both schizophrenia-associated loci with genes across the entire GRB (Fig. 3c), including SNX19, supports the idea that variants rs10791097 (found just downstream of, and originally thought to be a bystander locus to SNX19 [42]) and rs75059851 share some mechanistic aspects in the aetiology of the disease, and calls for testing for effects of their interaction despite the large genomic distance between them This example highlights how the GRBs can serve as functional units in which the effects of multiple SNPs can be considered as potentially interacting. While a greater coverage of high-resolution tissue-specific chromatin contacts, allelespecific gene expression, transcriptome maps and genomewide binding profiles for a wider range of transcription factors will partially close this gap in the future, the GRB approach will stand as an elegant method of shortlisting (or adding additional evidence for) genes through which regulatory non-coding variants exert their effects on disease emergence
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