A Transcriptome Wide Association Study implicates specific pre- and post-synaptic abnormalities in Schizophrenia

Abstract

Schizophrenia is a complex highly heritable disorder. Genome-wide association studies have identified multiple loci that influence the risk of developing schizophrenia, although the causal variants driving these associations and their impacts on specific genes are largely unknown. Here we link genetic findings to gene expression in the human brain by performing a transcriptome-wide association study (TWAS) in which we integrate the largest published genome-wide association dataset of schizophrenia, with publically available post mortem expression data from the dorsolateral prefrontal cortex (DLPFC). We identify a significant correlation between schizophrenia risk and expression at eighty-nine genes in DLPFC, including forty-two genes not identified in earlier TWAS of this transcriptomic resource. Genes whose expression correlate with schizophrenia were enriched for those involved in nervous system development, abnormal synaptic transmission, reduced long term potentiation, and calcium-dependent cell-cell adhesion. Previous genetic studies have implicated post-synaptic glutamatergic and gabaergic processes in schizophrenia; here we extend this to include molecules that regulate presynaptic transmitter release. We identify specific candidate genes to which we assign predicted directions of effect in terms of expression level, facilitating downstream experimental studies geared towards a better mechanistic understanding of schizophrenia pathogenesis.. CC-BY-NC 4.0 International license It is made available under a was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

Understanding the genetics of neuropsychiatric disorders: the potential role of genomic regulatory blocks

“…distance of 500 kb), 2 Mb distance by Huo et al [26] and in a zebrafish phenotype atlas [25]. In fact, both TWAS analyses reported FANCL as a significant hit, but failed to further corroborate the link between this locus and the FANCL by the Hi-C data [23], nor the gene list analysis [24].…”

“…Recently, the complexity of the gene regulation has become more broadly appreciated [20,21], and there have been efforts to look beyond the closest gene and at the broader genomic context of the locus to identify the target gene affected by the variant [8,[22][23][24]. They potentially affected genomic region around the SNP encompassing all genes to be tested for the effect is generally defined in two main ways: (i) by setting a fixed distance around every SNP [24][25][26], typically 0.5-1 Mb (in extreme case 2 Mb) region upstream and downstream of the disease-associated variant, or (ii) using topologically associated domains (TADs), which are based on prior chromatin interaction experiments [27]. The former approach uses no additional information, therefore making no assumption on which locus is likely to be involved in long-range genomic interactions and thus considers all genes within a set distance around every locus.…”

“…The FANTOM5 consortium produced cap analysis of gene expression data (CAGE) for over a thousand human tissues and cell lines, assaying the exact position and quantity of transcription across the genome. The first advantage of this dataset that make it particularly amenable to investigating developmental aspects of schizophrenia is that unlike some of the recent schizophrenia-associated RNA-seq datasets (used in [23,24]) and the GTEx project [43], FANTOM5 has transcriptional profiles of tissue, including neural tissue, from 75 foetal and newborn subjects. Secondly, it was found that enhancers undergo non-productive transcription initiation in contexts in which they are active [44], making it possible to capture the expression of a gene with the activity of all of the enhancers in its vicinity using a single CAGE experiment.…”

“…P-value calculated based on N = 10,000 randomisations example of the obesity linked discussed above [17], there is also a strong positive correlation of elements Enh5-Enh8 with BCL11A transcription (despite a 2.5 Mb separation between the gene and the regulatory elements). Due to the extreme distance between this enhancer cluster and the promoter of the BCL11A gene, this connection will be missed by any of the methods relying on a fixed genomic cut-off for the enhancer-promoter interactions, even in the most generous case presented in the recent schizophrenia TWAS [23,24] (max. distance of 500 kb), 2 Mb distance by Huo et al [26] and in a zebrafish phenotype atlas [25].…”

“…Since the conception of this study, several smaller schizophrenia GWAS datasets have emerged [8,23,24,26,27], with many signals from the 2014 PGC study replicated, and some new loci discovered. The most significant change in these is a notable trend towards functional characterisation of SNPs in view of finding regulatory variants using eQTL information [8,24,26,66], chromatin contacts [8,27] and transcription factor binding profiles [26]. We have analysed the three largest datasets [8,26,67] in the same way as the PGC GWAS represented here ( Supplementary Fig.…”