Abstract
The human brain is one of the last frontiers of biomedical research. Genome-wide association studies (GWAS) have succeeded in identifying thousands of haplotype blocks associated with a range of neuropsychiatric traits, including disorders such as schizophrenia, Alzheimer’s and Parkinson’s disease. However, the majority of single nucleotide polymorphisms (SNPs) that mark these haplotype blocks fall within non-coding regions of the genome, hindering their functional validation. While some of these GWAS loci may contain cis-acting regulatory DNA elements such as enhancers, we hypothesized that many are also transcribed into non-coding RNAs that are missing from publicly available transcriptome annotations. Here, we use targeted RNA capture (‘RNA CaptureSeq’) in combination with nanopore long-read cDNA sequencing to transcriptionally profile 1,023 haplotype blocks across the genome containing non-coding GWAS SNPs associated with neuropsychiatric traits, using post-mortem human brain tissue from three neurologically healthy donors. We find that the majority (62%) of targeted haplotype blocks, including 13% of intergenic blocks, are transcribed into novel, multi-exonic RNAs, most of which are not yet recorded in GENCODE annotations. We validated our findings with short-read RNA-seq, providing orthogonal confirmation of novel splice junctions and enabling a quantitative assessment of the long-read assemblies. Many novel transcripts are supported by independent evidence of transcription including cap analysis of gene expression (CAGE) data and epigenetic marks, and some show signs of potential functional roles. We present these transcriptomes as a preliminary atlas of non-coding transcription in human brain that can be used to connect neurological phenotypes with gene expression.
Highlights
Over the past decade, genome-wide association studies (GWAS) have facilitated a multitude of discoveries in human genetics, identifying variants associated with a number of complex phenotypes and diseases (Visscher et al, 2017; Visscher Peter, 2012)
Using the NHGRI GWAS database (Welter et al, 2013; Macarthur et al, 2017), we identified 1,023 discrete haplotype blocks across the genome containing 1,352 non-coding single nucleotide polymorphisms (SNPs) associated with neuropsychiatric phenotypes
Brains were dissected into four different regions: caudate, prefrontal cortex (PFC), primary visual cortex (VCx) and superior colliculus (SupCol)
Summary
Genome-wide association studies (GWAS) have facilitated a multitude of discoveries in human genetics, identifying variants associated with a number of complex phenotypes and diseases (Visscher et al, 2017; Visscher Peter, 2012). The causal variant could lie anywhere within the haplotype block, which extends outward to all SNPs that are in linkage disequilibrium (LD) with the GWAS SNP. This is further complicated by pleiotropy, whereby one locus can influence multiple seemingly unrelated phenotypic traits. A third and related challenge is that the majority of SNPs identified by GWAS fall outside of proteincoding parts of the genome, which has hindered their functional characterization (Hindorff et al, 2009; Welter et al, 2013; Schierding et al, 2014; Xiao et al, 2017)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
