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Transcriptional-Regulatory Convergence Across Functional MDD Risk Variants Identified by Massively Parallel Reporter Assays [Expt2]

ABSTRACT: Using Massively Parallel Reporter Assays (MPRAs), we functionally screened over 1,000 SNPs, prioritized from 39 neuropsychiatric trait/disease GWAS loci based on overlap with predicted regulatory features—including expression quantitative trait loci (eQTL) and histone marks—from human brains and cell cultures. Using mouse neuroblastoma Neuro2a (N2a) cells, we identify over 100 SNPs with allelic effects on expression. Functional SNPs were enriched for binding sequences of retinoic acid-receptive transcription factors (TFs); with additional allelic differences unmasked in cells treated with all-trans retinoic acid (ATRA). Motifs overrepresented at functional SNPs corresponded to a set of TFs highly specific to serotonergic neurons and collectively downregulated in schizophrenia. Our application of MPRAs to screen MDD-associated SNPs suggested a shared transcriptional regulatory program across loci, a subset of which are unmasked by retinoids. Additional code and results corresponding to this GEO submission can be found at https://bitbucket.org/jdlabteam/n2a_atra_mdd_mpra_paper/src Note that while paired-end sequencing was technically performed, only read 1 (i.e., the barcode-spanning read) of each pair was utilized for analysis, and thus only read 1 files are provided. (fastq files are processed as plain text using string-matching for stringent barcode identification, so header inconsistencies regarding single/paired end read design should not cause issues using our pipeline; however, if read 2 files are required to perform your own form of analysis, contact mulveyb@wustl.edu ; we are happy to provide them.)

ORGANISM(S): Mus musculus Escherichia coli

PROVIDER: GSE167518 | GEO | 2021/06/30

REPOSITORIES: GEO

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Project description:Although genetic studies have identified many hundreds of loci associated with human traits and diseases, pinpointing the causal alleles remains difficult, particularly for non-coding variants. To address this challenge, we have enhanced the sensitivity and reproducibility of the massively parallel reporter assay (MPRA), adapting it to identify variants that directly modulate gene expression. We then applied it to over 29,000 single nucleotide and insertion/deletion polymorphisms from 3,965 cis-expression quantitative trait loci (eQTL). We demonstrate strong correlation between our MPRA approach and existing measures of regulatory function, and determine an approximate sensitivity of ~20% with a positive predictive value of 60-65% to detect an eQTL causal allele. We identify 842 variants showing differential expression between alleles, including 53 well-annotated variants associated with diseases and traits. Thus, we have created a resource of concrete leads for understanding the genetic basis of specific phenotypes and illustrate the promise of this kind of approach for comprehensively interrogating how non-coding polymorphism shapes human biology. The study consists of two separate MPRA experiments, a 78,958 oligo (79k study) and a 7,500 oligo library (7.5k). For each library we processed independent transfections into two lymphoblastoid cell lines; in total we completed 5 replicates of NA12878 and 3 replicates of NA19239. For the 79k library we also performed 5 replicate transfections into the hepatocarcinoma cell line HepG2. Raw data is provided as Illumina reads of the 20 bp barcode from the RNA extracted 24 hours post transfection as well as from the plasmid library used for transfection. We also provide oligo/barcode combinations from the âgfp vector in the form of a tab delimited file containing the raw sequence reads of the barcode (column 1) and genomic sequence (column 2). Processed count files are unnormalized counts for each oligo acquired by summing all barcode matches together for each replicate.

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Transcriptional-Regulatory Convergence Across Functional MDD Risk Variants Identified by Massively Parallel Reporter Assays [Expt2]

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