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Chunk #50 — METHODS — Transcriptomic imputation model construction and TWAS.

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Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains.
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Transcriptomic imputation models were constructed as previously described28 for dorso-lateral prefrontal cortex (DLPFC) transcript levels80. The genetic dataset of the PsychENCODE cohort was uniformly processed for quality control (QC) steps before genotype imputation. The analysis was restricted to samples with European ancestry as previously described28. Genotypes were imputed using the University of Michigan server81 with the Haplotype Reference Consortium (HRC) reference panel82. Gene expression information (both at the level of gene and transcript) was derived from RNA-seq counts which were adjusted for known and hidden confounds, followed by quantile normalization80. For the construction of the transcriptomic imputation models, we used EpiXcan28, an elastic net-based method, which weighs SNPs based on available epigenetic annotation information83. We performed the transcript-trait association analysis for ADHD as previously described28. Briefly, we applied the S-PrediXcan method28 to integrate the ADHD GWAS meta-analysis summary statistics and the transcriptomic imputation models constructed above to obtain association results at both the level of genes and transcripts.