Journal Article

Gene expression imputation across multiple brain regions provides insights into schizophrenia risk

Rajagopal, Veera M., Als, Thomas D., Purcell, Shaun, T. Nguyen, Hoang, Stahl, Eli A., Fromer, Menachem, Dobbyn, Amanda, Girdhar, Kiran, Huckins, Laura M., Gamazon, Eric R., Ruderfer, Douglas M., Domenici, Enrico, Kramer, Robin, Demontis, Ditte, Hoffman, Gabriel, Walters, James T. R., Boocock, James, Roussos, Panos, Im, Hae Kyung, Børglum, Anders D., Sieberts, Solveig K., Wang, Weiqing, O’Donovan, Michael C., Devlin, Bernie, Cox, Nancy J., Owen, Michael J., Sklar, Pamela, Sullivan, Patrick, Pardiñas, Antonio F.

2019

Overview

Transcriptomic imputation approaches combine eQTL reference panels with large-scale genotype data in order to test associations between disease and gene expression. These genic associations could elucidate signals in complex genome-wide association study (GWAS) loci and may disentangle the role of different tissues in disease development. We used the largest eQTL reference panel for the dorso-lateral prefrontal cortex (DLPFC) to create a set of gene expression predictors and demonstrate their utility. We applied DLPFC and 12 GTEx-brain predictors to 40,299 schizophrenia cases and 65,264 matched controls for a large transcriptomic imputation study of schizophrenia. We identified 413 genic associations across 13 brain regions. Stepwise conditioning identified 67 non-MHC genes, of which 14 did not fall within previous GWAS loci. We identified 36 significantly enriched pathways, including hexosaminidase-A deficiency, and multiple porphyric disorder pathways. We investigated developmental expression patterns among the 67 non-MHC genes and identified specific groups of pre- and postnatal expression. This study uses gene expression predictors for the dorsolateral prefrontal cortex and other brain regions to perform a transcriptomic imputation analysis of schizophrenia, identifying 413 genic associations across 13 brain regions and 36 significantly enriched pathways.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 38 / 38/43 / 38/61 / 45/91 / 631/208/199 / 631/208/205/2138 / 631/208/212/2019 / 692/699/476/1799 / Acids / Agriculture / Animal Genetics and Genomics / Bioinformatics / Biology / Biomedical and Life Sciences / Biomedicine / Brain / Brain - physiopathology / Cancer Research / Case-Control Studies / Consortia / Disease / Gene expression / Gene Expression - genetics / Gene Function / Genes / Genetic engineering / Genetic Predisposition to Disease / Genome-wide association studies / Genome-Wide Association Study - methods / Genomes / Genomics / Genotype / Genotype & phenotype / Genotypes / Human Genetics / Humans / Investigations / Loci / Mental disorders / Ontology / Polymorphism, Single Nucleotide - genetics / Prefrontal cortex / Quantitative Trait Loci - genetics / Religious orders / Risk / Schizophrenia / Schizophrenia - genetics / Transcriptome - genetics / Working groups