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

Huckins, Laura M and Dobbyn, Amanda and Ruderfer, Douglas M and Hoffman, Gabriel and Wang, Weiqing and Pardiñas, Antonio F and Rajagopal, Veera M and Als, Thomas D and T Nguyen, Hoang and Girdhar, Kiran and Boocock, James and Roussos, Panos and Fromer, Menachem and Kramer, Robin and Domenici, Enrico and Gamazon, Eric R and Purcell, Shaun and Demontis, Ditte and Børglum, Anders D and Walters, James T R and O'Donovan, Michael C and Sullivan, Patrick and Owen, Michael J and Devlin, Bernie and Sieberts, Solveig K and Cox, Nancy J and Im, Hae Kyung and Sklar, Pamela and Stahl, Eli A and Knight, Jo (2019) Gene expression imputation across multiple brain regions provides insights into schizophrenia risk. Nature Genetics, 51 (4). pp. 659-674. ISSN 1061-4036

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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.

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Journal Article
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Nature Genetics
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Deposited On:
06 Aug 2019 13:00
Last Modified:
26 Sep 2020 06:08