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Mapping genetic and epigenetic factors influencing human hippocampal gene expression

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Stegle,  O       
Department Molecular Biology, Max Planck Institute for Developmental Biology, Max Planck Society;

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Borgwardt,  K       
Department Molecular Biology, Max Planck Institute for Developmental Biology, Max Planck Society;

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Citation

Priebe, L., Wolf, C., Alexander, M., Karbalai, N., Fröhlich, H., Stegle, O., et al. (2012). Mapping genetic and epigenetic factors influencing human hippocampal gene expression. European journal of human genetics, 20(Supplement 1): C08-5, 27.


Cite as: https://hdl.handle.net/21.11116/0000-000D-347C-E
Abstract
Several studies have investigated the effects of genetic variation on gene ex- pression (expression quantitative trait loci, eQTLs) in peripheral tissue, cell lines, or post-mortem brain tissue. EQTL studies from pre-mortem, fresh- frozen brain samples would be highly interesting but are hampered by the restricted accessibility of such samples. At the University of Bonn, we have access to a unique sample of pre-mortem human hippocampus samples originating from surgery of treatment-resistant epilepsy patients. To sy- stematically determine eQTLs in a total of 148 hippocampus samples, we generated whole-genome SNP (Illumina Human660W) and gene expression data (Illumina HumanHT-12v3). In addition to the conventional data ana- lysis, we applied a new “hidden factor” analysis that identifies and corrects for unknown confounding factors in the data and thus diminishes the false- positive and false-negative eQTL rate (PEER, https://github.com/PMBio/ peer/wiki). Fifteen hidden factors were identified and used as co-variates for expression analysis. We detected 78 trans-regulating (>1Mb between SNP and probe) eQTLs that withstood Bonferroni correction for multiple testing. Moreover, 1,925 cis-regulating (≤1Mb distance) eQTLs remained significant after permutation-based Westfall-Young correction. In an addi- tional step, we extended our analysis to the systematic investigation of the influence of DNA methylation on gene expression. Genome-wide methyla- tion measurement was performed using Illumina’s new HumanMethylati- on450 array which interrogates more than 485,000 methylation sites. To our knowledge, our study is the first to integrate genotype, expression and methylation data from pre-mortem brain tissue and will provide a valuable resource for the functional interpretation of genetic and epigenetic sites, in particular those associated with brain diseases.