Unperturbed expression bias of imprinted genes in schizophrenia

Attila Gulyás-Kovács,Eva Xia,Ifat Keydar,Andrew Chess,Douglas Ruderfer,Gabriel Hoffman,Menachem Fromer,Ravi Sachidanandam

doi:10.1038/s41467-018-04960-9

Abstract

How gene expression correlates with schizophrenia across individuals is beginning to be examined through analyses of RNA-seq from postmortem brains of individuals with disease and control brains. Here we focus on variation in allele-specific expression, following up on the CommonMind Consortium (CMC) RNA-seq experiments of nearly 600 human dorsolateral prefrontal cortex (DLPFC) samples. Analyzing the extent of allelic expression bias—a hallmark of imprinting—we find that the number of imprinted human genes is consistent with lower estimates (≈0.5% of all genes), and thus contradicts much higher estimates. Moreover, the handful of putatively imprinted genes are all in close genomic proximity to known imprinted genes. Joint analysis of the imprinted genes across hundreds of individuals allowed us to establish how allelic bias depends on various factors. We find that age and genetic ancestry have gene-specific, differential effect on allelic bias. In contrast, allelic bias appears to be independent of schizophrenia.

Highlights

How gene expression correlates with schizophrenia across individuals is beginning to be examined through analyses of RNA-seq from postmortem brains of individuals with disease and control brains
As it is known that the extent of imprinting of individual genes varies over different tissues, we chose to analyze the dorsolateral prefrontal cortex (DLPFC) region, which controls complex cognitive and executive functions, and is known to display functional abnormalities in SCZ
Based on 579 postmortem human DLPFC samples, we find evidence supporting only a handful of novel imprinted genes all of which reside in genomic locations nearby to known imprinted genes

Summary

Introduction

How gene expression correlates with schizophrenia across individuals is beginning to be examined through analyses of RNA-seq from postmortem brains of individuals with disease and control brains. We obtained DLPFC RNA-seq data from the CMC8 (http:// www.synapse.org/CMC) and analyzed allele-specific expression with the idea of (i) identifying imprinted genes in the adult human brain and (ii) explaining the variability in allelic bias across 579 individuals in terms of their psychiatric diagnosis, age at death, etc. This was facilitated by the balanced case–control groups (258 SCZ, 267 control, 54 bipolar, or other affective/mood disorder, AFF) and the large age variability in the cohort

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