Comparison of quantitative trait loci methods: Total expression and allelic imbalance method in brain RNA-seq

PLoS One. 2019 Jun 17;14(6):e0217765. doi: 10.1371/journal.pone.0217765. eCollection 2019.

Abstract

Background: Of the 108 Schizophrenia (SZ) risk-loci discovered through genome-wide association studies (GWAS), 96 are not altering the sequence of any protein. Evidence linking non-coding risk-SNPs and genes may be established using expression quantitative trait loci (eQTL). However, other approaches such allelic expression quantitative trait loci (aeQTL) also may be of use.

Methods: We applied both the eQTL and aeQTL analysis to a biobank of deeply sequenced RNA from 680 dorso-lateral pre-frontal cortex (DLPFC) samples. For each of 340 genes proximal to the SZ risk-SNPs, we asked how much SNP-genotype affected total expression (eQTL), as well as how much the expression ratio between the two alleles differed from 1:1 as a consequence of the risk-SNP genotype (aeQTL).

Results: We analyzed overlap with comparable eQTL-findings: 16 of the 30 risk-SNPs known to have gene-level eQTL also had gene-level aeQTL effects. 6 of 21 risk-SNPs with known splice-eQTL had exon-aeQTL effects. 12 novel potential risk genes were identified with the aeQTL approach, while 55 tested SNP-pairs were found as eQTL but not aeQTL. Of the tested 108 loci we could find at least one gene to be associated with 21 of the risk-SNPs using gene-level aeQTL, and with an additional 18 risk-SNPs using exon-level aeQTL.

Conclusion: Our results suggest that the aeQTL strategy complements the eQTL approach to susceptibility gene identification.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Alleles
  • Allelic Imbalance / genetics*
  • Brain / pathology*
  • Child
  • Child, Preschool
  • Exome Sequencing / methods
  • Female
  • Genetic Predisposition to Disease / genetics
  • Genome-Wide Association Study / methods*
  • Genotype
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide / genetics
  • Quantitative Trait Loci / genetics*
  • RNA-Seq / methods*
  • Schizophrenia / genetics
  • Young Adult

Grants and funding

Lundbeck A/S provided support in the form of salaries for authors LF, JN, NP, and MD, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.