Genome-wide DNA methylation and gene expression analyses of monozygotic twins discordant for intelligence levels

PLoS One. 2012;7(10):e47081. doi: 10.1371/journal.pone.0047081. Epub 2012 Oct 17.

Abstract

Human intelligence, as measured by intelligence quotient (IQ) tests, demonstrates one of the highest heritabilities among human quantitative traits. Nevertheless, studies to identify quantitative trait loci responsible for intelligence face challenges because of the small effect sizes of individual genes. Phenotypically discordant monozygotic (MZ) twins provide a feasible way to minimize the effects of irrelevant genetic and environmental factors, and should yield more interpretable results by finding epigenetic or gene expression differences between twins. Here we conducted array-based genome-wide DNA methylation and gene expression analyses using 17 pairs of healthy MZ twins discordant intelligently. ARHGAP18, related to Rho GTPase, was identified in pair-wise methylation status analysis and validated via direct bisulfite sequencing and quantitative RT-PCR. To perform expression profile analysis, gene set enrichment analysis (GSEA) between the groups of twins with higher IQ and their co-twins revealed up-regulated expression of several ribosome-related genes and DNA replication-related genes in the group with higher IQ. To focus more on individual pairs, we conducted pair-wise GSEA and leading edge analysis, which indicated up-regulated expression of several ion channel-related genes in twins with lower IQ. Our findings implied that these groups of genes may be related to IQ and should shed light on the mechanism underlying human intelligence.

Publication types

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

MeSH terms

  • Adult
  • DNA Methylation / genetics*
  • Epigenesis, Genetic
  • Female
  • GTPase-Activating Proteins / genetics
  • Gene Expression Profiling
  • Gene Expression Regulation*
  • Genetic Association Studies
  • Genetic Loci / genetics
  • Genetic Testing
  • Genome, Human / genetics*
  • Humans
  • Intelligence / genetics*
  • Male
  • Reproducibility of Results
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sequence Analysis, DNA
  • Twins, Monozygotic / genetics*
  • Up-Regulation / genetics
  • Young Adult

Substances

  • ARHGAP18 protein, human
  • GTPase-Activating Proteins

Associated data

  • GEO/GSE33478

Grants and funding

This work was supported by Grant-in-Aid for Scientific Research on Innovative Areas (22129006 to TT) from the Ministry of Education, Culture, Sports, Science and Technology of Japan; by Grants-in-Aid for Scientific Research (S) (21223002 to JA and TT); by Scientific Research (B) (20390099 to TT); and by Challenging Exploratory Research (23650136 to KK) from the Japan Society for the Promotion of Science. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.