Genetic architecture of epigenetic and neuronal ageing rates in human brain regions

Nat Commun. 2017 May 18;8:15353. doi: 10.1038/ncomms15353.

Abstract

Identifying genes regulating the pace of epigenetic ageing represents a new frontier in genome-wide association studies (GWASs). Here using 1,796 brain samples from 1,163 individuals, we carry out a GWAS of two DNA methylation-based biomarkers of brain age: the epigenetic ageing rate and estimated proportion of neurons. Locus 17q11.2 is significantly associated (P=4.5 × 10-9) with the ageing rate across five brain regions and harbours a cis-expression quantitative trait locus for EFCAB5 (P=3.4 × 10-20). Locus 1p36.12 is significantly associated (P=2.2 × 10-8) with epigenetic ageing of the prefrontal cortex, independent of the proportion of neurons. Our GWAS of the proportion of neurons identified two genome-wide significant loci (10q26 and 12p13.31) and resulted in a gene set that overlaps significantly with sets found by GWAS of age-related macular degeneration (P=1.4 × 10-12), ulcerative colitis (P<1.0 × 10-20), type 2 diabetes (P=2.8 × 10-13), hip/waist circumference in men (P=1.1 × 10-9), schizophrenia (P=1.6 × 10-9), cognitive decline (P=5.3 × 10-4) and Parkinson's disease (P=8.6 × 10-3).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Aging / genetics*
  • Brain / metabolism
  • Brain / pathology
  • Brain Mapping
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / metabolism
  • Child
  • Child, Preschool
  • Cognitive Dysfunction / genetics*
  • Cognitive Dysfunction / metabolism
  • Cognitive Dysfunction / pathology
  • DNA Methylation
  • Epigenesis, Genetic*
  • Female
  • Genome, Human*
  • Genome-Wide Association Study
  • Humans
  • Infant
  • Male
  • Middle Aged
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • Neurodegenerative Diseases / genetics*
  • Neurodegenerative Diseases / metabolism
  • Neurodegenerative Diseases / pathology
  • Neurons / metabolism
  • Neurons / pathology
  • Quantitative Trait Loci

Substances

  • Calcium-Binding Proteins
  • Nerve Tissue Proteins