Genome-wide association analysis of hippocampal volume identifies enrichment of neurogenesis-related pathways

Sci Rep. 2019 Oct 10;9(1):14498. doi: 10.1038/s41598-019-50507-3.

Abstract

Adult neurogenesis occurs in the dentate gyrus of the hippocampus during adulthood and contributes to sustaining the hippocampal formation. To investigate whether neurogenesis-related pathways are associated with hippocampal volume, we performed gene-set enrichment analysis using summary statistics from a large-scale genome-wide association study (N = 13,163) of hippocampal volume from the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Consortium and two year hippocampal volume changes from baseline in cognitively normal individuals from Alzheimer's Disease Neuroimaging Initiative Cohort (ADNI). Gene-set enrichment analysis of hippocampal volume identified 44 significantly enriched biological pathways (FDR corrected p-value < 0.05), of which 38 pathways were related to neurogenesis-related processes including neurogenesis, generation of new neurons, neuronal development, and neuronal migration and differentiation. For genes highly represented in the significantly enriched neurogenesis-related pathways, gene-based association analysis identified TESC, ACVR1, MSRB3, and DPP4 as significantly associated with hippocampal volume. Furthermore, co-expression network-based functional analysis of gene expression data in the hippocampal subfields, CA1 and CA3, from 32 normal controls showed that distinct co-expression modules were mostly enriched in neurogenesis related pathways. Our results suggest that neurogenesis-related pathways may be enriched for hippocampal volume and that hippocampal volume may serve as a potential phenotype for the investigation of human adult neurogenesis.

Publication types

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

MeSH terms

  • Activin Receptors, Type I / genetics
  • Aged
  • Alzheimer Disease / genetics*
  • Alzheimer Disease / pathology
  • Calcium-Binding Proteins / genetics
  • Cell Differentiation / genetics
  • Cognition / physiology
  • Dentate Gyrus / growth & development
  • Dentate Gyrus / metabolism
  • Dipeptidyl Peptidase 4 / genetics
  • Female
  • Gene Expression Regulation / genetics
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study
  • Hippocampus / growth & development
  • Hippocampus / metabolism
  • Humans
  • Male
  • Methionine Sulfoxide Reductases / genetics
  • Neurogenesis / genetics*
  • Neurons / metabolism
  • Organ Size / genetics*
  • Signal Transduction / genetics

Substances

  • Calcium-Binding Proteins
  • TESC protein, human
  • Methionine Sulfoxide Reductases
  • MSRB3 protein, human
  • ACVR1 protein, human
  • Activin Receptors, Type I
  • DPP4 protein, human
  • Dipeptidyl Peptidase 4