Genome-wide association study combining pathway analysis for typical sporadic amyotrophic lateral sclerosis in Chinese Han populations

Neurobiol Aging. 2014 Jul;35(7):1778.e9-1778.e23. doi: 10.1016/j.neurobiolaging.2014.01.014. Epub 2014 Jan 17.


Sporadic amyotrophic lateral sclerosis (sALS) is a severe neurodegenerative disease that causes progressive motor neuron death. Although the etiology of sALS remains unknown, genetic variants are thought to predispose individuals to the disease. Several recent genome-wide association studies have identified a number of loci that increase sALS susceptibility, but these only explain a small proportion of the disease. To extend the current genetic evidence and to identify novel candidates of sALS, we performed a pooling genome-wide association study by 859,311 autosomal single-nucleotide polymorphisms of IlluminaHumanOmniZhongHua-8 combining pathway analysis in 250 typical sALS cases precluding age, clinical course, and phenotype interference and 250 control subjects from Chinese Han populations (CHP). The results revealed that 8 novel loci of 1p34.3, 3p21.1, 3p22.2, 10p15.2, 22q12.1, 3q13.11, 11q25, 12q24.33, and 5 previously reported loci of CNTN4 (kgp11325216), ATXN1 (kgp8327591), C9orf72 (kgp6016770), ITPR2 (kgp3041552), and SOD1 (kgp10760302) were associated with sALS from CHP. Furthermore, the pathway analysis based on the Gene Set Analysis Toolkit V2 showed that 10 top pathways were strongly associated with sALS from CHP, and among them, the 7 most potentially candidate pathways were phosphatidylinositol signaling system, Wnt signaling pathway, axon guidance, MAPK signaling pathway, neurotrophin signaling pathway, arachidonic acid metabolism, and T-cell receptor signaling pathway, a total of 39 significantly associate genes in 7 candidate pathways was suggested to involve in the pathogenesis of sALS from CHP. In conclusion, our results revealed several new loci and pathways related to sALS from CHP and extend the association evidence for partial loci, genes, and pathways, which were previously identified in other populations. Thus, our data provided new clues for exploring the pathogenesis of sALS.

Keywords: Chinese Han populations; Genome-wide association study; Locus; Pathway; Sporadic amyotrophic lateral sclerosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / genetics*
  • Asians
  • Ataxin-1
  • Ataxins
  • C9orf72 Protein
  • Chromosomes, Human / genetics
  • Contactins / genetics
  • Female
  • Genetic Loci / genetics*
  • Genetic Predisposition to Disease / genetics*
  • Genome-Wide Association Study*
  • Humans
  • Inositol 1,4,5-Trisphosphate Receptors / genetics
  • Male
  • Nerve Tissue Proteins / genetics
  • Nuclear Proteins / genetics
  • Polymorphism, Single Nucleotide
  • Proteins / genetics
  • Signal Transduction / genetics
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase-1


  • ATXN1 protein, human
  • Ataxin-1
  • Ataxins
  • C9orf72 Protein
  • C9orf72 protein, human
  • CNTN4 protein, human
  • Contactins
  • ITPR2 protein, human
  • Inositol 1,4,5-Trisphosphate Receptors
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Proteins
  • SOD1 protein, human
  • Superoxide Dismutase
  • Superoxide Dismutase-1