Genome-wide association study of N370S homozygous Gaucher disease reveals the candidacy of CLN8 gene as a genetic modifier contributing to extreme phenotypic variation

Am J Hematol. 2012 Apr;87(4):377-83. doi: 10.1002/ajh.23118. Epub 2012 Mar 3.


Mutations in GBA1 gene result in defective acid β-glucosidase and the complex phenotype of Gaucher disease (GD) related to the accumulation of glucosylceramide-laden macrophages. The phenotype is highly variable even among patients harboring identical GBA1 mutations. We hypothesize that modifier gene(s) underlie phenotypic diversity in GD and performed a GWAS study in Ashkenazi Jewish patients with type 1 GD (GD1), homozygous for N370S mutation. Patients were assigned to mild, moderate, or severe disease categories using composite disease severity scoring systems. Whole-genome genotyping for >500,000 SNPs was performed to search for association signals using OQLS algorithm in 139 eligible patients. Several SNPs in linkage disequilibrium within the CLN8 gene locus were associated with the GD1 severity: SNP rs11986414 was associated with GD1 severity at P value 1.26 × 10(-6) . Compared to mild disease, risk allele A at rs11986414 conferred an odds ratio of 3.72 for moderate/severe disease. Loss of function mutations in CLN8 causes neuronal ceroid-lipofuscinosis, but our results indicate that its increased expression may protect against severe GD1. In cultured skin fibroblasts, the relative expression of CLN8 was higher in mild GD compared to severely affected patients, in whom CLN8 risk alleles were overrepresented. In an in vitro cell model of GD, CLN8 expression was increased, which was further enhanced in the presence of bioactive substrate, glucosylsphingosine. Taken together, CLN8 is a candidate modifier gene for GD1 that may function as a protective sphingolipid sensor and/or in glycosphingolipid trafficking. Future studies should explore the role of CLN8 in pathophysiology of GD.

Publication types

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

MeSH terms

  • Alleles
  • Cells, Cultured / metabolism
  • Epistasis, Genetic*
  • Female
  • Fibroblasts / metabolism
  • Gaucher Disease / ethnology
  • Gaucher Disease / genetics*
  • Gaucher Disease / metabolism
  • Gaucher Disease / pathology
  • Genome-Wide Association Study
  • Genotype
  • Germany / ethnology
  • Glucosylceramidase / genetics
  • Homozygote
  • Humans
  • Jews / genetics
  • Macrophages / metabolism
  • Male
  • Membrane Proteins / genetics*
  • Membrane Proteins / physiology
  • Middle Aged
  • Mutation, Missense
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Psychosine / analogs & derivatives
  • Psychosine / metabolism
  • Severity of Illness Index


  • CLN8 protein, human
  • Membrane Proteins
  • Psychosine
  • sphingosyl beta-glucoside
  • Glucosylceramidase