Genetic analysis implicates APOE, SNCA and suggests lysosomal dysfunction in the etiology of dementia with Lewy bodies

Hum Mol Genet. 2014 Dec 1;23(23):6139-46. doi: 10.1093/hmg/ddu334. Epub 2014 Jun 27.

Abstract

Clinical and neuropathological similarities between dementia with Lewy bodies (DLB), Parkinson's and Alzheimer's diseases (PD and AD, respectively) suggest that these disorders may share etiology. To test this hypothesis, we have performed an association study of 54 genomic regions, previously implicated in PD or AD, in a large cohort of DLB cases and controls. The cohort comprised 788 DLB cases and 2624 controls. To minimize the issue of potential misdiagnosis, we have also performed the analysis including only neuropathologically proven DLB cases (667 cases). The results show that the APOE is a strong genetic risk factor for DLB, confirming previous findings, and that the SNCA and SCARB2 loci are also associated after a study-wise Bonferroni correction, although these have a different association profile than the associations reported for the same loci in PD. We have previously shown that the p.N370S variant in GBA is associated with DLB, which, together with the findings at the SCARB2 locus, suggests a role for lysosomal dysfunction in this disease. These results indicate that DLB has a unique genetic risk profile when compared with the two most common neurodegenerative diseases and that the lysosome may play an important role in the etiology of this disorder. We make all these data available.

Publication types

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

MeSH terms

  • Alzheimer Disease / etiology
  • Alzheimer Disease / genetics
  • Alzheimer Disease / pathology
  • Apolipoproteins E / genetics*
  • Case-Control Studies
  • Cohort Studies
  • Female
  • Genetic Association Studies
  • Genetic Loci
  • Humans
  • Lewy Body Disease / etiology*
  • Lewy Body Disease / genetics
  • Lewy Body Disease / pathology
  • Lysosome-Associated Membrane Glycoproteins / genetics*
  • Lysosomes / pathology*
  • Male
  • Parkinson Disease / etiology
  • Parkinson Disease / genetics
  • Parkinson Disease / pathology
  • Receptors, Scavenger / genetics*
  • Risk Factors
  • alpha-Synuclein / genetics*

Substances

  • Apolipoproteins E
  • Lysosome-Associated Membrane Glycoproteins
  • Receptors, Scavenger
  • SCARB2 protein, human
  • SNCA protein, human
  • alpha-Synuclein