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Is α-T catenin (VR22) an Alzheimer’s disease risk gene?
  1. Lars Bertram1,
  2. Kristina Mullin1,
  3. Michele Parkinson1,
  4. Monica Hsiao1,
  5. Thomas J Moscarillo2,
  6. Steven L Wagner3,
  7. K David Becker3,
  8. Gonul Velicelebi3,
  9. Deborah Blacker2,
  10. Rudolph E Tanzi1
  1. 1Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Diseases, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Massachusetts, USA
  2. 2Gerontology Research Unit, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Massachusetts, USA
  3. 3TorreyPines Therapeutics, La Jolla, California, USA
  1. Correspondence to:
 Dr L Bertram
 Genetics and Aging Research Unit, Massachusetts General Hospital-East (MassGeneral Institute for Neurodegenerative Diseases), 114, 16th Street, Charlestown, MA 02129, USA; bertram{at}helix.mgh.harvard.edu

Abstract

Background: Recently, conflicting reports have been published on the potential role of genetic variants in the α-T catenin gene (VR22; CTNNA3) on the risk for Alzheimer’s disease. In these papers, evidence for association is mostly observed in multiplex families with Alzheimer’s disease, whereas case–control samples of sporadic Alzheimer’s disease are predominantly negative.

Methods: After sequencing VR22 in multiplex families with Alzheimer’s disease linked to chromosome 10q21, we identified a novel non-synonymous (Ser596Asn; rs4548513) single nucleotide polymorphism (SNP). This and four non-coding SNPs were assessed in two independent samples of families with Alzheimer’s disease, one with 1439 subjects from 437 multiplex families with Alzheimer’s disease and the other with 489 subjects from 217 discordant sibships.

Results: A weak association with the Ser596Asn SNP in the multiplex sample, predominantly in families with late-onset Alzheimer’s disease (p = 0.02), was observed. However, this association does not seem to contribute substantially to the chromosome 10 Alzheimer’s disease linkage signal that we and others have reported previously. No evidence was found of association with any of the four additional SNPs tested in the multiplex families with Alzheimer’s disease. Finally, the Ser596Asn change was not associated with the risk for Alzheimer’s disease in the independent discordant sibship sample.

Conclusions: This is the first study to report evidence of an association between a potentially functional, non-synonymous SNP in VR22 and the risk for Alzheimer’s disease. As the underlying effects are probably small, and are only seen in families with multiple affected members, the population-wide significance of this finding remains to be determined.

  • CAG, Consortium on Alzheimer’s Genetics
  • NIMH, National Institute of Mental Health
  • SNP, single-nucleotide polymorphism

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Footnotes

  • Funding: This work was sponsored by grants from the NIMH, NIA (ADRC) and the Alzheimer Association. LB is supported by grants from the NIA (1R01 AG023667-01) and a “Young Investigator Award” from the National Alliance for Research on Schizophrenia and Depression (NARSAD).

  • Competing interests: None declared.

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