A SNP in the ACT gene associated with astrocytosis and rapid cognitive decline in AD

Belbin, O.; Dunn, J.L.; Chappell, S.; Ritchie, A.E.; Ling, Y.; Morgan, L.; Pritchard, A.; Warden, D.R.; Lendon, C.L.; Lehmann, D.J.; Mann, D.M.A.; Smith, A.D.; Kalsheker, N.; Morgan, K.

doi:10.1016/j.neurobiolaging.2007.02.021

« Previous Next »Neurobiology of Aging
Volume 29, Issue 8 , Pages 1167-1176, August 2008

A SNP in the ACT gene associated with astrocytosis and rapid cognitive decline in AD

O. Belbin
- Division of Clinical Chemistry, Institute of Genetics, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, UK
J.L. Dunn
- School of Physics and Astronomy, University of Nottingham, University Park, Nottingham NG7 2RD, UK
S. Chappell
- Division of Clinical Chemistry, Institute of Genetics, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, UK
A.E. Ritchie
- Division of Clinical Chemistry, Institute of Genetics, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, UK
Y. Ling
- Division of Clinical Chemistry, Institute of Genetics, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, UK
L. Morgan
- Division of Clinical Chemistry, Institute of Genetics, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, UK
A. Pritchard
- Department of Human Genetics, G Floor CBCRC Building, Queensland Institute of Medical Research, 300 Herston Road, Herston, Brisbane 4006, Australia
- Present address: Department of Human Genetics, Queensland Institute of Medical Research, Herston, QLD 4006, Australia.
D.R. Warden
- OPTIMA, Oxford Centre for Gene Function, Department of Physiology, Anatomy & Genetics, Oxford OX1 3PT, UK
C.L. Lendon
- Department of Human Genetics, G Floor CBCRC Building, Queensland Institute of Medical Research, 300 Herston Road, Herston, Brisbane 4006, Australia
- Present address: Department of Human Genetics, Queensland Institute of Medical Research, Herston, QLD 4006, Australia.
D.J. Lehmann
- OPTIMA, Oxford Centre for Gene Function, Department of Physiology, Anatomy & Genetics, Oxford OX1 3PT, UK
D.M.A. Mann
- Greater Manchester Neurosciences Centre, University of Manchester, Manchester M6 8HD, UK
A.D. Smith
- OPTIMA, Oxford Centre for Gene Function, Department of Physiology, Anatomy & Genetics, Oxford OX1 3PT, UK
N. Kalsheker
- Division of Clinical Chemistry, Institute of Genetics, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, UK
K. Morgan
- Division of Clinical Chemistry, Institute of Genetics, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, UK
- Corresponding author. Tel.: +44 115 8230724; fax: +44 115 9709167.

Received 15 November 2006; received in revised form 19 December 2006; accepted 10 February 2007. published online 19 March 2007.

Abstract

There is biochemical and animal model evidence supporting a pathological role of the ACT gene in AD. However, direct genetic evidence remains controversial and has been mostly limited to individual single nucleotide polymorphism (SNP) analysis. To resolve this apparent conflict we have used a high-density ACT SNP map, constructed haplotypes and explored correlations with phenotype. SNPs were identified by sequencing and used to construct haplotypes in 668 AD patients and 419 controls and a case–control association study was performed. Five SNPs, comprising five common haplotypes, represented 93% of ACT gene variation. Although no single SNP or haplotype was associated with AD status, a SNP in intron 2 was associated with later onset and more rapid cognitive decline (P=0.04). This SNP was both individually associated with severe astrocytosis (P=0.004) in AD patients and when combined with the signal sequence SNP (P=0.002). This suggests that astrocytosis may have a protective function for a limited period in some patients. These SNP associations either support a direct role for the ACT gene, in AD pathology or alternatively reflect linkage with polymorphisms in other genes nearby.