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Am J Neurodegener Dis 2012;1(2):191-198

Original Article
Beta-amyloid toxicity modifier genes and the risk of Alzheimer’s disease

Samantha L Rosenthal, Xingbin Wang, F Yesim Demirci, Michael M Barmada, Mary Ganguli, Oscar L Lopez,  M Ilyas

Department of Human Genetics, University Pittsburgh, Pittsburgh, PA, USA; Department of Psychiatry, University of
Pittsburgh, Pittsburgh, PA, USA; Alzheimer’s Disease Research Center, University of Pittsburgh, Pittsburgh, PA, USA;
Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA; Department of Epidemiology, University of
Pittsburgh, PA, USA.

Received July 31, 2012; accepted August 10, 2012; Epub August 13, 2012; published August 15, 2012

Abstract: Late-onset Alzheimer’s disease (LOAD) is a complex and multifactorial disease. So far ten loci have been
identified for LOAD, including APOE, PICALM, CLU, BIN1, CD2AP, CR1, CD33, EPHA1, ABCA7, and MS4A4A/MS4A6E,
but they explain about 50% of the genetic risk and thus additional risk genes need to be identified. Amyloid beta (Aβ)
plaques develop in the brains of LOAD patients and are considered to be a pathological hallmark of this disease.
Recently 12 new Aβ toxicity modifier genes (ADSSL1, PICALM, SH3KBP1, XRN1, SNX8, PPP2R5C, FBXL2, MAP2K4,
SYNJ1, RABGEF1, POMT2, and XPO1) have been identified that potentially play a role in LOAD risk. In this study, we
have examined the association of 222 SNPs in these 12 candidate genes with LOAD risk in 1291 LOAD cases and
958 cognitively normal controls. Single site and haplotype analyses were performed using PLINK. Following
adjustment for APOE genotype, age, sex, and principal components, we found single nucleotide polymorphisms
(SNPs) in PPP2R5C, PICALM, SH3KBP1, XRN1, and SNX8 that showed significant association with risk of LOAD. The
top SNP was located in intron 3 of PPP2R5C (P=0.009017), followed by an intron 19 SNP in PICALM (P=0.0102).
Haplotype analysis revealed significant associations in ADSSL1, PICALM, PPP2R5C, SNX8, and SH3KBP1 genes.  
Our data indicate that genetic variation in these new candidate genes affects the risk of LOAD. Further investigation of
these genes, including additional replication in other case-control samples and functional studies to elucidate the
pathways by which they affect Aβ, are necessary to determine the degree of involvement these genes have for LOAD
risk. (AJND1207005).

Keywords: Late-onset Alzheimer’s disease (LOAD), risk genes, SNPs, ADSSL1, PICALM, SH3KBP1, XRN1, SNX8,

Address all correspondence to:
M. Ilyas Kamboh, PhD
Department of Human Genetics
Graduate School of Public Health University of Pittsburgh
Pittsburgh, PA 15161, USA.
Telephone: 412-624-3066; Fax: 412-624-3020
E-mail: kamboh@pitt.edu