Identification of a novel risk locus for progressive supranuclear palsy by a pooled genomewide scan of 500,288 single-nucleotide polymorphisms.
To date, only the H1 MAPT haplotype has been consistently associated with risk of developing the neurodegenerative disease progressive supranuclear palsy (PSP). We hypothesized that additional genetic loci may be involved in conferring risk of PSP that could be identified through a pooling-based genomewide association study of >500,000 SNPs. Candidate SNPs with large differences in allelic frequency were identified by ranking all SNPs by their probe-intensity difference between cohorts. The MAPT H1 haplotype was strongly detected by this methodology, as was a second major locus on chromosome 11p12-p11 that showed evidence of association at allelic (P<.001), genotypic (P<.001), and haplotypic (P<.001) levels and was narrowed to a single haplotype block containing the DNA damage-binding protein 2 (DDB2) and lysosomal acid phosphatase 2 (ACP2) genes. Since DNA damage and lysosomal dysfunction have been implicated in aging and neurodegenerative processes, both genes are viable candidates for conferring risk of disease.
Melquist
Stacey
S
Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA.
Craig
David W
DW
Huentelman
Matthew J
MJ
Crook
Richard
R
Pearson
John V
JV
Baker
Matt
M
Zismann
Victoria L
VL
Gass
Jennifer
J
Adamson
Jennifer
J
Szelinger
Szabolcs
S
Corneveaux
Jason
J
Cannon
Ashley
A
Coon
Keith D
KD
Lincoln
Sarah
S
Adler
Charles
C
Tuite
Paul
P
Calne
Donald B
DB
Bigio
Eileen H
EH
Uitti
Ryan J
RJ
Wszolek
Zbigniew K
ZK
Golbe
Lawrence I
LI
Caselli
Richard J
RJ
Graff-Radford
Neill
N
Litvan
Irene
I
Farrer
Matthew J
MJ
Dickson
Dennis W
DW
Hutton
Mike
M
Stephan
Dietrich A
DA
D000135:Acid Phosphatase / Q000235:genetics; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D020022:Genetic Predisposition to Disease; D023281:Genomics / Q000379:methods; D006801:Humans; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D013494:Supranuclear Palsy, Progressive / Q000235:genetics*
C117669:DDB2 protein, human; D004268:DNA-Binding Proteins; C520783:ACP2 protein, human; D000135:Acid Phosphatase