Association of single-nucleotide polymorphisms of the tau gene with late-onset Parkinson disease.
BACKGROUND
The human tau gene, which promotes assembly of neuronal microtubules, has been associated with several rare neurologic diseases that clinically include parkinsonian features. We recently observed linkage in idiopathic Parkinson disease (PD) to a region on chromosome 17q21 that contains the tau gene. These factors make tau a good candidate for investigation as a susceptibility gene for idiopathic PD, the most common form of the disease.


OBJECTIVE
To investigate whether the tau gene is involved in idiopathic PD.


METHODS
Among a sample of 1056 individuals from 235 families selected from 13 clinical centers in the United States and Australia and from a family ascertainment core center, we tested 5 single-nucleotide polymorphisms (SNPs) within the tau gene for association with PD, using family-based tests of association. Both affected (n = 426) and unaffected (n = 579) family members were included; 51 individuals had unclear PD status. Analyses were conducted to test individual SNPs and SNP haplotypes within the tau gene.


METHODS
Family-based tests of association, calculated using asymptotic distributions.


RESULTS
Analysis of association between the SNPs and PD yielded significant evidence of association for 3 of the 5 SNPs tested: SNP 3, P =.03; SNP 9i, P =.04; and SNP 11, P =.04. The 2 other SNPs did not show evidence of significant association (SNP 9ii, P =.11, and SNP 9iii, P =.87). Strong evidence of association was found with haplotype analysis, with a positive association with one haplotype (P =.009) and a negative association with another haplotype (P =.007). Substantial linkage disequilibrium (P<.001) was detected between 4 of the 5 SNPs (SNPs 3, 9i, 9ii, and 11).


CONCLUSIONS
This integrated approach of genetic linkage and positional association analyses implicates tau as a susceptibility gene for idiopathic PD.
Martin
E R
ER
Center for Human Genetics, Box 2903, Duke University Medical Center, Durham, NC 27710, USA.
Scott
W K
WK
Nance
M A
MA
Watts
R L
RL
Hubble
J P
JP
Koller
W C
WC
Lyons
K
K
Pahwa
R
R
Stern
M B
MB
Colcher
A
A
Hiner
B C
BC
Jankovic
J
J
Ondo
W G
WG
Allen
F H
FH
Goetz
C G
CG
Small
G W
GW
Masterman
D
D
Mastaglia
F
F
Laing
N G
NG
Stajich
J M
JM
Ribble
R C
RC
Booze
M W
MW
Rogala
A
A
Hauser
M A
MA
Zhang
F
F
Gibson
R A
RA
Middleton
L T
LT
Roses
A D
AD
Haines
J L
JL
Scott
B L
BL
Pericak-Vance
M A
MA
Vance
J M
JM
D017668:Age of Onset; D000368:Aged; D002886:Chromosomes, Human, Pair 17; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D010300:Parkinson Disease / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D016875:tau Proteins / Q000235:genetics*
D016875:tau Proteins