Abstract
Whole gene duplications and triplications of alpha-synuclein (SNCA) can cause Parkinson's disease (PD), and variation in the promoter region (Rep1) and 3′ region of SNCA has been reported to increase disease susceptibility. Within our cohort, one affected individual from each of 92 multiplex PD families showing the greatest evidence of linkage to the region around SNCA was screened for dosage alterations and sequence changes; no dosage or non-synonymous sequence changes were found. In addition, 737 individuals (from 450 multiplex PD families) that met strict diagnostic criteria for PD and did not harbor a known causative mutation, as well as 359 neurologically normal controls, were genotyped for the Rep1 polymorphism and four SNPs in the 3′ region of SNCA. The four SNPs were in high LD (r2 > 0.95) and were analyzed as a haplotype. The effects of the Rep1 genotype and the 3′ haplotype were evaluated using regression models employing only one individual per family. Cases had a 3% higher frequency of the Rep1 263 bp allele compared with controls (OR = 1.54; empirical P-value = 0.02). There was an inverse linear relationship between the number of 263 bp alleles and age of onset (empirical P-value = 0.0004). The 3′ haplotype was also associated with disease (OR = 1.29; empirical P-value = 0.01), but not age of onset (P = 0.40). These data suggest that dosage and sequence changes are a rare cause of PD, but variation in the promoter and 3′ region of SNCA convey an increased risk for PD.
| Original language | English |
|---|---|
| Pages (from-to) | 1125-1131 |
| Number of pages | 7 |
| Journal | Movement Disorders |
| Volume | 24 |
| Issue number | 8 |
| DOIs | |
| State | Published - Jun 15 2009 |
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Keywords
- Alpha-synuclein
- Association
- Dosage
- Parkinson's disease
- Rep1
ASJC Scopus subject areas
- Clinical Neurology
- Neurology
Cite this
Alpha-synuclein and familial Parkinson's disease. / Pankratz, Nathan; Nichols, William C.; Elsaesser, Veronika E.; Pauciulo, Michael W.; Marek, Diane K.; Halter, Cheryl A.; Wojcieszek, Joanne; Rudolph, Alice; Pfeiffer, Ronald F.; Foroud, Tatiana.
In: Movement Disorders, Vol. 24, No. 8, 15.06.2009, p. 1125-1131.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Alpha-synuclein and familial Parkinson's disease
AU - Pankratz, Nathan
AU - Nichols, William C.
AU - Elsaesser, Veronika E.
AU - Pauciulo, Michael W.
AU - Marek, Diane K.
AU - Halter, Cheryl A.
AU - Wojcieszek, Joanne
AU - Rudolph, Alice
AU - Pfeiffer, Ronald F.
AU - Foroud, Tatiana
PY - 2009/6/15
Y1 - 2009/6/15
N2 - Whole gene duplications and triplications of alpha-synuclein (SNCA) can cause Parkinson's disease (PD), and variation in the promoter region (Rep1) and 3′ region of SNCA has been reported to increase disease susceptibility. Within our cohort, one affected individual from each of 92 multiplex PD families showing the greatest evidence of linkage to the region around SNCA was screened for dosage alterations and sequence changes; no dosage or non-synonymous sequence changes were found. In addition, 737 individuals (from 450 multiplex PD families) that met strict diagnostic criteria for PD and did not harbor a known causative mutation, as well as 359 neurologically normal controls, were genotyped for the Rep1 polymorphism and four SNPs in the 3′ region of SNCA. The four SNPs were in high LD (r2 > 0.95) and were analyzed as a haplotype. The effects of the Rep1 genotype and the 3′ haplotype were evaluated using regression models employing only one individual per family. Cases had a 3% higher frequency of the Rep1 263 bp allele compared with controls (OR = 1.54; empirical P-value = 0.02). There was an inverse linear relationship between the number of 263 bp alleles and age of onset (empirical P-value = 0.0004). The 3′ haplotype was also associated with disease (OR = 1.29; empirical P-value = 0.01), but not age of onset (P = 0.40). These data suggest that dosage and sequence changes are a rare cause of PD, but variation in the promoter and 3′ region of SNCA convey an increased risk for PD.
AB - Whole gene duplications and triplications of alpha-synuclein (SNCA) can cause Parkinson's disease (PD), and variation in the promoter region (Rep1) and 3′ region of SNCA has been reported to increase disease susceptibility. Within our cohort, one affected individual from each of 92 multiplex PD families showing the greatest evidence of linkage to the region around SNCA was screened for dosage alterations and sequence changes; no dosage or non-synonymous sequence changes were found. In addition, 737 individuals (from 450 multiplex PD families) that met strict diagnostic criteria for PD and did not harbor a known causative mutation, as well as 359 neurologically normal controls, were genotyped for the Rep1 polymorphism and four SNPs in the 3′ region of SNCA. The four SNPs were in high LD (r2 > 0.95) and were analyzed as a haplotype. The effects of the Rep1 genotype and the 3′ haplotype were evaluated using regression models employing only one individual per family. Cases had a 3% higher frequency of the Rep1 263 bp allele compared with controls (OR = 1.54; empirical P-value = 0.02). There was an inverse linear relationship between the number of 263 bp alleles and age of onset (empirical P-value = 0.0004). The 3′ haplotype was also associated with disease (OR = 1.29; empirical P-value = 0.01), but not age of onset (P = 0.40). These data suggest that dosage and sequence changes are a rare cause of PD, but variation in the promoter and 3′ region of SNCA convey an increased risk for PD.
KW - Alpha-synuclein
KW - Association
KW - Dosage
KW - Parkinson's disease
KW - Rep1
UR - http://www.scopus.com/inward/record.url?scp=67651160721&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=67651160721&partnerID=8YFLogxK
U2 - 10.1002/mds.22524
DO - 10.1002/mds.22524
M3 - Article
C2 - 19412953
AN - SCOPUS:67651160721
VL - 24
SP - 1125
EP - 1131
JO - Movement Disorders
JF - Movement Disorders
SN - 0885-3185
IS - 8
ER -