TY - JOUR
T1 - The Alzheimer disease BIN1 locus as a modifier of GBA-associated Parkinson disease
AU - Gan-Or, Z.
AU - Amshalom, I.
AU - Bar-Shira, A.
AU - Gana-Weisz, M.
AU - Mirelman, A.
AU - Marder, K.
AU - Bressman, S.
AU - Giladi, N.
AU - Orr-Urtreger, A.
N1 - Publisher Copyright:
© 2015, Springer-Verlag Berlin Heidelberg.
PY - 2015/11/1
Y1 - 2015/11/1
N2 - GBA mutations are among the most common genetic risk factors for Parkinson disease (PD) worldwide. We aimed to identify genetic modifiers of the age at onset (AAO) in GBA-associated PD. The study included a genome-wide discovery phase, including a cohort of 79 patients with the GBA p.N370S mutation, and candidate validation and replication analyses of 8 SNPs in patients with mild (n = 113) and severe (n = 41) GBA mutations. Genotyping was performed using the Affymetrix human SNP 6.0 array and TaqMan assays. In the genome-wide phase, none of the SNPs passed the genome-wide significance threshold. Eight SNPs were selected for further analysis from the top hits. In all GBA-associated PD patients (n = 153), the BIN1 rs13403026 minor allele was associated with an older AAO (12.4 ± 5.9 years later, p = 0.0001), compared to patients homozygous for the major allele. Furthermore, the AAO was 10.7 ± 6.8 years later in patients with mild GBA mutations, (p = 0.005, validation group), and 17.1 ± 2.5 years later in patients with severe GBA mutations (p = 0.01, replication). Our results suggest that alterations in the BIN1 locus, previously associated with Alzheimer disease, may modify the AAO of GBA-associated PD. More studies in other populations are required to examine the role of BIN1-related variants in GBA-associated PD.
AB - GBA mutations are among the most common genetic risk factors for Parkinson disease (PD) worldwide. We aimed to identify genetic modifiers of the age at onset (AAO) in GBA-associated PD. The study included a genome-wide discovery phase, including a cohort of 79 patients with the GBA p.N370S mutation, and candidate validation and replication analyses of 8 SNPs in patients with mild (n = 113) and severe (n = 41) GBA mutations. Genotyping was performed using the Affymetrix human SNP 6.0 array and TaqMan assays. In the genome-wide phase, none of the SNPs passed the genome-wide significance threshold. Eight SNPs were selected for further analysis from the top hits. In all GBA-associated PD patients (n = 153), the BIN1 rs13403026 minor allele was associated with an older AAO (12.4 ± 5.9 years later, p = 0.0001), compared to patients homozygous for the major allele. Furthermore, the AAO was 10.7 ± 6.8 years later in patients with mild GBA mutations, (p = 0.005, validation group), and 17.1 ± 2.5 years later in patients with severe GBA mutations (p = 0.01, replication). Our results suggest that alterations in the BIN1 locus, previously associated with Alzheimer disease, may modify the AAO of GBA-associated PD. More studies in other populations are required to examine the role of BIN1-related variants in GBA-associated PD.
KW - BIN1
KW - GBA
KW - Genetics
KW - Parkinson disease
UR - http://www.scopus.com/inward/record.url?scp=84956773191&partnerID=8YFLogxK
U2 - 10.1007/s00415-015-7868-3
DO - 10.1007/s00415-015-7868-3
M3 - Article
C2 - 26233692
AN - SCOPUS:84956773191
SN - 0340-5354
VL - 262
SP - 2443
EP - 2447
JO - Journal of Neurology
JF - Journal of Neurology
IS - 11
ER -