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.
BIN1 GBA Genetics Parkinson disease
This is a preview of subscription content, log in to check access.
This work was supported by Tel Aviv Sourasky Medical Center Grant of Excellence, by the Kahn Foundation, by the Chief Scientist of the Israeli Ministry of Health (Grant No. 3-4893), by the Legacy Heritage Biomedical Science Partnership Program of the Israel Science Foundation (Grant No.1922/08), and by the Michael J. Fox Foundation.
Compliance with ethical standards
Conflicts of interest
All authors declare no conflict of interest.
All participants signed an informed consent before entering the study. The Institutional and National Supreme Helsinki Committees for Genetic Studies approved the study protocols and the informed consents, which have been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.
Gan-Or Z, Bar-Shira A, Gurevich T et al (2011) Homozygosity for the MTX1 c.184T>A (p. S63T) alteration modifies the age of onset in GBA-associated Parkinson’s disease. Neurogenetics 12:325–332CrossRefPubMedGoogle Scholar
Vacic V, Ozelius LJ, Clark LN et al (2014) Genome-wide mapping of IBD segments in an Ashkenazi PD cohort identifies associated haplotypes. Hum Mol Genet 23(17):4693–4702Google Scholar
Nalls MA, Pankratz N, Lill CM et al (2014) Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson’s disease. Nat Genet 46:989–993PubMedCentralCrossRefPubMedGoogle Scholar
Gan-Or Z, Bar-Shira A, Mirelman A et al (2012) The age at motor symptoms onset in LRRK2-associated Parkinson’s disease is affected by a variation in the MAPT locus: a possible interaction. J Mol Neurosci 46:541–544CrossRefPubMedGoogle Scholar
Golub Y, Berg D, Calne DB et al (2009) Genetic factors influencing age at onset in LRRK2-linked Parkinson disease. Parkinsonism Relat Disord 15:539–541CrossRefPubMedGoogle Scholar
Moskvina V, Harold D, Russo G et al (2013) Analysis of genome-wide association studies of Alzheimer disease and of Parkinson disease to determine if these 2 diseases share a common genetic risk. JAMA Neurol 70(10):1268–1276PubMedGoogle Scholar
Lambert JC, Ibrahim-Verbaas CA, Harold D et al (2013) Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat Genet 45(12):1452–1458PubMedCentralCrossRefPubMedGoogle Scholar
Tan MS, Yu JT, Tan L (2013) Bridging integrator 1 (BIN1): form, function, and Alzheimer’s disease. Trends Mol Med 19:594–603CrossRefPubMedGoogle Scholar
Pienaar IS, Burn D, Morris C et al (2012) Synaptic protein alterations in Parkinson’s disease. Mol Neurobiol 45:126–143CrossRefPubMedGoogle Scholar
Nicot AS, Toussaint A, Tosch V et al (2007) Mutations in amphiphysin 2 (BIN1) disrupt interaction with dynamin 2 and cause autosomal recessive centronuclear myopathy. Nat Genet 39:1134–1139CrossRefPubMedGoogle Scholar