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Association of Sequence Alterations in the Putative Promoter of RAB7L1 with a Reduced Parkinson Disease Risk

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ORIGINAL CONTRIBUTION Association of Sequence Alterations in the Putative Promoter of RAB7L1 With a Reduced Parkinson Disease Risk Ziv Gan-Or, BMedSci; Anat Bar-Shira, PhD; Dvir Dahary, MSc; Anat Mirelman, PhD; Merav Kedmi, PhD; Tanya Gurevich, MD; Nir Giladi, MD; Avi Orr-Urtreger, MD, PhD Objective: To examine whether PARK16, which was re- Results: All tested SNPs were significantly associated with cently identified as a protective locus for Parkinson dis- PD (odds ratios=0.64-0.76; P=.0002-.014). Two of them, ease (PD) in Asian, white, and South American popula- rs1572931 and rs823144, were localized to the putative pro- tions, is also associated with PD in the genetically moter region of RAB7L1 and their sequence variations al- homogeneous Ashkenazi Jewish population. teredthepredictedtranscriptionfactorbindingsitesofCdxA, p300, GATA-1, Sp1, and c-Ets-1. Only 0.4% of patients were Design: Case-control study. homozygous for the protective rs1572931 genotype (T/T), comparedwith3.0%amongcontrols(P=5ϫ10−5).ThisSNP was included in a haplotype that reduced the risk for PD by Setting: A medical center affiliated with a university. 10- to 12-fold (P=.002-.01) in all patients with PD and in a subgroupofpatientswhodonotcarrytheAshkenazifounder Subjects: Five single-nucleotide polymorphisms (SNPs) mutations in the GBA or LRRK2 genes. located between RAB7L1 and SLC41A1 were analyzed in 720 patients with PD and 642 controls, all of Ashkenazi Conclusions: Our data demonstrate that specific SNP Jewish origin. variations and haplotypes in the PARK16 locus are asso- ciated with reduced risk for PD in Ashkenazim. Al- Main Outcome Measures: Haplotypes were defined though it is possible that alterations in the putative pro- and risk estimates were determined for each SNP and hap- moter of RAB7L1 are associated with this effect, the role lotype. Bioinformatic analysis defined the putative pro- of other genes in this locus cannot be ruled out. moter region of RAB7L1 and the transcription factor bind- ing sites that are potentially affected by 2 of the tested SNPs. Arch Neurol. 2012;69(1):105-110 ARKINSON DISEASE (PD) firmed in ethnic Chinese,6,7 European,8,9 and (OMIM 168600) is a multi- Chilean10 populations but was not con- factorial, age-related disor- firmed in other studies in Spanish, Euro- der affecting about 2% of the pean, and North American populations.11-13 elderly population. More than The high prevalence of founder GBA and a decade of study of familial and sporadic LRRK2 mutations in more than a third of the P 14,15 PD has revealed PD as a disorder with com- Ashkenazi Jewish patients with PD is an plex genetic background involving mul- additional demonstration for the genetic ho- tiple affected genes and genetic loci1,2 and mogeneity of this population.16 This phe- 3 Author Affiliations: The also multiple environmental risk factors. nomenon renders this population useful for Genetic Institute (Messrs Most of the genes studied were associated detecting other common genetic variations Gan-Or and Dahary and with increased risk for PD; however, 2 large- that affect PD risk. Herein, we aimed to ex- Drs Bar-Shira, Kedmi, and scale genome-wide association studies in amine whether such alterations exist in the Orr-Urtreger) and Movement Japanese and North American and Euro- PARK16 locus in Ashkenazim. Disorders Unit, Parkinson pean populations identified PARK16, a novel Center and Department of locus on chromosome 1q32 (OMIM METHODS Neurology (Drs Mirelman, 613164) that was associated with a reduced Gurevich, and Giladi), Tel-Aviv PD risk.4,5 This region encompasses 5 genes: Sourasky Medical Center, and STUDY POPULATION The Sackler Faculty of Medicine SLC45A3 (OMIM 605097), NUCKS1 (Mr Gan-Or and Drs Gurevich, (OMIM 611912), RAB7L1 (OMIM 603949), The PD patient cohort included 720 con- Giladi, and Orr-Urtreger), SLC41A1 (OMIM 610801), and PM20D1 secutively recruited individuals (62.6% Tel-Aviv University, (OMIM 613164).4,5 Recently, the associa- men) (Table 1), with a mean (SD) age at Tel-Aviv, Israel. tion between PARK16 and PD was also con- enrollment of 67.5 (10.4) years. The 642 ARCH NEUROL / VOL 69 (NO. 1), JAN 2012 WWW.ARCHNEUROL.COM 105 ©2012 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 Table 1. Characterization of the Ashkenazi Patients With PD No. (%) Noncarriers Carriers Carriers of GBA or LRRK2 of GBA of LRRK2 G2019S Mutations Mutations Mutations Total Sample size 479a 142b 99c,d 720 Women 168 (35.1) 55 (38.7) 47 (47.5) 270 (37.5) AAO, mean (SD), y 60.7 (11.4) 57.4 (10.7) 57.0 (11.4) 59.6 (11.3) AAOϽ50 y 75 (15.9) 35 (24.8) 20 (21.1) 130 (18.3) Age at enrollment, mean (SD), y 68.5 (10.4) 64.9 (10.1) 66.4 (10.5) 67.5 (10.4) Family history of PD First-degree relative 66 (13.8) 22 (15.5) 31 (31.3) 119 (16.5) First- or second-degree relative 100 (20.9) 38 (26.8) 43 (43.4) 181 (25.1) Abbreviations: AAO, age at onset; PD, Parkinson disease. a Data regarding AAO was not available for 5 patients. b Data regarding AAO was not available for 1 patient. c Data regarding AAO was not available for 4 patients. d Including 10 patients who carry both the LRRK2 G2019S mutation and an Ashkenazi founder GBA mutation. control samples included 267 sex-matched elderly controls /TFSEARCH.html). The parameters used for this comparison were with a mean (SD) age at enrollment of 69.1 (10.9) years vertebrate matrices only, with a threshold score of 75.0 points (62.9% men) and 375 young controls (mostly women, 20-45 (of a maximum 100.0), as was previously described.17,18 years old). All patients and controls were of full Ashkenazi Jewish origin. Details regarding the cohort recruitment, STATISTICAL ANALYSIS diagnostic criteria, and interview procedures were previ- 14,15 ously published. All participants signed informed con- Differences in continuous variables were tested using analysis sent before entering the study. The Institutional and of variance or a t test. A ␹2 or Fisher exact test was used for National Supreme Helsinki Committees for Genetic Studies comparison of categorical variables. Bonferroni correction for approved the study protocols and the informed consents. multiple comparisons was applied and a cutoff P value of .01 was set for the analysis of the 5 SNPs (Table 2). Since the al- GENETIC VARIATIONS ANALYSIS lele and genotype frequencies of all tested SNPs did not differ between the young and elderly controls (Table 2) or between Genomic DNA was isolated from peripheral blood using stan- men and women (data not shown), these variables were not dard protocols or from saliva according to the manufacturer’s included as covariates in the analysis. To test for any deviation instructions (Oragene; DNA Genotek). Table 1 details some from Hardy-Weinberg equilibrium among patients with PD and demographic and clinical characteristics and the frequencies controls, a goodness of fit test with 1 df was applied. Calcula- of the GBA and LRRK2 G2019S mutations in our cohort of 720 tions of odds ratios (ORs) for minor allele carriers were done patients with PD. Mutations in the LRRK2 and GBA genes were using the online Hutchon calculator.19 For haplotype analysis, identified as previously described,14,15 and the LRRK2 G2019S HPlus software version 3.2 was used.20 Analysis of the Affyme- mutation (rs34637584) was also detected using TaqMan as- trix SNP 6.0 array results was done using the Golden Helix SNP say ID C_63498123_10 in the StepOnePlus Real-Time PCR Sys- & Variation Suite software (Golden Helix, Inc). To calculate tem (Applied Biosystems). The 5 tested single-nucleotide poly- linkage equilibrium (DЈ and r2), we used the CubeX online cal- morphisms (SNPs) within the PARK16 locus (eTable 1, http: culator.21 SPSS software version 17 (IBM SPSS Inc) was used //www.archneurol.com) were analyzed using TaqMan assays. for all other data analyses. A 1588–base pair (bp) fragment that contains the putative promoter region of RAB7L1, exon 1 and part of exon 2, and the coding sequences of exons 2 through 6 and their exon- RESULTS intron boundaries were amplified (Biometra GmbH) (the spe- cific primers are detailed in eTable 2) and sequenced using the IDENTIFICATION OF SNPs THAT ARE BigDye Terminator cycle sequencing chemistry in the auto- ASSOCIATED WITH MODIFIED PD RISK mated ABI 3100 Genetic Analyzer (Applied Biosystems). The PARK16 locus was defined by Satake et al4 on chro- BIOINFORMATIC ANALYSIS OF THE RAB7L1 mosome 1q32 between 203 910 000 and 204 070 000 (ge- PUTATIVE PROMOTER REGION nome assembly GCRh37). To select candidate SNPs for this study, we used unpublished results from a genome- The following tracks, implemented in the University of Califor- wide analysis of 426 DNA samples done in our labora- nia, Santa Cruz, Genome Browser, were used to predict the pu- tory (A.O., unpublished data, June 2009). The samples tative promoter region of RAB7L1: CpG Islands, ENCODE Tran- were from 128 elderly controls and 298 patients with PD, scription Factor ChIP-seq, and ENCODE Promoter-Associated Histone Mark (University of California, Santa Cruz). To analyze all of Ashkenazi origin. Since the patients samples were the possible effects of the rs823144 and rs1572931 SNPs located greatly enriched for LRRK2 G2019S carriers (25.2%) and within this promoter on the putative transcription factor bind- for GBA mutations carriers (31.2%), they did not repre- ing sites, 15-bp sequences from each side of the SNP were ana- sent the true carrier rate in the Ashkenazi PD popula- lyzed using TFSEARCH (http://www.cbrc.jp/research/db tion.
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