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High-Resolution Whole-Genome Association Study of Parkinson Disease Demetrius M Am. J. Hum. Genet. 77:685–693, 2005 High-Resolution Whole-Genome Association Study of Parkinson Disease Demetrius M. Maraganore,1 Mariza de Andrade,2 Timothy G. Lesnick,2 Kari J. Strain,2 Matthew J. Farrer,3 Walter A. Rocca,1,2 P. V. Krishna Pant,4 Kelly A. Frazer,4 David R. Cox,4 and Dennis G. Ballinger4 Departments of 1Neurology and 2Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN; 3Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL; and 4Perlegen Sciences, Mountain View, CA We performed a two-tiered, whole-genome association study of Parkinson disease (PD). For tier 1, we individually genotyped 198,345 uniformly spaced and informative single-nucleotide polymorphisms (SNPs) in 443 sibling pairs discordant for PD. For tier 2a, we individually genotyped 1,793 PD-associated SNPs (P ! .01 in tier 1) and 300 genomic control SNPs in 332 matched case–unrelated control pairs. We identified 11 SNPs that were associated with PD (P ! .01 ) in both tier 1 and tier 2 samples and had the same direction of effect. For these SNPs, we combined data from the case–unaffected sibling pair (tier 1) and case–unrelated control pair (tier 2) samples and employed a liberalization of the sibling transmission/disequilibrium test to calculate odds ratios, 95% confidence intervals, and P values. A SNP within the semaphorin 5A gene (SEMA5A) had the lowest combined P value (P p 7.62 # 1056). The protein encoded by this gene plays an important role in neurogenesis and in neuronal apoptosis, which is consistent with existing hypotheses regarding PD pathogenesis. A second SNP tagged the PARK11 late-onset PD susceptibility locus (P p 1.70 # 1055 ). In tier 2b, we also selected for genotyping additional SNPs that were borderline significant (P ! .05 ) in tier 1 but that tested a priori biological and genetic hypotheses regarding sus- ceptibility to PD (n p 941 SNPs). In analysis of the combined tier 1 and tier 2b data, the two SNPs with the lowest P values (P p 9.07 # 1056 ;P p 2.96 # 1055 ) tagged the PARK10 late-onset PD susceptibility locus. Independent replication across populations will clarify the role of the genomic loci tagged by these SNPs in conferring PD susceptibility. Introduction proach (tier 1 and tiers 2a and 2b). All methods of the study were approved by the investigational review board Association-based genome scans provide localizing in- of the Mayo Clinic. formation that is much more precise (often extending over a few thousand base pairs) than the corresponding Tier 1 information from linkage-based studies (which often ex- tend over many millions of base pairs). To date, there For tier 1, we included sibling pairs that were discor- has been only one published high-resolution genome dant for PD. Cases were enrolled prospectively from the scan for association for any human disease (Klein et al. clinical practice of the Department of Neurology of the 2005). Here, we report the results of a high-resolution, Mayo Clinic in Rochester, MN, from June 1996 through whole-genome association study of Parkinson disease May 2004. They all resided within Minnesota or one of (PD [MIM 168600]). Our findings contribute to the cre- the surrounding four states (Wisconsin, Iowa, South Da- ation of a genomic predisposition map for PD, and we kota, or North Dakota). All cases underwent a standard- illustrate a tiered genotyping approach that can be ap- ized clinical assessment performed by a neurologist sub- plied to the study of other complex diseases. specialized in movement disorders. Cases had at least two of four cardinal signs of parkinsonism (rest tremor, Material and Methods rigidity, bradykinesia, and/or postural instability) and no We performed a high-resolution, whole-genome asso- features atypical for PD (such as unexplained upper mo- ciation study of PD, using a two-tiered genotyping ap- tor neuron signs or cerebellar signs). When nonmotor manifestations such as dysautonomia or dementia were Received June 3, 2005; accepted for publication July 28, 2005; elec- present, they were mild and occurred late in the disease tronically published September 9, 2005. course. Subjects with secondary causes of parkinsonism Address for correspondence and reprints: Dr. Dennis Ballinger,Perle- (e.g., history of neuroleptic exposure, encephalitis, or gen Sciences, Inc., 2021 Stierlin Court, Mountain View, CA 22102. multiple strokes) were excluded. All patients treated with E-mail: [email protected] у ᭧ 2005 by The American Society of Human Genetics. All rights reserved. a daily dosage total of 1 g of levodopa (in combination 0002-9297/2005/7705-0002$15.00 with carbidopa) had a more than minimal improvement 685 686 Am. J. Hum. Genet. 77:685–693, 2005 in parkinsonism symptoms and signs. We obtained a Table 1 genealogical history from all cases, and, when permitted, Distribution of Gap Sizes between Adjacent we contacted available siblings for a telephone inter- Informative Tier 1 SNPs, within Chromosomal view, to exclude parkinsonism via a validated screening Contigs from NCBI Build 34 instrument (Rocca et al. 1998). For cases, we obtained The table is available in its entirety in the online blood after a clinical assessment performed either at the edition of The American Journal of Human Genetics. Mayo Clinic or in the subjects’ homes. For siblings who screened negative for PD (i.e., who had none of the fol- lowing: prior diagnosis of PD, prior treatment with levo- genotyping. The genotyping for tiers 2a and 2b was per- dopa, or three or more of nine symptoms), we obtained formed using customized oligonucleotide microarrays. blood via mail-in kits (we did no clinical assessment). For tier 2a, a subset of SNPs that were associated with All subjects provided written informed consent; their PD (P ! .01 in tier 1) were genotyped. An additional whole blood was obtained, via venipuncture, for DNA predefined set of 311 SNPs was genotyped for genomic extraction (via the Puregene method [Gentra Sciences]) control (Hinds et al. 2004). Conditional logistic regres- and storage. Cases were matched to a single participating sion analyses were performed, to test for and model as- sibling, without PD or parkinsonism, first by sex (when sociations between the SNPs and PD. The analyses were possible) and then by closest age. adjusted for age and sex, as appropriate. We calculated For each subject (matched discordant sibling pairs), ORs, 95% CIs, and P values (as for tier 1, using a log ∼1 mg of DNA was shipped to Perlegen Sciences for additive or “trend” model). We also checked for popu- laboratory study. Whole-genome amplification was per- lation structure, using the genomic-control method (Dev- formed as described elsewhere (Dean et al. 2002). For lin and Roeder 1999; Bacanu et al. 2000; Devlin et al. each subject, DNA was individually genotyped, for a set 2004). This method treats the subjects as unmatched and of 248,535 SNPs, with unique positions on National does not include adjustments for covariates; however, it Center for Biotechnology Information (NCBI) build 34. should still provide guidelines for assessing the degree These SNPs were selected to have relatively uniform of stratification in tier 2. For the SNPs associated with spacing across the genome and to preferentially in- PD (P ! .01 ) in both the tier 1 and 2a analyses, we clude haplotype-defining common SNPs from the Perle- pooled data for the case–unaffected sibling and case– gen haplotype map (Patil et al. 2001). Details regarding unrelated control pairs and again analyzed the data, us- the distribution of genomic gaps is provided in table 1. ing a liberalization of the sTDT (Schaid and Rowland The genotyping platform employed high-density oligo- 1998). This allowed us to maximize statistical power for nucleotide, photolithographic microarrays (DNA chips), the analyses to obtain a more precise ranking of repli- such that one hybridization yielded genotypes for 85,000 cated SNPs by ascending P values and a more precise SNPs in a single individual. estimate of ORs and 95% CIs. We performed a liberalization of the sibling transmis- For tier 2b, we also selected for genotyping additional sion/disequilibrium test (sTDT) (Schaid and Rowland SNPs that in tier 1 were only borderline significant but 1998) to identify SNPs that had significant allele-fre- that tested a priori biological or genetic hypotheses re- quency differences in cases versus unaffected siblings, garding genomic susceptibility to PD. These SNPs did adjusting the analyses for age and sex. For each SNP, not achieve a P value !.01 in the tier 1 sample overall. we calculated odds ratios (ORs), 95% CIs, and P values However, some of these SNPs (1) had P values !.001 (using a log-additive or “trend” model). in tier 1 strata defined by sex or by median age at study; (2) had P values !.05 and were positioned within 10 kb of the linkage-derived candidate genes a-synu- Tier 2 clein (SNCA [MIM 163890]), parkin (MIM 602544), ubiquitin carboxy-terminal hydrolase L1 (UCHL1 [MIM For tiers 2a and 2b, we individually genotyped case– 191342]), microtubule-associated protein t (MAPT unrelated control pairs. Cases were enrolled as for tier [MIM 157140]), oncogene DJ1 (DJ1 [MIM 602533]), 1 but had no siblings available. Unrelated controls were and PTEN-induced kinase 1 (PINK1 [MIM 608309]); identified via random digit dialing from the same five- (3) had P values !.05 and were positioned within ad- state region as the cases and were screened negative for ditional loci linked to PD (i.e., PARK3 [MIM 602404], parkinsonism via the same validated telephone instru- PARK8 [MIM 607060], PARK9 [MIM 606693], ment as for siblings in tier 1. DNA was collected at the PARK10 [MIM 606852], PARK11 [MIM 607688]); (4) time of clinical assessment for cases and via mail-in kits had P values !.05 and were positioned within exons or for controls.
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