Mayo-Perlegen LEAPS (Linked Efforts to Accelerate Parkinson's Solutions) Collaboration

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=7.62E-6). 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=1.70E-5). 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 susceptibility to PD (n=941 SNPs). In analysis of the combined tier 1 and
tier 2b data, the two SNPs with the lowest P values (P=9.07E-6; P=2.96E-5) 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.
Note: The following instruments were used: 1)clinical assessments form and manual; 2) sibling screening form and manual; 3) unrelated
control screening and manual; and 4) risk factors questionnaire and manual. All cases underwent #1, as did sibling controls screening
positive (see below). Unrelated controls were not examined. All siblings underwent #2. All unrelated controls underwent #3. All subjects
(cases, sibling controls, and unrelated controls) underwent #4.

Any publications using the data are to cite the original American Journal of Human Genetics article (Maraganore et al., 2005).
Investigators using the data collection instruments are to acknowledge Drs. Maraganore and Rocca, and cite grants ES-10751 and NS-33978.]]>
Clinical Assessments (Data Collection Instrument)Clinical Assessments (Manual of Instruction)Screening of Siblings (Manual of Instruction)Screening of Siblings (Data Collection Instrument)Screening of Unrelated Controls (Manual of Instruction)Screening of Unrelated Controls (Data Collection Instrument)This genome-wide association scan (tier 1) between genotype and the Parkinson 's disease status was computed by the dbGaP group at NCBI. Samples were 443 sibling pairs that were discordant for Parkinson disease. They had been recruited from the clinical practice of the Department of Neurology of the Mayo Clinic in Rochester, MN, between June 1996 through May 2004. Genotype data were provided by Drs. Maraganore and Rocca using Perlegen DNA chip (85k SNP markers) and three chips per individual.This allelic association (tier 2a) between genotype and the Parkinson's disease status was computed by the dbGaP group at NCBI. Cases were 330 Parkinson disease patients, which had been recruited but not analyzed in tier1. Unrelated controls were from the same regions as the cases and screened negative for Parkinsonism using the same validated telephone instrument that had been used for siblings in tier 1. Case-unrelated-control pairs were formed by 1 to1 matching of sex and age (within 3 years). A subset of SNP markers which appeared to be associated with Parkinson's disease in the tier 1 analysis was examined subsequently using customized Perlegene oligonucleotide microarraysThis allelic association (tier 2b) between genotype and the Parkinson's disease status was computed by the dbGaP group at NCBI. Samples (1546) are combination of 443 case-control sib pairs (tier 1) and 330 case-unrelated control pairs (tier 2a). A subset of SNP markers which appeared to be associated with Parkinson's disease in the tier 1 analysis were examined subsequently using customized Perlegene oligonucleotide microarrays.
Criteria for Cases: Cases were enrolled prospectively from the clinical practice of the Department of Neurology of the Mayo Clinic in
Rochester, MN, from June 1996 through May 2004. They all resided within Minnesota or one of the surrounding four states (Wisconsin, Iowa,
South Dakota, or North Dakota). All cases underwent a standardized clinical assessment performed by a neurologist sub-specialized in
movement disorders. Cases had at least two of four cardinal signs of parkinsonism (rest tremor, rigidity, bradykinesia, and/or postural
instability) and no features atypical for PD (such as unexplained upper motor neuron signs or cerebellar signs). When non-motor
manifestations such as dysautonomia or dementia were present, they were mild and occurred late in the disease course. Subjects with
secondary causes of parkinsonism (e.g., history of neuroleptic exposure, encephalitis, or multiple strokes) were excluded. All patients
treated with a daily dosage total of 1 g of levodopa (in combination with carbidopa) had a more than minimal improvement in parkinsonism
symptoms and signs.

Criteria for Controls: Unaffected siblings of cases, matched on gender when able then on closest age at study (tier 1); or unrelated
population controls, matched on gender and age at study (tier 2). All controls screened negative for parkinsonism via telephone
interview, or were confirmed to not have parkinsonism via clinical assessment.
]]>