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A Case-Control Association Study of the 12 Single-Nucleotide Polymorphisms Implicated in Parkinson Disease by a Recent Genome Scan

2006; Elsevier BV; Volume: 78; Issue: 6 Linguagem: Inglês

10.1086/504725

1537-6605

Yonghong Li, Charles M. Rowland, Steven J. Schrodi, W Laird, Kristina Tacey, David A. Ross, Diane U. Leong, Joseph J. Catanese, John J. Sninsky, Andrew Grupe,

Genomics and Chromatin Dynamics

To the Editor: To validate associations of SNPs that Maraganore et al.1Maraganore DM de Andrade M Lesnick TG Strain KJ Farrer MJ Rocca WA Pant PVK Frazer KA Cox DR Ballinger DG High-resolution whole-genome association study of Parkinson disease.Am J Hum Genet. 2005; 77: 685-693Abstract Full Text Full Text PDF PubMed Scopus (425) Google Scholar reported as associated with Parkinson disease (PD [MIM 168600]), we constructed a case-control series from PD cases and matched population/convenience controls that are available through the National Institute of Neurological Disorders and Stroke (NINDS) Human Genetics Resources at the Coriell Institute. Cases met United Kingdom Brain Bank criteria for idiopathic PD,2Hughes AJ Daniel SE Kilford L Lees AJ Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases.J Neurol Neurosurg Psychiatry. 1992; 55: 181-184Crossref PubMed Scopus (8455) Google Scholar and controls were neurologically normal. This series comprises 311 pairs of age- and sex-matched cases and controls. Cases had an age at disease onset ranging from 50 to 87 years (average [±SD] 63.8 ± 8.9 years) and were sampled at the age of 52–92 years (average [±SD] 70.1 ± 8.5 years). Controls were also sampled at the age of 52–92 years (average [±SD] 70.2 ± 8.5 years). All cases and controls are white, and each group includes 165 females (53.1%) and 146 males (46.9%), respectively. Cases in this series do not carry the Gly2019Ser mutation in LRRK2 [MIM 609007], which may occur in idiopathic PD,3Gilks WP Abou-Sleiman PM Gandhi S Jain S Singleton A Lees AJ Shaw K Bhatia KP Bonifati V Quinn NP Lynch J Healy DG Holton JL Revesz T Wood NW A common LRRK2 mutation in idiopathic Parkinson’s disease.Lancet. 2005; 365: 415-416Abstract Full Text Full Text PDF PubMed Scopus (628) Google Scholar and several tests did not reveal evidence of significant population stratification for 78 individually genotyped null markers (data not shown). We individually genotyped the 11 SNPs that were reported significant and one of the two SNPs that map to the PARK10 [MIM 606852] locus (the two reported-significant SNPs are highly correlated: r2=0.99), using allele-specific real-time PCR in our PD case-control sample set. Cases and controls were run on the same plate in a blinded fashion. Our genotyping method has an overall accuracy of >99%.4Li Y Nowotny P Holmans P Smemo S Kauwe JS Hinrichs AL Tacey K et al.Association of late-onset Alzheimer’s disease with genetic variation in multiple members of the GAPD gene family.Proc Natl Acad Sci USA. 2004; 101: 15688-15693Crossref PubMed Scopus (123) Google Scholar As an additional indication of genotyping quality, we calculated deviation from Hardy-Weinberg equilibrium (HWE) in cases and controls. One marker had an HWE exact P value of <.05 (.017 for rs2245218 in cases), but further examination of our genotype data did not reveal questionable calls. Therefore, these data were included in our analysis. All SNPs were tested for allelic association with PD with the use of χ2 statistics to calculate two-sided P values (table 1). Power calculations were done for a sample size of 311 pairs for each SNP, with the use of a one-sided allelic χ2-hypothesis test at a significance level of 0.05 and with the assumption that the control-allele frequencies of the unrelated controls and odds ratios (ORs) in table 4 in Maraganore et al.1Maraganore DM de Andrade M Lesnick TG Strain KJ Farrer MJ Rocca WA Pant PVK Frazer KA Cox DR Ballinger DG High-resolution whole-genome association study of Parkinson disease.Am J Hum Genet. 2005; 77: 685-693Abstract Full Text Full Text PDF PubMed Scopus (425) Google Scholar are true population parameters. Power calculation for rs7520966 was based on the tier 2 OR given in the text of Maraganore et al.,1Maraganore DM de Andrade M Lesnick TG Strain KJ Farrer MJ Rocca WA Pant PVK Frazer KA Cox DR Ballinger DG High-resolution whole-genome association study of Parkinson disease.Am J Hum Genet. 2005; 77: 685-693Abstract Full Text Full Text PDF PubMed Scopus (425) Google Scholar since it did not appear in their table 4.Table 1Allelic Tests of SNPs Associated with Late-Onset PDCasebCounts of genotype 11, 12, and 22.ControlbCounts of genotype 11, 12, and 22.Allelic TestdbSNP Accession NumberaThe top 11 markers are presented in the same order as in table 4 in Maraganore et al.1GeneChromosomePosition (Mbp)111222SumMAFcMinor-allele frequency.111222SumMAFOR (95% CI)PdTwo-sided P value for all strata and for female and male substrata in rs7878232.Power (%)rs7702187SEMA5A59.4986215310.168883217308.1611.05 (.78–1.42).7497rs102008942228.6148262311.080366238307.117.66 (.45–.96).0393rs23139824139.1247258307.083445256305.087.95 (.64–1.42).8196rs17329669736.61073224307.151360246309.1071.49 (1.07–2.09).0294rs772360555.4686218310.158570232307.1301.25 (.91–1.72).1795ss465488561059.0252256310.090461241306.113.78 (.54–1.13).1992rs168510092166.5653251310.105445259308.0861.24 (.85–1.82).2694rs2245218PRDM2113.91264234310.142683215304.156.89 (.65–1.22).4894rs7878232: Male and femaleX150.5………307.230………301.244.92 (.71–1.20).5566 Female……1347101161.22796189159.248.89 (.62–1.28).52… Male……………146.233………142.239.96 (.56–1.66).90…rs15092694139.1563243311.117765235307.129.90 (.64–1.26).5592rs117370744125.416116178310.23913102192307.2081.19 (.91–1.56).2090rs7520966LOC200008154.416117175308.24219129160308.271.86 (.66–1.11).2497a The top 11 markers are presented in the same order as in table 4 in Maraganore et al.1Maraganore DM de Andrade M Lesnick TG Strain KJ Farrer MJ Rocca WA Pant PVK Frazer KA Cox DR Ballinger DG High-resolution whole-genome association study of Parkinson disease.Am J Hum Genet. 2005; 77: 685-693Abstract Full Text Full Text PDF PubMed Scopus (425) Google Scholarb Counts of genotype 11, 12, and 22.c Minor-allele frequency.d Two-sided P value for all strata and for female and male substrata in rs7878232. Open table in a new tab Two markers, rs10200894 and rs17329669, were replicated in our sample set at P<.1 (P=.03 and P=.02, respectively) with the same risk alleles as in Maraganore et al.,1Maraganore DM de Andrade M Lesnick TG Strain KJ Farrer MJ Rocca WA Pant PVK Frazer KA Cox DR Ballinger DG High-resolution whole-genome association study of Parkinson disease.Am J Hum Genet. 2005; 77: 685-693Abstract Full Text Full Text PDF PubMed Scopus (425) Google Scholar although with slightly lower ORs. rs10200894 is an intergenic variant located on chromosome 2 near a linkage peak previously identified in late-onset PD,5Pankratz N Nichols WC Uniacke SK Halter C Rudolph A Shults C Conneally PM Foroud T Significant linkage of Parkinson disease to chromosome 2q36-37.Am J Hum Genet. 2003; 72: 1053-1057Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar and rs17329669 is in an intergenic region on chromosome 7. Further investigations in these regions, including further genetic mapping and the identification of potential causative variants, are thus warranted. Indeed, several SNPs in the vicinity of rs10200894 and rs17329669 reached significance in the Maraganore et al.1Maraganore DM de Andrade M Lesnick TG Strain KJ Farrer MJ Rocca WA Pant PVK Frazer KA Cox DR Ballinger DG High-resolution whole-genome association study of Parkinson disease.Am J Hum Genet. 2005; 77: 685-693Abstract Full Text Full Text PDF PubMed Scopus (425) Google Scholar discovery sample set (P<.05) but were not followed up because they did not reach their significance threshold of P<.01. ELMO1 [MIM 606420], a gene whose product is predicted to be involved in apoptosis and cell migration, resides in a region that, according to the HapMap, is in high linkage disequilibrium with rs17329669. The more abundant splice variant of ELMO1 appears to be exclusively expressed in brain6Gumienny TL Brugnera E Tosello-Trampont AC Kinchen JM Haney LB Nishiwaki K Walk SF Nemergut ME Macara IG Francis R Schedl T Qin Y Van Aelst L Hengartner MO Ravichandran KS CED-12/ELMO, a novel member of the CrkII/Dock180/Rac pathway, is required for phagocytosis and cell migration.Cell. 2001; 107: 27-41Abstract Full Text Full Text PDF PubMed Scopus (457) Google Scholar and, thus, constitutes an excellent biological candidate gene for PD. All other markers were not significant in our sample set at the 0.1 level, including the marker reported most significant in SEMA5A [MIM 609297] and the marker in LOC200008, which maps to the PARK10 locus that appears to affect both disease risk and age of onset.7Hicks AA Petursson H Jonsson T Stefansson H Johannsdottir HS Sainz J Frigge ML Kong A Gulcher JR Stefansson K Sveinbjornsdottir S A susceptibility gene for late-onset idiopathic Parkinson’s disease.Ann Neurol. 2002; 52: 549-555Crossref PubMed Scopus (263) Google Scholar, 8Li YJ Scott WK Hedges DJ Zhang F Gaskell PC Nance MA Watts RL et al.Age at onset in two common neurodegenerative diseases is genetically controlled.Am J Hum Genet. 2002; 70: 985-993Abstract Full Text Full Text PDF PubMed Scopus (267) Google Scholar, 9Oliveira SA Li YJ Noureddine MA Zuchner S Qin X Pericak-Vance MA Vance JM Identification of risk and age-at-onset genes on chromosome 1p in Parkinson disease.Am J Hum Genet. 2005; 77: 252-264Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar Our failure to replicate the majority of the associated markers may be due to false-positive results in the initial study or to locus heterogeneity. Although the power in our validation sample set is ⩾90% for 11 of the 12 tested SNPs, this may be an overestimation due to an OR inflation (“jackpot effect”) in the original study. In addition, our sample set included only late-onset cases, commonly defined by age at onset >50 years, whereas the study by Maraganore et al. included both early- and late-onset cases.1Maraganore DM de Andrade M Lesnick TG Strain KJ Farrer MJ Rocca WA Pant PVK Frazer KA Cox DR Ballinger DG High-resolution whole-genome association study of Parkinson disease.Am J Hum Genet. 2005; 77: 685-693Abstract Full Text Full Text PDF PubMed Scopus (425) Google Scholar Thus, it is possible that nonreplicated markers are associated with early-onset PD but make a lesser contribution to the more common, late-onset form of the disease. Additional studies are required to further assess the association of these markers with PD. We thank the contributors to and the organizers of NINDS Human Genetics Resources, particularly Dr. Katrina Gwinn Hardy and Jeanne Beck, for making the clinical samples available to the Parkinson disease research community, and we thank the families and individuals for their participation. We also thank our colleagues at Celera Diagnostics, particularly Alla Smolgovsky and David Wolfson, for providing expert technical support.