Identification of a Novel Risk Locus for Progressive Supranuclear Palsy by a Pooled Genomewide Scan of 500,288 Single-Nucleotide Polymorphisms
2007; Elsevier BV; Volume: 80; Issue: 4 Linguagem: Inglês
10.1086/513320
ISSN1537-6605
AutoresStacey Melquist, David W. Craig, Matthew J. Huentelman, Richard Crook, John V. Pearson, Matt Baker, Victoria Zismann, Jennifer Gass, Jennifer Adamson, Szabolcs Szelinger, Jason J. Corneveaux, Ashley Cannon, Keith D. Coon, Sarah Lincoln, Charles H. Adler, Paul Tuite, Donald B. Calne, Eileen H. Bigio, Ryan J. Uitti, Zbigniew K. Wszołek, Lawrence I. Golbe, Richard J. Caselli, Neill R. Graff‐Radford, Irene Litvan, Matthew J. Farrer, Dennis W. Dickson, Mike Hutton, Dietrich A. Stephan,
Tópico(s)Genomics and Rare Diseases
ResumoTo date, only the H1 MAPT haplotype has been consistently associated with risk of developing the neurodegenerative disease progressive supranuclear palsy (PSP). We hypothesized that additional genetic loci may be involved in conferring risk of PSP that could be identified through a pooling-based genomewide association study of >500,000 SNPs. Candidate SNPs with large differences in allelic frequency were identified by ranking all SNPs by their probe-intensity difference between cohorts. The MAPT H1 haplotype was strongly detected by this methodology, as was a second major locus on chromosome 11p12-p11 that showed evidence of association at allelic (P<.001), genotypic (P<.001), and haplotypic (P<.001) levels and was narrowed to a single haplotype block containing the DNA damage-binding protein 2 (DDB2) and lysosomal acid phosphatase 2 (ACP2) genes. Since DNA damage and lysosomal dysfunction have been implicated in aging and neurodegenerative processes, both genes are viable candidates for conferring risk of disease. To date, only the H1 MAPT haplotype has been consistently associated with risk of developing the neurodegenerative disease progressive supranuclear palsy (PSP). We hypothesized that additional genetic loci may be involved in conferring risk of PSP that could be identified through a pooling-based genomewide association study of >500,000 SNPs. Candidate SNPs with large differences in allelic frequency were identified by ranking all SNPs by their probe-intensity difference between cohorts. The MAPT H1 haplotype was strongly detected by this methodology, as was a second major locus on chromosome 11p12-p11 that showed evidence of association at allelic (P<.001), genotypic (P<.001), and haplotypic (P<.001) levels and was narrowed to a single haplotype block containing the DNA damage-binding protein 2 (DDB2) and lysosomal acid phosphatase 2 (ACP2) genes. Since DNA damage and lysosomal dysfunction have been implicated in aging and neurodegenerative processes, both genes are viable candidates for conferring risk of disease. Progressive supranuclear palsy (PSP [MIM 601104]) is the second-most-common form of parkinsonism, with a population prevalence rate of 6–6.4 per 100,000.1Steele JC Richardson JC Olszewski J Progressive supranuclear palsy: a heterogeneous degeneration involving the brain stem, basal ganglia and cerebellum with vertical gaze and pseudobulbar palsy, nuchal dystonia and dementia.Arch Neurol. 1964; 10: 333-359Crossref PubMed Scopus (1332) Google Scholar, 2Litvan I Update on progressive supranuclear palsy.Curr Neurol Neurosci Rep. 2004; 4: 296-302Crossref PubMed Scopus (34) Google Scholar Clinical features include vertical-gaze palsy and postural instability.3Litvan I Agid Y Calne D Campbell G Dubois B Duvoisin RC Goetz CG Golbe LI Grafman J Growdon JH et al.Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome): report of the NINDS-SPSP International Workshop.Neurology. 1996; 47: 1-9Crossref PubMed Scopus (1943) Google Scholar, 4Litvan I Agid Y Jankovic J Goetz C Brandel JP Lai EC Wenning G D'Olhaberriague L Verny M Chaudhuri KR et al.Accuracy of clinical criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome).Neurology. 1996; 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55: 1122-1124Crossref PubMed Scopus (66) Google Scholar The MAPT locus exists as two major haplotype groups, termed "H1" and "H2"16Baker M Litvan I Houlden H Adamson J Dickson D Perez-Tur J Hardy J Lynch T Bigio E Hutton M Association of an extended haplotype in the tau gene with progressive supranuclear palsy.Hum Mol Genet. 1999; 8: 711-715Crossref PubMed Scopus (636) Google Scholar in European populations, with the H2 haplotype defined by >100 SNPs that are inherited in strong linkage disequilibrium (LD) with each other, reflecting the total absence of H1-H2 recombination.21Cruts M Rademakers R Gijselinck I van der Zee J Dermaut B de Pooter T de Rijk P Del-Favero J van Broeckhoven C Genomic architecture of human 17q21 linked to frontotemporal dementia uncovers a highly homologous family of low-copy repeats in the tau region.Hum Mol Genet. 2005; 14: 1753-1762Crossref PubMed Scopus (75) Google Scholar Inheritance of two copies of the H1 haplotype (H1/H1) is a major genetic risk factor for PSP.16Baker M Litvan I Houlden H Adamson J Dickson D Perez-Tur J Hardy J Lynch T Bigio E Hutton M Association of an extended haplotype in the tau gene with progressive supranuclear palsy.Hum Mol Genet. 1999; 8: 711-715Crossref PubMed Scopus (636) Google Scholar A large collection of pathologically confirmed PSP samples was used recently to fine map PSP risk on H1 chromosomes in PSP cases and controls. 22Rademakers R Melquist S Cruts M Theuns J Del-Favero J Poorkaj P Baker M Sleegers K Crook R De Pooter T et al.High-density SNP haplotyping suggests altered regulation of tau gene expression in progressive supranuclear palsy.Hum Mol Genet. 2005; 14: 3281-3292Crossref PubMed Scopus (134) Google Scholar, 23Pittman AM Myers AJ Abou-Sleiman P Fung HC Kaleem M Marlowe L Duckworth J Leung D Williams D Kilford L et al.Linkage disequilibrium fine mapping and haplotype association analysis of the tau gene in progressive supranuclear palsy and corticobasal degeneration.J Med Genet. 2005; 42: 837-846Crossref PubMed Scopus (195) Google Scholar PSP risk was associated with an extended subhaplotype, and narrowing the region for PSP risk to a 22-kb region in intron 0 of MAPT was accomplished by examining younger patients with, presumably, a larger genetic component to their disease.22Rademakers R Melquist S Cruts M Theuns J Del-Favero J Poorkaj P Baker M Sleegers K Crook R De Pooter T et al.High-density SNP haplotyping suggests altered regulation of tau gene expression in progressive supranuclear palsy.Hum Mol Genet. 2005; 14: 3281-3292Crossref PubMed Scopus (134) Google Scholar, 23Pittman AM Myers AJ Abou-Sleiman P Fung HC Kaleem M Marlowe L Duckworth J Leung D Williams D Kilford L et al.Linkage disequilibrium fine mapping and haplotype association analysis of the tau gene in progressive supranuclear palsy and corticobasal degeneration.J Med Genet. 2005; 42: 837-846Crossref PubMed Scopus (195) Google Scholar The most likely explanation of the association with the MAPT H1 haplotype and PSP is that variants in the H1 (and H2) haplotypes confer risk of (protect against) disease by altering expression at the locus, with the risky H1 haplotypes expressing higher levels of MAPT.22Rademakers R Melquist S Cruts M Theuns J Del-Favero J Poorkaj P Baker M Sleegers K Crook R De Pooter T et al.High-density SNP haplotyping suggests altered regulation of tau gene expression in progressive supranuclear palsy.Hum Mol Genet. 2005; 14: 3281-3292Crossref PubMed Scopus (134) Google Scholar, 23Pittman AM Myers AJ Abou-Sleiman P Fung HC Kaleem M Marlowe L Duckworth J Leung D Williams D Kilford L et al.Linkage disequilibrium fine mapping and haplotype association analysis of the tau gene in progressive supranuclear palsy and corticobasal degeneration.J Med Genet. 2005; 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We hypothesized that additional genetic loci involved in conferring risk of PSP could be identified through genomewide association (GWA) methods. The cost of performing an association study that involved individual genotyping of thousands of SNPs for a series this size was prohibitive, so, instead, we used a pooled-DNA approach to identify additional risk factors. Whereas a pooling-based genomewide scan of thousands of SNPs has been proposed in principle, in large part, these studies have not been used for the discovery of genes predisposing to complex diseases,27Bansal A van den Boom D Kammerer S Honisch C Adam G Cantor CR Kleyn P Braun A Association testing by DNA pooling: an effective initial screen.Proc Natl Acad Sci USA. 2002; 99: 16871-16874Crossref PubMed Scopus (135) Google Scholar, 28Meaburn E Butcher LM Schalkwyk LC Plomin R Genotyping pooled DNA using 100K SNP microarrays: a step towards genomewide association scans.Nucleic Acids Res. 2006; 34: e28Crossref Scopus (88) Google Scholar likely because of technical concerns or lack of technology and analysis tools. The patients used in the initial pooling study, the "original" series, were largely derived from pathologically confirmed subjects collected by the PSP Society and sent to D.W.D. for brain autopsy. As described elsewhere, the patient samples in this brain bank were donated from the United States and Canada.29Josephs KA Dickson DW Diagnostic accuracy of progressive supranuclear palsy in the Society for Progressive Supranuclear Palsy brain bank.Mov Disord. 2003; 18: 1018-1026Crossref PubMed Scopus (124) Google Scholar The patient series is similar to the one that we employed in previous studies to fine map the H1 genetic risk,22Rademakers R Melquist S Cruts M Theuns J Del-Favero J Poorkaj P Baker M Sleegers K Crook R De Pooter T et al.High-density SNP haplotyping suggests altered regulation of tau gene expression in progressive supranuclear palsy.Hum Mol Genet. 2005; 14: 3281-3292Crossref PubMed Scopus (134) Google Scholar with 288 subjects with a primary pathological diagnosis of PSP used to create the pool of PSP-affected patients. A total of 344 age- and sex-matched cognitively normal control individuals were obtained through the Normal and Pathological Aging protocol at the Mayo Clinic (Scottsdale),30Caselli RJ Osborne D Reiman EM Hentz JG Barbieri CJ Saunders AM Hardy J Graff-Radford NR Hall GR Alexander GE Preclinical cognitive decline in late middle-aged asymptomatic apolipoprotein E-e4/4 homozygotes: a replication study.J Neurol Sci. 2001; 189: 93-98Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar, 31Caselli RJ Hentz JG Osborne D Graff-Radford NR Barbieri CJ Alexander GE Hall GR Reiman EM Hardy J Saunders AM Apolipoprotein E and intellectual achievement.J Am Geriatr Soc. 2002; 50: 49-54Crossref PubMed Scopus (9) Google Scholar to create the pool of control individuals. All patient and control individuals were white from the United States and Canada, and institutional review board (IRB)–approved protocols were used in the collection of all samples. Replicate pools of patients with PSP and control individuals were created as described elsewhere.32Pearson JV Huentelman MJ Halperin RF Tembe WD Melquist S Homer N Brun M Szelinger S Coon KD Zismann VL et al.Identification of the genetic basis for complex disorders by use of pooling-based genomewide single-nucleotide-polymorphism association studies.Am J Hum Genet. 2007; 80: 126-139Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar Samples were genotyped on 20 replicate Affymetrix 500K arrays and 20 Affymetrix 100K, in accordance with the Affymetrix protocols, whereby each of the five replicate pools was genotyped on two replicate arrays. This design therefore yielded probe-intensity data for both platforms on 10 replicate arrays per cohort. Data were analyzed using GenePool software (TGen Bioinformatics Research Unit).32Pearson JV Huentelman MJ Halperin RF Tembe WD Melquist S Homer N Brun M Szelinger S Coon KD Zismann VL et al.Identification of the genetic basis for complex disorders by use of pooling-based genomewide single-nucleotide-polymorphism association studies.Am J Hum Genet. 2007; 80: 126-139Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar In brief, probe-intensity data were directly read from cell-intensity (CEL) files, and relative allele signal (RAS) values were calculated for each quartet. These values yield independent measures of different hybridization events and are consequently treated as individual data points. We used a silhouette statistic to rank all genotyped SNPs,33Lovmar L Ahlford A Jonsson M Syvanen AC Silhouette scores for assessment of SNP genotype clusters.BMC Genomics. 2005; 6: 35Crossref PubMed Scopus (57) Google Scholar because it avoids introducing unnecessary variance by averaging probe-intensity data from probes with different hybridization properties. Silhouette scores range from 1, where significant separation between data points has been achieved and cluster assignment can be made with confidence, to −1, where differences in allelic frequencies are less reliable. Poorly performing SNPs were identified by Affymetrix as unreliable in the transition to Mendel3 libraries or exhibited high variance between replicate arrays and were removed from the analysis; 428,867 SNPs remained. SNPs were ranked on the basis of silhouette score, whereby the SNP with the highest score was ranked 1 and the SNP with the lowest score was ranked 428,867, with use of Affymetrix's Mendel3 libraries for the Affymetrix 500K arrays and HindIII and XbaI libraries for the Affymetrix 100K arrays, then were sorted by chromosome and physical position. With this ranking, it is assumed that SNPs approaching a rank of 1 will have larger differences in allelic frequency. With each sample ranked by silhouette score, we calculated a sliding-window statistic of the mean rank for consecutively neighboring SNPs across a fixed window size. Window sizes from 2 to 31 were used. Since the MAPT H1 haplotype is associated with disease with a haplotypic odds ratio (OR) of ∼3–4,16Baker M Litvan I Houlden H Adamson J Dickson D Perez-Tur J Hardy J Lynch T Bigio E Hutton M Association of an extended haplotype in the tau gene with progressive supranuclear palsy.Hum Mol Genet. 1999; 8: 711-715Crossref PubMed Scopus (636) Google Scholar, 22Rademakers R Melquist S Cruts M Theuns J Del-Favero J Poorkaj P Baker M Sleegers K Crook R De Pooter T et al.High-density SNP haplotyping suggests altered regulation of tau gene expression in progressive supranuclear palsy.Hum Mol Genet. 2005; 14: 3281-3292Crossref PubMed Scopus (134) Google Scholar, 23Pittman AM Myers AJ Abou-Sleiman P Fung HC Kaleem M Marlowe L Duckworth J Leung D Williams D Kilford L et al.Linkage disequilibrium fine mapping and haplotype association analysis of the tau gene in progressive supranuclear palsy and corticobasal degeneration.J Med Genet. 2005; 42: 837-846Crossref PubMed Scopus (195) Google Scholar, 34Pittman AM Myers AJ Duckworth J Bryden L Hanson M Abou-Sleiman P Wood NW Hardy J Lees A de Silva R The structure of the tau haplotype in controls and in progressive supranuclear palsy.Hum Mol Genet. 2004; 13: 1267-1274Crossref PubMed Scopus (106) Google Scholar it served as an internal positive control for the study. For analysis, we used the 500K data to identify chromosomal regions of interest (i.e., those with small mean-rank scores). The 100K data were then used to confirm that a region identified in the 500K analysis contained SNPs with large allelic frequency differences. The SNP with the single best statistical rank on the 500K chip was rs901746 on chromosome 11p12, and the second-best SNP was rs17662235, near MAPT. The top 1,000 SNPs, based on individual statistical rank, are given in table 1. Multimarker statistics also identified both chromosome 11p12 and chromosome 17q21 (MAPT) regions with sliding windows of multiple sizes. Although we recognize that this type of statistic is biased because of genomewide LD, it allowed us to identify clusters of high-ranking SNPs that neighbor one another, which reduced the possibility of technical errors influencing the results. Shown in figure 1A, the MAPT locus, labeled as having the #2 SNP overall, showed the greatest evidence of differences between case and control pools with use of the sliding-window analysis, largely because of 38 SNPs within the top 1,000 SNPs overall and a total of 75 SNPs in the region with a rank score of <10,000 (fig. 1B and table 1). Examination of the individual SNPs with high rank scores over this locus showed SNPs that were derived from a region covering the full extent of the MAPT H1 haplotype, spanning nearly 1 Mb (fig. 1B).36Stefansson H Helgason A Thorleifsson G Steinthorsdottir V Masson G Barnard J Baker A Jonasdottir A Ingason A Gudnadottir VG et al.A common inversion under selection in Europeans.Nat Genet. 2005; 37: 129-137Crossref PubMed Scopus (577) Google Scholar All of the 75 SNPs with genotype-frequency data in the database resembled MAPT H2 variants (which differentiate between H1 and H2 MAPT haplotypes) rather than H1 variants (which differentiate between H1 subhaplotypes); this is because, in white populations, the SNP minor-allele frequency was ∼0.2, whereas the minor allele of the SNP was absent or rare in Asian populations and African populations.36Stefansson H Helgason A Thorleifsson G Steinthorsdottir V Masson G Barnard J Baker A Jonasdottir A Ingason A Gudnadottir VG et al.A common inversion under selection in Europeans.Nat Genet. 2005; 37: 129-137Crossref PubMed Scopus (577) Google Scholar, 37Evans W Fung HC Steele J Eerola J Tienari P Pittman A Silva R Myers A Vrieze FW Singleton A et al.The tau H2 haplotype is almost exclusively Caucasian in origin.Neurosci Lett. 2004; 369: 183-185Crossref PubMed Scopus (87) Google Scholar In addition, two of the SNPs with low rank scores (rs12150111 and rs807072) were identified definitively as MAPT H2 variants from prior MAPT genomic sequencing efforts.22Rademakers R Melquist S Cruts M Theuns J Del-Favero J Poorkaj P Baker M Sleegers K Crook R De Pooter T et al.High-density SNP haplotyping suggests altered regulation of tau gene expression in progressive supranuclear palsy.Hum Mol Genet. 2005; 14: 3281-3292Crossref PubMed Scopus (134) Google ScholarTable 1Predicted Allelic Frequencies for the Top 1,000 SNPsFrequencycFrequencies are expressed as percentages. Predicted allelic frequencies are the median frequency of all replicate arrays and refer to the A allele as defined by Affymetrix 500K. The median value is used, since an extreme outlier is occasionally observed. (SD) of Predicted AlleleSNP RankaThe rank order of the SNPs is based on a silhouette-test statistic calculated on probe intensity measures from replicate arrays, implemented in GenePool 0.81 (TGen Bioinformatics Research Unit). Only SNPs for which allelic frequencies could be calculated using the k-correction method35 from a training database of 1,000 individually genotyped samples are included.dbSNP NumberChromosomePositionbChromosomal positions for each SNP are based on National Center for Biotechnology Information build 35.1.CaseControl1rs901746114721689561.3 (.042)81.1 (.027)2rs1766223517415895532.7 (.019)15.3 (.028)3rs269980872617574760.5 (.039)45.2 (.043)4rs17662853174160462526.7 (.068)14.0 (.039)5rs11898241211584726775.6 (.057)61.0 (.042)6rs17563501174115747896.4 (.050)79.9 (.021)7rs2141299174159676394.7 (.035)77.7 (.023)8rs17574228174146035512.4 (.016)24.8 (.035)9rs273270617417074638.5 (.036)22.1 (.044)10rs7139545132467742974.2 (.022)85.7 (.039)11rs645053055909526530.6 (.047)51.3 (.041)12rs2668695174164790313.3 (.034)27.3 (.038)13rs3759297123202911963.6 (.033)80.0 (.030)14rs10798036118278461945.0 (.045)61.1 (.046)15rs1021350241162492393.7 (.023)79.4 (.039)16rs770050655603235565.5 (.029)85.5 (.031)17rs7198242166820599624.0 (.083)5.9 (.048)18rs2532286174159744196.6 (.045)89.6 (.048)19rs753427114740600155.7 (.035)68.6 (.051)20rs9649052713431109949.4 (.012)58.6 (.034)21rs17604700152992212951.6 (.053)34.6 (.078)22rs11623728149688240927.6 (.019)18.6 (.018)23rs15579967743054493.4 (.039)77.9 (.054)24rs22024455738117657.7 (.047)74.5 (.056)25rs152703623321518550.3 (.035)63.7 (.039)26rs2035515810782583792.1 (.025)82.4 (.019)27rs11745421516812364411.8 (.044)0.7 (.017)28rs42998834108106963.2 (.033)74.0 (.028)29rs10838681114723164067.6 (.030)80.8 (.041)30rs10517938416872914977.6 (.044)84.9 (.028)31rs12918956167078183642.0 (.070)57.0 (.059)32rs9567416134380674136.3 (.100)15.2 (.044)33rs210769974936780819.6 (.082)45.4 (.182)34rs4794984172933304866.1 (.037)78.8 (.037)35rs8088596187262094165.2 (.032)50.1 (.049)36rs2116457812987698353.9 (.039)67.3 (.029)37rs762038142030460871.0 (.028)83.3 (.035)38rs13364331011334806532.8 (.038)46.2 (.039)39rs762039435520636836.1 (.035)23.8 (.039)40rs65900391112344698972.7 (.029)57.0 (.040)41rs10824896105146309381.7 (.046)89.2 (.018)42rs35463619118451486.2 (.044)95.7 (.051)43rs1302082023389217948.8 (.042)59.9 (.039)44rs520605118152743668.8 (.021)84.7 (.058)45rs1192669138306477864.6 (.027)55.1 (.011)46rs1693644191820165570.9 (.068)88.7 (.045)47rs8036777154820871046.8 (.060)66.3 (.030)48rs1299704310868843232.0 (.022)42.7 (.047)49rs1550532223404684858.4 (.042)69.4 (.038)50rs939455063896093956.3 (.059)41.7 (.035)51rs12717171611280065253.2 (.027)62.0 (.032)52rs2548879167720030754.7 (.081)27.9 (.077)53rs10256927712516785971.8 (.021)79.4 (.022)54rs7407281185575660167.4 (.045)82.4 (.032)55rs1122452314491003877.7 (.039)63.4 (.029)56rs12962651185647604547.9 (.052)61.0 (.040)57rs207092914739562730.0 (.045)17.0 (.028)58rs2036535172877512647.9 (.046)38.8 (.022)59rs112116702134604242.7 (.041)29.4 (.024)60rs4372225121183083875.3 (.070)92.3 (.048)61rs17660065174151810297.2 (.045)82.1 (.081)62rs1725604710150757051.8 (.035)41.7 (.017)63rs2194711515499426817.8 (.043)7.2 (.044)64rs6753459219089025925.0 (.041)14.2 (.039)65rs1041834214184189240.9 (.034)31.7 (.012)66rs684734941371719227.6 (.040)45.2 (.061)67rs6101206205905003359.8 (.040)41.0 (.032)68rs273267517416359651.6 (.048)16.9 (.046)69rs7396713118802026639.0 (.073)27.5 (.030)70rs118353141210641203275.3 (.034)57.2 (.062)71rs1520961153552394785.5 (.056)71.8 (.067)72rs47409199784489238.0 (.042)20.2 (.039)73rs8088963185719829448.5 (.057)37.6 (.017)74rs695271223232728559.2 (.050)47.9 (.057)75rs937783165876120914.3 (.037)6.3 (.013)76rs995584918305258184.2 (.042)70.0 (.027)77rs10791979115591654677.2 (.068)55.7 (.079)78rs2805386911076155569.4 (.018)56.6 (.072)79rs4845237118711445282.1 (.062)61.3 (.061)80rs444011936193631440.0 (.092)60.2 (.080)81rs1289951111762506187.2 (.021)76.5 (.061)82rs466955021027343715.3 (.055)7.2 (.016)83rs671237026976674535.7 (.072)20.3 (.057)84rs6469264811059477920.0 (.089)6.4 (.041)85rs32337683085107115.5 (.071)39.5 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