variants was most likely due to the location of MAPT in a genomically instable region. Twenty-eight SNPs were located in highly conserved regions distributed across the gene. Four conserved SNPs were located in the MAPT promoter and might affect expression, while one con- served SNP was located in intron 10 possibly affecting exon 10 splic- ing. Analysis of the haplotypic organization of the variants demon- strated little linkage disequilibrium across the complete gene and a recombination hotspot about 20 kb upstream of exon 1. We observed three common haplotypes, one of which represented the inverted hap- lotype H2A showing 424 sequence differences with the H1 haplotypes. The H1 haplotypes were defined by 152 sequence variants organized in two common haplotypes H1A and H1B and a large number of rare haplotypes. Conclusions: We identified many variants in the MAPT gene that, alone or in concert with each other, might result in haplotype- dependent expression, splicing and stability of MAPT. This variability might contribute to the susceptibility of MAPT in many neurodegen- erative brain diseases. However, the location of MAPT in a genomically instable region has resulted in a complex haplotypic organization, complicating genetic association studies. P3-163 IDENTIFICATION OF A NOVEL RISK GENE FOR PROGRESSIVE SUPRANUCLEAR PALSY BY A GENOME-WIDE SCAN OF 500,288 SNPS Stacey Melquist 1 , Matthew J. Huentelman 2 , David W. Craig 2 , Matt Baker 1 , Richard Crook 1 , John V. Pearson 2 , Victoria L. Zisman 2 , Jennifer Gass 1 , Jennifer Adamson 1 , Szabolcs Szelinger 2 , Jason J. Cournevaux 2 , Ashley Cannon 1 , Keith D. Coon 2 , Dennis W. Dickson 1 , Dietrich Stephan 2 , Michael Hutton 1 , 1 Mayo Clinic, Jacksonville, FL, USA; 2 The Translational Genomics Research Institute, Phoenix, AZ, USA. Contact e-mail: melquist.stacey@mayo.edu Background: Progressive Supranuclear Palsy (PSP) is the second most common form of parkinsonism. Clinical features include vertical gaze palsy and postural instability. PSP is characterized neuropathologically by neuronal and glial inclusions, in the basal ganglia and brain stem, com- posed of aggregated MAPT. Mutations in the MAPT have been identified in patients with a clinical presentation of PSP. A recent report also de- scribed linkage to chr1q31.1 in a family with autosomal-dominant PSP. However, only the H1 haplotype in MAPT has been consistently associated with increased risk for idiopathic PSP. Our prior analysis of young cases from a large, pathologically-confirmed PSP series refined the region har- boring risk to 22kb in intron 0 of MAPT. Objectives: We hypothesized that additional genetic loci may be involved in conferring risk for PSP. Methods: Affymetrix GeneChip Mapping 500K SNP arrays were used in a genome-wide association analysis to look for PSP risk loci in a large, pathologically-confirmed pooled PSP case and control set. This series was used previously to finemap the MAPT H1 haplotype. Interesting regions identified by a novel algorithm developed at Translational Genomics Re- search Institute were followed up by individually genotyping PSP case and control samples included in the pools, as well as a second independent replication series. Once the region was confirmed in the replication series, additional SNPs were chosen to further delineate the region harboring risk variant(s). Analysis was performed at both the single marker and haplo- typic levels using standard approaches. Results: The MAPT H1 haplotype was strongly detected by this methodology, providing proof of concept in the study design. In addition, a second major locus on chromosome 11p11.2 and a minor locus on chromosome 4 showed evidence for asso- ciation at a genotypic (p=0.0002, p=0.004, respectively) and haplotypic level. The chromosome 11p11.2 locus was narrowed to a region containing just a few candidate genes, with the DNA repair gene DDB2 showing the strongest evidence for association. Conclusions: The identification of DDB2 as a gene likely harboring risk for PSP suggests that alteration in DNA repair capacity could play a vital role in the neurodegenerative process in PSP and perhaps other related disorders. P3-164 ASSOCIATION OF THE S100 GENE WITH LOW COGNITIVE PERFORMANCE AND DEMENTIA IN THE ELDERLY: A THOROUGHLY GENOMIC AND TRANSCRIPTOMIC ANALYSIS Jean-Charles Lambert 1 , Ste ´phanie Ferreira 1 , Jacobjin Gusselkloo 2 , Lene Christiansen 3 , Guillaume Brysbaert 1 , Eline Slagboom 4 , Corinne Lendon 5 , Thierry Petit 6 , Florence Richard 1 , Claudine Berr 7 , David Mann 8 , Kaare Christensen 9 , Rudy Westendorp 2 , Philippe Amouyel 1 , 1 INSERM U744, Institut Pasteur de Lille, Lille, France; 2 University of Leiden, Leiden, The Netherlands; 3 University of South Denmark, Copenhagen, Denmark; 4 University of Leiden, Leiden, The Netherlands; 5 University of Birmingham, Birmingham, United Kingdom; 6 Zoo la palmyre, Royan, France; 7 INSERM E0331, Hopital La Colombie `re, Montepellier, France; 8 University of Manchester, Manchester, United Kingdom; 9 Univeristy of South Denmark, Copenhagen, Denmark. Contact e-mail: jean-charles.lambert@pasteur- lille.fr Several evidences suggest the S100 gene may be important in the con- tinuum from cognitive decline to dementia. We undertook a thorough analysis of this locus. We searched for single nucleotide polymorphisms (SNP) within the gene and characterized a new primate-specific exon within the intron 3. We called the new mRNA isoform containing this exon, S1002. We evaluated the impact of 25 S100 SNPs on cognitive function in a sample of subjects older than 65. We finally concentrated our analyses on a SNP located in intron 2. This SNP was associated with poorer cognitive performance in the elderly in three independent populations, and with an increased risk of dementia, more specifically Alzheimer’s disease (AD) in four independent populations. A 40% increase in S1002 expres- sion was observed in AD brains compared with controls. In AD brains, over-expression of the S1002 isoform was correlated with higher Tau loads. Finally, the intron 2 SNP SNP was associated with a 77% increase in S1002 mRNA level in AD brains. Our findings suggest that a genetic variant in S100 increases the risk of low cognitive performance, of dementia and of AD, possibly by favoring a splicing event leading to the S1002 isoform in the brain. P3-165 MRI TRAITS ARE HERITABLE AMONG ALZHEIMER DISEASE CASES AND THEIR SIBLINGS IN THE MIRAGE STUDY Kathryn L. Lunetta 1 , Porat M. Erlich 1 , Rodney C.P. Go 2 , Robert P. Friedland 3 , Ranjan Duara 4 , Alexander Kurz 5 , A. Dessa Sadovnick 6 , Abi Akomolafe 7 , Helena Chui 8 , Helen Petrovitch 9 , Magda Tsolaki 10 , Thomas O. Obisesan 11 , Marwan NN. Sabbagh 12 , Martin Farlow 13 , Norman R. Relkin 14 , Karen T. Cuenco 1 , L. Adrienne Cupples 1 , Robert C. Green 1 , Lindsay A. Farrer 1 , Charles DeCarli 15 , 1 Boston University, Boston, MA, USA; 2 University of Alabama, Birmingham, AL, USA; 3 Case Western Reserve University, Cleveland, OH, USA; 4 University of Miami School of Medicine, Miami Beach, FL, USA; 5 Technische Universitaet Muenchen, Munich, Germany; 6 University of British Columbia, Vancouver, BC, Canada; 7 Morehouse School of Medicine, Atlanta, GA, USA; 8 Rancho Los Amigos National Rehabilitation Center, Downey, CA, USA; 9 Pacific Health Research Institute, Honolulu, HI, USA; 10 G. Papanicolaou Hospital, Exholi Thessaloniki, Greece; 11 Howard University Hospital, Washington, DC, USA; 12 Sun Health Research Institute, Sun City, AZ, USA; 13 Indiana University School of Medicine, Indianapolis, IN, USA; 14 Cornell Medical University, New York, NY, USA; 15 University of California at Davis, Sacramento, CA, USA. Contact e-mail: klunetta@bu.edu Background: Magnetic resonance imaging (MRI) traits can serve as more precise measures of degenerative or cerebrovascular brain injury than can be ascertained through history, risk factors, clinical signs or symptoms. Moreover, they are potentially useful intermediate phenotypes for genetic S422 Poster P3: Tuesday Posters