large-scale linkage disequilibrium mapping to identify rheumatoid arthritis-associated genes

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Large-scale Linkage Disequilibrium Mapping to Identify Rheumatoid Arthritis-associated Genes. Ryo Yamada IMS U of Tokyo Tokyo Japan 1 st International Symposium on Key Issues on Infectious Diseases June 5 2007 Grand Hilton Hotel Seoul Korea. Rheumatoid Arthritis. - PowerPoint PPT Presentation

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  • Large-scale Linkage Disequilibrium Mapping to Identify Rheumatoid Arthritis-associated GenesRyo YamadaIMS U of TokyoTokyo Japan1st International Symposium on Key Issues on Infectious DiseasesJune 5 2007 Grand Hilton Hotel Seoul Korea

  • Rheumatoid ArthritisWorld-wide distribution with prevalence from 0.6% to 1.0%Woman-dominantComplex etiologyGenetic componentsEnvironmental components Destructive polyarthritisExtra-articular involvementAutoimmunity

  • Genetics and Genetic Analysis of Rheumatoid ArthritisTwin and family studiesRelative risk to monozygotic twin ( MZ )12~62Relative risk to siblings (sib)2~17HLA locus explains 1/3-1/2 of total genetic components.There are multiple non-HLA genes.Multiple linkage studiesMany candidate-approach studies

  • SNP-based large scale LD-mappingThe first stageFrom the end of 20th century to 2003Human genome sequence was being completedSNPs and LD were being characterizedHigh-throughput SNP genotyping platforms were being developedThe second stageFrom 2003 HapMap project offered variation map for whole-genome studyMultiple commercial genotyping packages are availableSignificant reduction in the typing cost

  • Two Ways of Whole Genome LD MappingFirst stage

  • SNP distribution of RIKEN study

  • 836 vs. 658 two-stage joint screeningSNPsSamplesReplication-based analysisSNPsSamplesStage 1Stage 2One-Stage DesignJoint analysisSNPsSamplesStage 1Stage 2Two-Stage DesignMichael Boehnke : Design Considerations in Large Scale Genetic Association StudiesHapMap Tutorials

  • 12,890 / 21,153 genes12,890 60.9% genes were evaluated with block/SNPsNo. SNPs per gene and density of SNPs5.06.4 /gene0.20.3 /kb

    No. coding genes in autosomal chromosomes 21,153Covered with SNPs not in blockCovered with blockNot covered4,5098,3818,26312,890Gene20052000200120022003200410k20k40k30k50kRIEN project started27,283Genes

    Graph5

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  • Japanese, Korean :RA-specificCaucasians : SLE RA and other autoimmunitiesJapanese : RACaucasian : IBDJapanese : RA and other autoimmunitiesMajor findings from SNP-based studies

  • Major findings from SNP-based studiesJapanese study (RIKEN)PADI4 : RAPost-translational enzyme to produce targets of the most RA-specific autoantibodies.SLC22A4 /A5 : RA & CrohnErgothioneine or carnitine transporter expressed in hematologic lineages.FCRL3 : RA, SLR & AITDFc receptor homolog on B-cell membraneUS study (A.Begovich et al.)PTPN22 : T1DM, SLE, RA & AITDLymphoid-specific intracellular phophatase

  • Validation with meta-analysis

  • MAnti-oxydant transporter

  • Multiple Genes and Multiple Diseases

  • SummaryCoding gene-based SNP-LD mapping identified multiple RA-susceptible genes with functional variants.Some genes are associated with multiple autoimmume diseases.

  • What will change in the next stage of LD-mapping?SNP markersGenesGenotyping technologies and further developments SNPs and other polymorphismsLarger study scale and the associated problems in analysisWhat are the genetic association studies?

  • International HapMap Consortium Expands Mapping EffortMap of Human Genetic Variation Will Speed Search for Disease Genes

    BETHESDA, Md., Mon., Feb. 7, 2005No. markers is increasing and a chart for LD-mapping is now available.Genome-scan kits are available.SNPs

  • Central Dogma and DNA Variations and their functionalitymRNAPeptideTranscriptionTranslationTranscription initiation pointTranscription termination pointSplicing and mRNA maturationTranslation initiation pointCodon tripletsTranslation termination pointPost-translational peptide modificationsMoleculesGenes

  • SusceptibleNon-susceptibleDNA-mRNA-Protein relation is not straight, but comparison between DNA variations and phenotype variations bypassing mRNA/proteins simplifies the analysis structure.GenomeTranscriptomeProteomeMetabolomePhenomeAll-or-non simplest caseGenes

  • Another big world of heritable items (genes)

    Non-coding RNA x 23,000 in mammals

    Functional RNA-genes Non-coding genesGenes

  • Coding geneNon-coding-geneDNAFunctional RNAEffects on transcriptionEffects on translationEffects on phenotypesGenes

  • Genotyping technologies and further developments100K marker-panel250K marker-panel500K marker-panel1M marker-panel Whole genome typing of all samples

    Typing

  • Jennifer L. Freeman et al. Genome Res. 2006; 16: 949-961Other polymorphismsSNPsCNVs

  • Sampling from a structured populationBiased samplingEven samplingLarge study-associated problems

  • PPP-valueMarkersLarge study-associated problemsMany significant results when samples are biased with population structure.

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