large-scale linkage disequilibrium mapping of rheumatoid arthritis-associated genes in japan ～...

Large-scale Linkage Disequilibrium MappingofRheumatoid Arthritis-associated Genes in JapanResults and PerspectivesDecember 9, 2005Human Genome Variation and Their Association to Complex DiseasesSeoul, Korea

Ryo YamadaUnit of Human Disease Genomics, CGM, Kyoto University, Kyoto JapanLab. For Rheumatic Diseases, SRC, RIKEN, Yokohama, Japan

DNA-variations and their Effects on Transcripts, Peptides, Molecules Phenotypeshttp://www.microbe.org/espanol/news/human_genome.asp

Missense SNPs in PADI4 geneRA-susceptible haplotype and non-susceptible haplotype with three missense SNPs and one silent SNP in coding regionAllele specific mRNA stability and enzymatic activity and risk to RAAllele-specific molecular differenceNo allele-specific difference in molecular structure

Central Dogma & DNA VariationsmRNAPeptideTranscriptionTranslationTranscription initiation pointTranscription termination pointSplicing and mRNA maturationTranslation initiation pointCodon tripletsTranslation termination pointPost-translational peptide modificationsMolecules

Not one way, but Multiple Bifurcations & Quantitative VariationsTranscript variationsPeptide variationsMolecular variations

Phenotype1Phenotype2Phenotype3Phenotype4

Monogenic determinationRecessive traitDisease mutation and mal-functional moleculeDisease phenotypeNon-disease phenotype

Monogenic TraitComplex TraitMissenseSilentNon-codingDepth of transmission of allele-specific molecular difference depends on type of polymorphismMissense mutation and significant change of molecular function

SusceptibleNon-susceptibleAssociation study of Complex Traits with DNA-markersDNARNAPeptides

SusceptibleNon-susceptibleAssociation study with DNA-markersSimplified Architecture Bypasses Elements between DNA and Phenotypes Pros and Cons

Time courseTriggering EventDisease ManifestationsDiagnosisClinical F/UBirthNo observation In pre-clinical phaseRNA, proteins and othersDNAMore dynamic and more direct information from Non-DNA analyses; Amount of Information is more but might be difficult to define their representatives among them.DNA-analyses Data is Simple and Fixed throughout the Life.Time courseBirt

Another big world of RNA genes

Non-coding RNA x 23,000 in mammals

Coding-gene World and VariationsCoding DNACoding mRNA

Large-scale LD mapping and Identification of RA-Susceptible PADI4 Polymorphisms and Follow-up Replication Studies

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

Two Ways of Whole Genome LD Mapping

SNP distribution of RIKEN study

SNPsSamplesReplication-based analysisSNPsSamplesStage 1Stage 2One-Stage DesignJoint analysisSNPsSamplesStage 1Stage 2Two-Stage DesignMichael Boehnke : Design Considerations in Large Scale Genetic Association StudiesHapMap Tutorials836 vs. 658 two-stage joint screening

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

0.3962085756

0.2131612537

0.3906301707

Sheet1

83810.39620857560.6093698293

45090.21316125370.3906301707

82630.3906301707

21153

Sheet1

Sheet2

Sheet3

Graph6

0.6093698293

0.3906301707

Sheet1

83810.39620857560.6093698293

45090.21316125370.3906301707

82630.3906301707

21153

Sheet1

Sheet2

Sheet3

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

MAnti-oxydant transporter

SLC22A4Intronic SNPsTranscriptional regulationFCRL3Transcriptional regulationPTPN22Missense SNPMolecular function?RRRRRR

Multiple Genes and Multiple Diseases

Rheumatoid Arthritis and PADI4Citrulline and a-CCP AntibodyAntiperinuclearAnti-keratinAnti-SaVery many and heterogeneous autoantibodies are detectable in RA sera.Sensitivity and specificity vary.Some of RA-autoantibodies are extremely specific but their relatively low sensitivity limited their clinical utility.Their epitope target turned out to be common and citrulline residue in the molecules.Anti-CCP antibody has established as a reliable clinical marker of RA and they could predict development of RA several years before clinical onset.Citrulline is a non-coding native amino-acid and they are in proteins only after enzymatic conversion from arginine by PADI.

Anti-citrullinated peptide anyibody~Most reliable autoantibody for RA

Sheet1

Table 1 Sensitivity and specificity of anti-citrullinated peptide antibody assays for rheumatoid arthritis

AuthorsYear of publicationSubjectsAntigen and assay methodSensitivitySpecificity

Simon et al.199348 cases and 56 controlshuman dermal filaggrin (IB)75%89%

Shellekens et al.1998134 cases vs. 154 controlsCCP* (ELISA)76%96%

Shellekens et al.2000134 cases vs. 154 controlsCCP (ELISA)68%98%

Goldbach-Mansky et al.2000106 early cases vs. early non-RA arthiritideshuman dermal filaggrin (ELISA)33%93%

Bizzaro et al.200198 cases vs. 232 controlsCCP (ELISA)41%98%

Suzuki et al.2003549 cases vs. 208 controlsCCP (ELISA)88%89%

human recombinant-citrullinated-filaggrin69%95%

CCP*: cyclic ctrullinated peptide

Sheet2

Sheet3

Ca2+-dependent post-translational modificationLoss of ionic NH2+ of Arg residueEffects on intra- and inter- molecular interactions

PADI4 Citrullination Antigenicity

Association Plots in the PADI Cluster-log10(P)PADI4

Enzyme substrateMissenes SNPs, but no allelic difference in enzyme activity.

RA-susceptible variant transcript is more stable.

Hypothetical mechanism of RA-susceptible variant

Multiplestudies on PADI4padi_92 or padi_94AsianCaucasian3 Positive reports&3 Negative reports

PerspectivesGenetic determinants of prognosis and clinical responsivenessCoding genes and non-coding genesEthnic diversity and genetic factorsCombination of multiple genetic factors with or without environment factors

Network of genes with susceptible polymorphisms and genes without susceptible variations but functionally important A network of proteinprotein interactions in yeast by Benno Schwikowski, Peter Uetz3 & StanleyNature Biotechnology 18 :1257-1261 (2000)

CaucasiansJapanesePDCD1MIF1CTLA4SLC22A4/A5PTPN22TNFRSF1PADI4Susceptible allelePreliminary calculation with random-effect model

Graph7

0.073

0.927

Sheet1

Allele frequencyEnglishJapanese

casecontrolcasecontrol

SNP No.Allele(n=772)(n=465)(n=823)(n=655)

A0.0850.0730.930.053001.00

T0.140.090.910.0007001.00

C0.350.220.780.00020.230.200.800.013

T0.340.260.740.00590.870.870.130.7914

G0.430.360.640.0280.650.620.380.215

T0.450.420.580.310.460.370.630.00046

SLC22A4/A5haplotype0.420.580.001.00

1-Pcont1-Pcont

Sheet1

PDCD1 C

Sheet2

PDCD1 J

Sheet3

PTPN22 C

PTPN22 J

MIF11 C

MIF11 C

tnfrsf1b_1

TNFRSF1b_1

CTLA4 C

CTLA4 J

PADI4 C

PADI4 J

SLC22A4/A5

SLC22A4/A5 J




A0.0850.0730.930.053001.00

T0.140.090.910.0007001.00

C0.350.220.780.00020.230.200.800.013

T0.340.260.740.00590.870.870.130.7914

G0.430.360.640.0280.650.620.380.215

T0.450.420.580.310.460.370.630.00046


1-Pcont1-Pcont

0.073

0.927

0

1

0.090.090.090.090.090.090.090.09

0.910.910.910.910.910.910.910.91

0

1

0.2160.216

0.7840.784

0.2160.216

0.7840.784

0.26

0.74

0.87

0.13

0.36

0.64

0.62

0.38

0.42

0.58

0.37

0.63

0.42

0.58

0

1

Graph8

0

1

Sheet1




A0.0850.0730.930.053001.00

T0.140.090.910.0007001.00

C0.350.220.780.00020.230.200.800.013

T0.340.260.740.00590.870.870.130.7914

G0.430.360.640.0280.650.620.380.215

T0.450.420.580.310.460.370.630.00046


1-Pcont1-Pcont

Sheet1

PDCD1 C

Sheet2

PDCD1 J

Sheet3

PTPN22 C

PTPN22 J

MIF11 C

MIF11 C

tnfrsf1b_1

TNFRSF1b_1

CTLA4 C

CTLA4 J

PADI4 C

PADI4 J

SLC22A4/A5

SLC22A4/A5 J




A0.0850.0730.930.053001.00

T0.140.090.910.0007001.00

C0.350.220.780.00020.230.200.800.013

T0.340.260.740.00590.870.870.130.7914

G0.430.360.640.0280.650.620.380.215

T0.450.420.580.310.460.370.630.00046


1-Pcont1-Pcont

0.073

0.927

0

1

0.090.090.090.090.090.090.090.09

0.910.910.910.910.910.910.910.91

0

1

0.2160.216

0.7840.784

0.2160.216

0.7840.784

0.26

0.74

0.87

0.13

0.36

0.64

0.62

0.38

0.42

0.58

0.37

0.63

0.42

0.58

0

1

Graph9

0.090.090.090.090.090.090.090.09

0.910.910.910.910.910.910.910.91

Sheet1




A0.0850.0730.930.053001.00

T0.140.090.910.0007001.00

C0.350.220.780.00020.230.200.800.013

T0.340.260.740.00590.870.870.130.7914

G0.430.360.640.0280.650.620.380.215

T0.450.420.580.310.460.370.630.00046


1-Pcont1-Pcont

Sheet1

PDCD1 C

Sheet2

PDCD1 J

Sheet3

PTPN22 C

PTPN22 J

MIF11 C

MIF11 C

tnfrsf1b_1

TNFRSF1b_1

CTLA4 C

CTLA4 J

PADI4 C

PADI4 J

SLC22A4/A5

SLC22A4/A5 J




A0.0850.0730.930.053001.00

T0.140.090.910.0007001.00

C0.350.220.780.00020.230.200.800.013

T0.340.260.740.00590.870.870.130.7914

G0.430.360.640.0280.650.620.380.215

T0.450.420.580.310.460.370.630.00046


1-Pcont1-Pcont

0.073

0.927

0

1

0.090.090.090.090.090.090.090.09

0.910.910.910.910.910.910.910.91

0

1

0.2160.216

0.7840.784

0.2160.216

0.7840.784

0.26

0.74

0.87

0.13

0.36

0.64

0.62

0.38

0.42

0.58

0.37

0.63

0.42

0.58

0

1

Graph10

0

1

Sheet1




A0.0850.0730.930.053001.00

T0.140.090.910.0007001.00

C0.350.220.780.00020.230.200.800.013

T0.340.260.740.00590.870.870.130.7914

G0.430.360.640.0280.650.620.380.215

T0.450.420.580.310.460.370.630.00046


1-Pcont1-Pcont

Sheet1

PDCD1 C

Sheet2

PDCD1 J

Sheet3

PTPN22 C

PTPN22 J

MIF11 C

MIF11 C

tnfrsf1b_1

TNFRSF1b_1

CTLA4 C

CTLA4 J

PADI4 C

PADI4 J

SLC22A4/A5

SLC22A4/A5 J




A0.0850.0730.930.053001.00

T0.140.090.910.0007001.00

C0.350.220.780.00020.230.200.800.013

T0.340.260.740.00590.870.870.130.7914

G0.430.360.640.0280.650.620.380.215

T0.450.420.580.310.460.370.630.00046


1-Pcont1-Pcont

0.073

0.927

0

1

0.090.090.090.090.090.090.090.09

0.910.910.910.910.910.910.910.91

0

1

0.2160.216

0.7840.784

0.2160.216

0.7840.784

0.26

0.74

0.87

0.13

0.36

0.64

0.62

0.38

0.42

0.58

0.37

0.63

0.42

0.58

0

1

Graph11

0.2160.216

0.7840.784

Sheet1




A0.0850.0730.930.053001.00

T0.140.090.910.0007001.00

C0.350.220.780.00020.230.200.800.013

T0.340.260.740.00590.870.870.130.7914

G0.430.360.640.0280.650.620.380.215

T0.450.420.580.310.460.370.630.00046


1-Pcont1-Pcont

Sheet1

PDCD1 C

Sheet2

PDCD1 J

Sheet3

PTPN22 C

PTPN22 J

MIF11 C

MIF11 C

tnfrsf1b_1

TNFRSF1b_1

CTLA4 C

CTLA4 J

PADI4 C

PADI4 J

SLC22A4/A5

SLC22A4/A5 J




A0.0850.0730.930.053001.00

T0.140.090.910.0007001.00

C0.350.220.780.00020.230.200.800.013

T0.340.260.740.00590.870.870.130.7914

G0.430.360.640.0280.650.620.380.215

T0.450.420.580.310.460.370.630.00046


1-Pcont1-Pcont

0.073

0.927

0

1

0.090.090.090.090.090.090.090.09

0.910.910.910.910.910.910.910.91

0

1

0.2160.216

0.7840.784

0.2160.216

0.7840.784

0.26

0.74

0.87

0.13

0.36

0.64

0.62

0.38

0.42

0.58

0.37

0.63

0.42

0.58

0

1

Graph12

0.2160.216

0.7840.784

Sheet1




A0.0850.0730.930.053001.00

T0.140.090.910.0007001.00

C0.350.220.780.00020.230.200.800.013

T0.340.260.740.00590.870.870.130.7914

G0.430.360.640.0280.650.620.380.215

T0.450.420.580.310.460.370.630.00046


1-Pcont1-Pcont

Sheet1

PDCD1 C

Sheet2

PDCD1 J

Sheet3

PTPN22 C

PTPN22 J

MIF11 C

MIF11 C

tnfrsf1b_1

TNFRSF1b_1

CTLA4 C

CTLA4 J

PADI4 C

PADI4 J

SLC22A4/A5

SLC22A4/A5 J




A0.0850.0730.930.053001.00

T0.140.090.910.0007001.00

C0.350.220.780.00020.230.200.800.013

T0.340.260.740.00590.870.870.130.7914

G0.430.360.640.0280.650.620.380.215

T0.450.420.580.310.460.370.630.00046


1-Pcont1-Pcont

0.073

0.927

0

1

0.090.090.090.090.090.090.090.09

0.910.910.910.910.910.910.910.91

0

1

0.2160.216

0.7840.784

0.2160.216

0.7840.784

0.26

0.74

0.87

0.13

0.36

0.64

0.62

0.38

0.42

0.58

0.37

0.63

0.42

0.58

0

1

Graph16

0.62

0.38

Sheet1




A0.0850.0730.930.053001.00

T0.140.090.910.0007001.00

C0.350.220.780.00020.230.200.800.013

T0.340.260.740.00590.870.870.130.7914

G0.430.360.640.0280.650.620.380.215

T0.450.420.580.310.460.370.630.00046


1-Pcont1-Pcont

Sheet1

PDCD1 C

Sheet2

PDCD1 J

Sheet3

PTPN22 C

PTPN22 J

MIF11 C

MIF11 C

tnfrsf1b_1

TNFRSF1b_1

CTLA4 C

CTLA4 J

PADI4 C

PADI4 J

SLC22A4/A5

SLC22A4/A5 J




A0.0850.0730.930.053001.00

T0.140.090.910.0007001.00

C0.350.220.780.00020.230.200.800.013

T0.340.260.740.00590.870.870.130.7914

G0.430.360.640.0280.650.620.380.215

T0.450.420.580.310.460.370.630.00046


1-Pcont1-Pcont

0.073

0.927

0

1

0.090.090.090.090.090.090.090.09

0.910.910.910.910.910.910.910.91

0

1

0.2160.216

0.7840.784

0.2160.216

0.7840.784

0.26

0.74

0.87

0.13

0.36

0.64

0.62

0.38

0.42

0.58

0.37

0.63

0.42

0.58

0

1

Graph17

0.42

0.58

Sheet1




A0.0850.0730.930.053001.00

T0.140.090.910.0007001.00

C0.350.220.780.00020.230.200.800.013

T0.340.260.740.00590.870.870.130.7914

G0.430.360.640.0280.650.620.380.215

T0.450.420.580.310.460.370.630.00046


1-Pcont1-Pcont

Sheet1

PDCD1 C

Sheet2

PDCD1 J

Sheet3

PTPN22 C

PTPN22 J

MIF11 C

MIF11 C

tnfrsf1b_1

TNFRSF1b_1

CTLA4 C

CTLA4 J

PADI4 C

PADI4 J

SLC22A4/A5

SLC22A4/A5 J




A0.0850.0730.930.053001.00

T0.140.090.910.0007001.00

C0.350.220.780.00020.230.200.800.013

T0.340.260.740.00590.870.870.130.7914

G0.430.360.640.0280.650.620.380.215

T0.450.420.580.310.460.370.630.00046


1-Pcont1-Pcont

0.073

0.927

0

1

0.090.090.090.090.090.090.090.09

0.910.910.910.910.910.910.910.91

0

1

0.2160.216

0.7840.784

0.2160.216

0.7840.784

0.26

0.74

0.87

0.13

0.36

0.64

0.62

0.38

0.42

0.58

0.37

0.63

0.42

0.58

0

1

Graph18

0.37

0.63

Sheet1




A0.0850.0730.930.053001.00

T0.140.090.910.0007001.00

C0.350.220.780.00020.230.200.800.013

T0.340.260.740.00590.870.870.130.7914

G0.430.360.640.0280.650.620.380.215

T0.450.420.580.310.460.370.630.00046


1-Pcont1-Pcont

Sheet1

PDCD1 C

Sheet2

PDCD1 J

Sheet3

PTPN22 C

PTPN22 J

MIF11 C

MIF11 C

tnfrsf1b_1

TNFRSF1b_1

CTLA4 C

CTLA4 J

PADI4 C

PADI4 J

SLC22A4/A5

SLC22A4/A5 J




A0.0850.0730.930.053001.00

T0.140.090.910.0007001.00

C0.350.220.780.00020.230.200.800.013

T0.340.260.740.00590.870.870.130.7914

G0.430.360.640.0280.650.620.380.215

T0.450.420.580.310.460.370.630.00046


1-Pcont1-Pcont

0.073

0.927

0

1

0.090.090.090.090.090.090.090.09

0.910.910.910.910.910.910.910.91

0

1

0.2160.216

0.7840.784

0.2160.216

0.7840.784

0.26

0.74

0.87

0.13

0.36

0.64

0.62

0.38

0.42

0.58

0.37

0.63

0.42

0.58

0

1

Graph19

0.42

0.58

Sheet1




A0.0850.0730.930.053001.00

T0.140.090.910.0007001.00

C0.350.220.780.00020.230.200.800.013

T0.340.260.740.00590.870.870.130.7914

G0.430.360.640.0280.650.620.380.215

T0.450.420.580.310.460.370.630.00046


1-Pcont1-Pcont

Sheet1

PDCD1 C

Sheet2

PDCD1 J

Sheet3

PTPN22 C

PTPN22 J

MIF11 C

MIF11 C

tnfrsf1b_1

TNFRSF1b_1

CTLA4 C

CTLA4 J

PADI4 C

PADI4 J

SLC22A4/A5

SLC22A4/A5 J




A0.0850.0730.930.053001.00

T0.140.090.910.0007001.00

C0.350.220.780.00020.230.200.800.013

T0.340.260.740.00590.870.870.130.7914

G0.430.360.640.0280.650.620.380.215

T0.450.420.580.310.460.370.630.00046


1-Pcont1-Pcont

0.073

0.927

0

1

0.090.090.090.090.090.090.090.09

0.910.910.910.910.910.910.910.91

0

1

0.2160.216

0.7840.784

0.2160.216

0.7840.784

0.26

0.74

0.87

0.13

0.36

0.64

0.62

0.38

0.42

0.58

0.37

0.63

0.42

0.58

0

1

Graph20

0

1

Sheet1




A0.0850.0730.930.053001.00

T0.140.090.910.0007001.00

C0.350.220.780.00020.230.200.800.013

T0.340.260.740.00590.870.870.130.7914

G0.430.360.640.0280.650.620.380.215

T0.450.420.580.310.460.370.630.00046


1-Pcont1-Pcont

Sheet1

PDCD1 C

Sheet2

PDCD1 J

Sheet3

PTPN22 C

PTPN22 J

MIF11 C

MIF11 C

tnfrsf1b_1

TNFRSF1b_1

CTLA4 C

CTLA4 J

PADI4 C

PADI4 J

SLC22A4/A5

SLC22A4/A5 J




A0.0850.0730.930.053001.00

T0.140.090.910.0007001.00

C0.350.220.780.00020.230.200.800.013

T0.340.260.740.00590.870.870.130.7914

G0.430.360.640.0280.650.620.380.215

T0.450.420.580.310.460.370.630.00046


1-Pcont1-Pcont

0.073

0.927

0

1

0.090.090.090.090.090.090.090.09

0.910.910.910.910.910.910.910.91

0

1

0.2160.216

0.7840.784

0.2160.216

0.7840.784

0.26

0.74

0.87

0.13

0.36

0.64

0.62

0.38

0.42

0.58

0.37

0.63

0.42

0.58

0

1

Graph2

0.26

0.74

ctla4

EnglishJapanese



G0.430.360.0280.650.620.215

0.215,1268

0.028,472

P --2

---------------------------------------------

P z

---------------------------------------------

1 0.2150000 1268 0.7891917

2 0.0280000 472 1.9110356

---------------------------------------------

z(overall) = 1.90935

p(overall) = 0.02811

= 0.62927

= 1

P = 0.42762

effect size r = 0.0457731

N fs.05 = 0.69

========================================

mif


susceptibleJIAcontrolRAcontrol

SNP No.allele(n=526)(n=259)(n=1033)(n=993)

C0.350.220.00020.230.200.013

pdcd1

Allele frequencySwedishJapanese



A0.0850.0730.05300

ptpn22

Allele frequencyWhite AmericanJapanese



T0.140.090.000700

tnfrsr1b

TNFRSF1B

Allele frequencyCaucasiansJapanese



T0.670.260.02060.870.170.0256

0.740.8311/22

TNFRSF1B




T0.670.740.02060.870.830.0256

tnfrsr1b

PADI4

PADI4




T0.450.420.310.460.370.00046

P --2

---------------------------------------------

P z

---------------------------------------------

1 0.3100000 1237 0.4958503

2 0.0004600 1478 3.3139134

---------------------------------------------



= 3.97074

= 1

P = 0.04630


N fs.05 = 3.36

========================================

Graph4

0.26

0.74

ctla4

EnglishJapanese



G0.430.360.0280.650.620.215

0.215,1268

0.028,472

P --2

---------------------------------------------

P z

---------------------------------------------

1 0.2150000 1268 0.7891917

2 0.0280000 472 1.9110356

---------------------------------------------



= 0.62927

= 1

P = 0.42762


N fs.05 = 0.69

========================================

mif




C0.350.220.00020.230.200.013

pdcd1




A0.0850.0730.05300

ptpn22




T0.140.090.000700

tnfrsr1b

TNFRSF1B




T0.670.260.02060.870.170.0256

0.740.8311/22

TNFRSF1B




T0.670.740.02060.870.830.0256

tnfrsr1b

PADI4

PADI4




T0.450.420.310.460.370.00046

P --2

---------------------------------------------

P z

---------------------------------------------

1 0.3100000 1237 0.4958503

2 0.0004600 1478 3.3139134

---------------------------------------------



= 3.97074

= 1

P = 0.04630


N fs.05 = 3.36

========================================

MBD003A5BDA.xls

Graph16

0.62

0.38

Sheet1



SNP No.Allele(n=772)(n=465)P value(n=823)(n=655)P value

pdcd1_1A0.0850.0730.930.053001.00

ptpn22_1T0.140.090.910.0007001.00

mif_1C0.350.220.780.00020.230.200.800.013

tnfrsf1b_1T0.340.260.740.00590.870.870.130.7914

ctla4_1G0.430.360.640.0280.650.620.380.215

padi4_92T0.450.420.580.310.460.370.630.00046


1-Pcont1-Pcont

Sheet1

0

0

PDCD1 C

Sheet2

0

0

PDCD1 J

Sheet3

00000000

00000000

PTPN22 C

0

0

PTPN22 J

00

00

MIF11 C

00

00

MIF11 C

0

0

tnfrsf1b_1

0

0

TNFRSF1b_1

0

0

CTLA4 C

0

0

CTLA4 J

0

0

PADI4 C

0

0

PADI4 J

0

0

SLC22A4/A5

0

0

SLC22A4/A5 J



SNP No.Allele(n=772)(n=465)P value(n=823)(n=655)P value

pdcd1_1A0.0850.0730.930.053001.00

ptpn22_1T0.140.090.910.0007001.00

mif_1C0.350.220.780.00020.230.200.800.013

tnfrsf1b_1T0.340.260.740.00590.870.870.130.7914

ctla4_1G0.430.360.640.0280.650.620.380.215

padi4_92T0.450.420.580.310.460.370.630.00046


1-Pcont1-Pcont

0.073

0.927

0

1

0.090.090.090.090.090.090.090.09

0.910.910.910.910.910.910.910.91

0

1

0.2160.216

0.7840.784

0.2160.216

0.7840.784

0.26

0.74

0.87

0.13

0.36

0.64

0.62

0.38

0.42

0.58

0.37

0.63

0.42

0.58

0

1

Graph15

0.36

0.64

Sheet1




A0.0850.0730.930.053001.00

T0.140.090.910.0007001.00

C0.350.220.780.00020.230.200.800.013

T0.340.260.740.00590.870.870.130.7914

G0.430.360.640.0280.650.620.380.215

T0.450.420.580.310.460.370.630.00046


1-Pcont1-Pcont

Sheet1

PDCD1 C

Sheet2

PDCD1 J

Sheet3

PTPN22 C

PTPN22 J

MIF11 C

MIF11 C

tnfrsf1b_1

TNFRSF1b_1

CTLA4 C

CTLA4 J

PADI4 C

PADI4 J

SLC22A4/A5

SLC22A4/A5 J




A0.0850.0730.930.053001.00

T0.140.090.910.0007001.00

C0.350.220.780.00020.230.200.800.013

T0.340.260.740.00590.870.870.130.7914

G0.430.360.640.0280.650.620.380.215

T0.450.420.580.310.460.370.630.00046


1-Pcont1-Pcont

0.073

0.927

0

1

0.090.090.090.090.090.090.090.09

0.910.910.910.910.910.910.910.91

0

1

0.2160.216

0.7840.784

0.2160.216

0.7840.784

0.26

0.74

0.87

0.13

0.36

0.64

0.62

0.38

0.42

0.58

0.37

0.63

0.42

0.58

0

1

Graph5

0.17

0.83

ctla4

EnglishJapanese



G0.430.360.0280.650.620.215

0.215,1268

0.028,472

P --2

---------------------------------------------

P z

---------------------------------------------

1 0.2150000 1268 0.7891917

2 0.0280000 472 1.9110356

---------------------------------------------



= 0.62927

= 1

P = 0.42762


N fs.05 = 0.69

========================================

mif




C0.350.220.00020.230.200.013

pdcd1




A0.0850.0730.05300

ptpn22




T0.140.090.000700

tnfrsr1b

TNFRSF1B




T0.670.260.02060.870.170.0256

0.740.8311/22

TNFRSF1B




T0.670.740.02060.870.830.0256

tnfrsr1b

PADI4

PADI4




T0.450.420.310.460.370.00046

P --2

---------------------------------------------

P z

---------------------------------------------

1 0.3100000 1237 0.4958503

2 0.0004600 1478 3.3139134

---------------------------------------------



= 3.97074

= 1

P = 0.04630


N fs.05 = 3.36

========================================

Ethnic variations

SNP Research Center, RIKEN, Yokohama, JapanLab. for Rheumatic DIseasesKazuhiko YamamotoAkari SuzukiYuta KochiMikako Mori

Akihiro SekineTatsuhiko Tsunoda

Yusuke NakamuraClinical Institutes of CollaborationUniversity of Tokyo HospitalsTetsuji SawadaNational Sagamihara HospitalShigeto TohmaToshihiro Matsui

Center for Genomic Medicine, Kyoto University, Kyoto, JapanFumihiko MatsudaShohei ChidaAlexandre VasilescuHitomi Hiratani

Victor RenaultMasao YamaguchiKatsura HirosawaKenei Ohigashi

Testing for an association in a one-stage design is straightforward

Two-stage samples can be analyzed either using either a replication based analysis or joint analysis

In both cases the SNPs are genotyped on a subset of cases and controls and those SNPs exceeding a liberal significance level are then genotyped in the remaining cases and controls.

In replication-based analysis, the genotype data collected in stage 2 is analyzed independently of the stage 1 data, allowing any significant stage 2 result to be deemed a replication.

In joint analysis, the test statistics for stage 1 and 2 are combined> outPlusKoreaFixed effects ( Mantel-Haenszel ) Meta-AnalysisCall: meta.MH(ntrt = n.case, nctrl = n.ctrl, ptrt = sus.case, pctrl = sus.ctrl, names = study, data = outobj)Mantel-Haenszel OR =1.23 95% CI ( 1.15, 1.31 )Test for heterogeneity: X^2( 6 ) = 10.41 ( p-value 0.1085 )

large-scale linkage disequilibrium mapping of rheumatoid arthritis-associated genes in japan ～...

Documents

coding genes

nondna analyses

multiple nonhla genes

nonsusceptible haplotype

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stage joint screening12

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