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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
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DNA-variations and their Effects on Transcripts, Peptides, Molecules Phenotypeshttp://www.microbe.org/espanol/news/human_genome.asp
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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
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Central Dogma & DNA VariationsmRNAPeptideTranscriptionTranslationTranscription initiation pointTranscription termination pointSplicing and mRNA maturationTranslation initiation pointCodon tripletsTranslation termination pointPost-translational peptide modificationsMolecules
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Not one way, but Multiple Bifurcations & Quantitative VariationsTranscript variationsPeptide variationsMolecular variations
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Phenotype1Phenotype2Phenotype3Phenotype4
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Phenotype1Phenotype2Phenotype3Phenotype4
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Monogenic determinationRecessive traitDisease mutation and mal-functional moleculeDisease phenotypeNon-disease phenotype
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Monogenic TraitComplex TraitMissenseSilentNon-codingDepth of transmission of allele-specific molecular difference depends on type of polymorphismMissense mutation and significant change of molecular function
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SusceptibleNon-susceptibleAssociation study of Complex Traits with DNA-markersDNARNAPeptides
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SusceptibleNon-susceptibleAssociation study with DNA-markersSimplified Architecture Bypasses Elements between DNA and Phenotypes Pros and Cons
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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
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Another big world of RNA genes
Non-coding RNA x 23,000 in mammals
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Coding-gene World and VariationsCoding DNACoding mRNA
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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
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Two Ways of Whole Genome LD Mapping
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SNP distribution of RIKEN study
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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
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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
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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
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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)
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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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
casecontrolcasecontrol
SNP No.Allele(n=123)(n=349)(n=781)(n=487)
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
Allele frequencyEnglishJapanese
susceptibleJIAcontrolRAcontrol
SNP No.allele(n=526)(n=259)(n=1033)(n=993)
C0.350.220.00020.230.200.013
pdcd1
Allele frequencySwedishJapanese
casecontrolcasecontrol
SNP No.Allele(n=1175)(n=3404)(n=824)(n=649)
A0.0850.0730.05300
ptpn22
Allele frequencyWhite AmericanJapanese
casecontrolcasecontrol
SNP No.Allele(n=475)(n=475)(n=822)(n=649)
T0.140.090.000700
tnfrsr1b
TNFRSF1B
Allele frequencyCaucasiansJapanese
casecontrolcasecontrol
SNP No.Allele(n=480)(n=137)(n=824)(n=648)
T0.670.260.02060.870.170.0256
0.740.8311/22
TNFRSF1B
Allele frequencyCaucasiansJapanese
casecontrolcasecontrol
SNP No.Allele(n=480)(n=137)(n=824)(n=648)
T0.670.740.02060.870.830.0256
tnfrsr1b
PADI4
PADI4
Allele frequencyEnglishJapanese
casecontrolcasecontrol
SNP No.Allele(n=772)(n=465)(n=823)(n=655)
T0.450.420.310.460.370.00046
P --2
---------------------------------------------
P z
---------------------------------------------
1 0.3100000 1237 0.4958503
2 0.0004600 1478 3.3139134
---------------------------------------------
z(overall) = 2.69391
p(overall) = 0.00353
= 3.97074
= 1
P = 0.04630
effect size r = 0.0517009
N fs.05 = 3.36
========================================
Graph4
0.26
0.74
ctla4
EnglishJapanese
casecontrolcasecontrol
SNP No.Allele(n=123)(n=349)(n=781)(n=487)
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
Allele frequencyEnglishJapanese
susceptibleJIAcontrolRAcontrol
SNP No.allele(n=526)(n=259)(n=1033)(n=993)
C0.350.220.00020.230.200.013
pdcd1
Allele frequencySwedishJapanese
casecontrolcasecontrol
SNP No.Allele(n=1175)(n=3404)(n=824)(n=649)
A0.0850.0730.05300
ptpn22
Allele frequencyWhite AmericanJapanese
casecontrolcasecontrol
SNP No.Allele(n=475)(n=475)(n=822)(n=649)
T0.140.090.000700
tnfrsr1b
TNFRSF1B
Allele frequencyCaucasiansJapanese
casecontrolcasecontrol
SNP No.Allele(n=480)(n=137)(n=824)(n=648)
T0.670.260.02060.870.170.0256
0.740.8311/22
TNFRSF1B
Allele frequencyCaucasiansJapanese
casecontrolcasecontrol
SNP No.Allele(n=480)(n=137)(n=824)(n=648)
T0.670.740.02060.870.830.0256
tnfrsr1b
PADI4
PADI4
Allele frequencyEnglishJapanese
casecontrolcasecontrol
SNP No.Allele(n=772)(n=465)(n=823)(n=655)
T0.450.420.310.460.370.00046
P --2
---------------------------------------------
P z
---------------------------------------------
1 0.3100000 1237 0.4958503
2 0.0004600 1478 3.3139134
---------------------------------------------
z(overall) = 2.69391
p(overall) = 0.00353
= 3.97074
= 1
P = 0.04630
effect size r = 0.0517009
N fs.05 = 3.36
========================================
MBD003A5BDA.xls
Graph16
0.62
0.38
Sheet1
Allele frequencyEnglishJapanese
casecontrolcasecontrol
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
SLC22A4/A5haplotype0.420.580.001.00
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
Allele frequencyEnglishJapanese
casecontrolcasecontrol
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
SLC22A4/A5haplotype0.420.580.001.00
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
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
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
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
casecontrolcasecontrol
SNP No.Allele(n=123)(n=349)(n=781)(n=487)
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
Allele frequencyEnglishJapanese
susceptibleJIAcontrolRAcontrol
SNP No.allele(n=526)(n=259)(n=1033)(n=993)
C0.350.220.00020.230.200.013
pdcd1
Allele frequencySwedishJapanese
casecontrolcasecontrol
SNP No.Allele(n=1175)(n=3404)(n=824)(n=649)
A0.0850.0730.05300
ptpn22
Allele frequencyWhite AmericanJapanese
casecontrolcasecontrol
SNP No.Allele(n=475)(n=475)(n=822)(n=649)
T0.140.090.000700
tnfrsr1b
TNFRSF1B
Allele frequencyCaucasiansJapanese
casecontrolcasecontrol
SNP No.Allele(n=480)(n=137)(n=824)(n=648)
T0.670.260.02060.870.170.0256
0.740.8311/22
TNFRSF1B
Allele frequencyCaucasiansJapanese
casecontrolcasecontrol
SNP No.Allele(n=480)(n=137)(n=824)(n=648)
T0.670.740.02060.870.830.0256
tnfrsr1b
PADI4
PADI4
Allele frequencyEnglishJapanese
casecontrolcasecontrol
SNP No.Allele(n=772)(n=465)(n=823)(n=655)
T0.450.420.310.460.370.00046
P --2
---------------------------------------------
P z
---------------------------------------------
1 0.3100000 1237 0.4958503
2 0.0004600 1478 3.3139134
---------------------------------------------
z(overall) = 2.69391
p(overall) = 0.00353
= 3.97074
= 1
P = 0.04630
effect size r = 0.0517009
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 )