Large-scale Linkage Disequilibrium Mapping to Identify Rheumatoid

Arthritis-associated Genes

Ryo YamadaIMS U of Tokyo

Tokyo Japan1st International Symposium on Key Issues on Infectious

DiseasesJune 5 2007

Grand Hilton Hotel Seoul Korea

Rheumatoid Arthritis World-wide distribution

with prevalence from 0.6% to 1.0%

Woman-dominant Complex etiology

Genetic components Environmental

components Destructive polyarthritis Extra-articular

involvement Autoimmunity

Genetics and Genetic Analysis of Rheumatoid Arthritis

Twin and family studies Relative risk to monozygotic twin ( λMZ )

12~62

Relative risk to siblings (λsib) 2~17

HLA locus explains 1/3-1/2 of total genetic components.

There are multiple non-HLA genes. Multiple linkage studies Many candidate-approach studies

SNP-based large scale LD-mapping

The first stage From the end of 20th century to 2003 Human genome sequence was being completed SNPs and LD were being characterized High-throughput SNP genotyping platforms were being devel

oped The second stage

From 2003 ～ HapMap project offered variation map for whole-genome st

udy Multiple commercial genotyping packages are available Significant reduction in the typing cost

98

76541 2 3

1 2 3 7698

4 5

Coding Gene-based Approach

Map-based Approach

Gene A Gene B

Gene A Gene B

Gene D

Gene C

Gene C

Gene D

Two Ways of Whole Genome LD Mapping～ First stage ～

SNP distribution of RIKEN study

SNPs

Sam

ples

Replication-based analysisSNPs

Sam

ple

s

Stage 1

Stag

e 2

One-Stage DesignOne-Stage Design

Joint analysisSNPs

Sam

ples Stage 1

Stag

e 2

Two-Stage DesignTwo-Stage Design

Michael Boehnke : Design Considerations in Large Scale Genetic Association Studies

HapMap Tutorials

836 vs. 658 two-stage joint screening

12,890 / 21,153 genes

12,890 （ 60.9% ） genes were evaluated with block/SNPs

No. SNPs per gene and density of SNPs

5.0±6.4 /gene0.2±0.3 /kb

No. coding genes in autosomal chromosomes ： 21,153

Covered with SNPs

not in block

Covered with block

Not covered

4,509

8,381

8,263 12,89

0

Gene

20052000 2001

2002 2003 2004

10k20k

40k30k

50k

RIEN project started

27,283Genes

Japanese, Korean :

RA-specific

Caucasians :

SLE RA and other autoimmunities

Japanese : RA

Caucasian : IBD

Japanese :

RA and other autoimmunities

Major findings from SNP-based studies

Major findings from SNP-based studies

Japanese study (RIKEN) PADI4 : RA

Post-translational enzyme to produce targets of the most RA-specific autoantibodies.

SLC22A4 /A5 : RA & Crohn Ergothioneine or carnitine transporter expressed in he

matologic lineages. FCRL3 : RA, SLR & AITD

Fc receptor homolog on B-cell membrane

US study (A.Begovich et al.) PTPN22 : T1DM, SLE, RA & AITD

Lymphoid-specific intracellular phophatase

Validation with meta-analysis

MΦ

Anti-oxydant transporter

Multiple Genes and Multiple Diseases

Summary

Coding 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 markers Genes Genotyping technologies and

further developments SNPs and other polymorphisms Larger study scale and the

associated problems in analysis What 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, 2005

Populations CEU CHB+JPN YRI

Total Non-Redundant 3,904,218 3,936,482 3,846,092

Total QC+ SNPs 4,871,127 4,881,441 4,774,448

Total Gentyped SNPs 6,838,923 6,799,238 6,798,546

No. 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 functionality

ＤＮＡ

mRNA

Peptide

Transcription

Translation

Transcription initiation point

Transcription termination point

Splicing and mRNA maturation

Translation initiation point

Codon triplets

Translation termination point

Variations

Variations

Variations

Variations

Variations

Post-translational peptide modifications

Molecules

Genes

Susceptible Non-susceptible

DNA-mRNA-Protein relation is not straight, but comparison between DNA variations and

phenotype variations bypassing mRNA/proteins simplifies the analysis structure.

Genome

TranscriptomeProteome

Metabolome

Phenome

All-or-non simplest case

Genes

Another big world of heritable items (genes)

Non-coding RNA x 23,000 in mammals

Functional RNA-genes Non-coding genes

Genes

Coding gene

Non-coding-gene

DNAFunctional

RNA

Effects on transcription

Effects on translation

Effects on phenotypes

Genes

Genotyping technologies and further developments

100K marker-panel 250K marker-panel 500K marker-panel …1M marker-panel … … Whole genome typing of all

samples

Typing

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

Other polymorphisms

SNPs CNVs

Biased samplingEven sampling

Sampling from a structured populationLarge study-associated problems

00.10.20.30.40.50.60.70.80.9

1

0.01

0.11

0.21

0.31

0.41

0.51

0.61

0.71

0.81

0.91

Fisher's exact P

パー

セン

タイ

ル 構造化なし

構造化あり、ケースコントロール均質構造化あり、ケースコントロール不均一

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1 0 1 0 1 1

P 値昇順プロット

P 値P-value

Markers

Large study-associated problems

Many significant results when samples are biased with population structure.

Species are distinct categorical phenotypes with many genetic differences.Species-specific genetic factors are difficult to nail down.

Association studies?

Human individuals are unique but phenotypic variations are less distinct than species.Intra-species genetic variations are much less than inter-species, but still difficult to identify association between phenotypic and genetic variations.

Association studies?

Nature Reviews Genetics 3, 380-390 (2002); doi:10.1038/nrg795GENEALOGICAL TREES, COALESCENT THEORY AND THE ANALYSIS OF GENETIC POLYMORPHISMS

Nature Reviews Genetics 3, 380-390 (2002); doi:10.1038/nrg795GENEALOGICAL TREES, COALESCENT THEORY AND THE ANALYSIS OF GENETIC POLYMORPHISMS

Inter-species differences

Intra-species differences

Phylogeny and Ancestral Recombination Graph

Association studies?

Genetic Approach and Molecular Validation

Genetic Approach Dissection of combined effects of multiple

variations in many genes on phenotypes in human.

Molecular Validation Molecular assays to reveal causative links

between genetic variations and phenotype manifestation.

Genetic Validation with Controlled Interventions Transgenic animals are also used for validation

of findings from genetic studies in human.

Lab of Functional Genomics

IMS @ U of Tokyo

Mark Lathrop

Yukinori Okada

Harumi Nagai

Lab for Rheumatic Diseases @ SRC RIKEN

Kazuhiko Yamamoto

Akari Suzuki

Yuta Kochi

Kenichi Shimane

Keiko Myozen

Kyoko Kobayashi

Miyako Ohtake

Emi Kanno

Yoshinobu Hayashi

Keiko Komakine

Yusuke Nakamura

CGM @ Kyoto U

Fumihiko Matsuda

Koichiro Ohmura

Meiko Takahashi

Alexandre Vasilescu

Victor Renault

Masao Yamaguchi

Katsura Hirosawa

Kenei Ohigashi

Akiko Yoshizumi

Miki Kokubo

Shoko Matsubara

Time course

Triggering Event

Disease Manifestations

Diagnosis

Clinical F/UBirth

No observation In pre-clinical phase

RNA, proteins and others DNA

DNA-analyses Data is Simple and Fixed throughout the Life.

No quantitative, chronological or spatial variation is present for DNA polymorphisms.

Time course

Birt

RNA, proteins and others DNA