Saitama medical university

1. 疾患研究からいくので、お手元のレビューから離れる部分もあります…2. 11月 ASHG から戻ると僕の言うことが変わっている可能性があります…!!!

諸注意 (広い心が必要です)

Saitama medical university

最近 GWAS が可哀想

Saitama medical university

GWAS 批判されまくり“it is now clear that common risk variants fail to explain the vast majority of genetic heritability for any human disease”

NBA Journal Club (4th)Ochanomizu univ., Tokyo | 24th August 2010

KOHDA Masakazu

On beyond GWAS

Saitama medical university

Self introduction

Saitama medical university

好きなもの: GWAS生まれのDTC

Saitama medical university

嫌いなもの: 怪しい遺伝子検査

Saitama medical university

30分くらいの資料10分くらいバックグラウンド10分くらい今の疾患研究10分くらいこれからの疾患研究?

Missing heritability

GWAS

疾患研究

Mine the gray zone

背景・歴史

GWASとは何か

GWASで見えない遺伝率

‘Gray zone’のマイニング

Saitama medical university

疾患研究

GWAS登場!

CNV登場!!

Exome登場!!!

Linkageで解析

よく分かんないのは Missing heritability って呼ぼうぜ!

SNPと連鎖不平衡で…全ゲノム相関解析できるんじゃね?

あれ、SNPアレイでコピーナンバー検出できるじゃね?

GWAS でも CNV も低調だから rare variant やろうぜ!

<= 今ココ

疾患研究の歴史

See also: The pursuit of genome-wide association studies: wh... [J Hum Genet. 2010]

Saitama medical university

•GWAS (SNPs)•CNVs (正確には CNPs)•Rare variants•Common diseases •Rare diseases

疾患研究の分類

疾患研究の分類

Finding the missing heritability of complex diseas... [Nature. 2009] - PubMed resulthttp://www.ncbi.nlm.nih.gov/pubmed/19812666

(5%)(0.1%)

疾患研究の分類

Finding the missing heritability of complex diseas... [Nature. 2009] - PubMed resulthttp://www.ncbi.nlm.nih.gov/pubmed/19812666

Exome

?GWAS

(5%)(0.1%)

Saitama medical university

GWAS

Saitama medical university

Published Genome-Wide Associations through 3/2010,

779 published GWA at p<5x10-8 for 148 traits

NHGRI GWA Catalog

www.genome.gov/GWAStudies

779A Catalog of Published Genome-Wide Association Studies

http://www.genome.gov/26525384

Saitama medical university

GWASの良さ

Saitama medical university

Unsuspected association を検出できる

仮説フリーで探索可能

Genomewide association studies and assessment of t... [N Engl J Med. 2010] - PubMed resulthttp://www.ncbi.nlm.nih.gov/pubmed/20647212

Saitama medical university

GWASの仕組み

Genomewide association studies and assessment of t... [N Engl J Med. 2010] - PubMed resulthttp://www.ncbi.nlm.nih.gov/pubmed/20647212

Genomewide association studies and assessment of t... [N Engl J Med. 2010] - PubMed resulthttp://www.ncbi.nlm.nih.gov/pubmed/20647212

Serious flaws revealed in "longevity genes" study : Genetic Futurehttp://scienceblogs.com/geneticfuture/2010/07/serious_potential_flaws_in_lon.php

"longevity genes" study

Good GWAS

Saitama medical university

土台になるアイデアはシンプル作業仮説を必要としない強さ

GWAS

Saitama medical university

Missing heritability

Saitama medical university

GWASが見つけられない遺伝要因

Saitama medical university

GWAS はチカラ不足?

GWAS で見つかる common risk SNP は同胞 (Sibling) の発症率から見積もられる遺伝率の大半を説明できない

*

* After reproductive life?

Saitama medical university

Structural variation and unexplained heritability

Saitama medical university

CNP が解決してくれる?Table 2 Selected disease associations with rare CNVs and common CNPs

CNV: Copy Number VariantCNP: common (>= 5% MAF) Copy Number Polymorphism

CNV と SNP の比較実験2007 SNP 2010 CNP (CNV)

CNP で SNP と独立しているものはないだろう

Saitama medical university

Rare variants andunexplained heritability

GWAS登場!

CNV登場!!

Exome登場!!!

Linkageで解析

よく分かんないのは Missing heritability って呼ぼうぜ!

SNPと連鎖不平衡で…全ゲノム相関解析できるんじゃね?

あれ、SNPアレイでコピーナンバー検出できるじゃね?

GWAS でも CNV も低調だから rare variant やろうぜ!

<= 今ココ / でも後退してね?

疾患研究の歴史

See also: The pursuit of genome-wide association studies: wh... [J Hum Genet. 2010]

Saitama medical university

Rare が解決してくれる?Table 2 Selected disease associations with rare CNVs and common CNPs

CNV: Copy Number VariantCNP: common (>= 5% MAF) Copy Number Polymorphism

疾患研究の分類

Finding the missing heritability of complex diseas... [Nature. 2009] - PubMed resulthttp://www.ncbi.nlm.nih.gov/pubmed/19812666

Exome

GWAS

(5%)(0.1%)

ココ?

ココ?

疾患研究の分類

Finding the missing heritability of complex diseas... [Nature. 2009] - PubMed resulthttp://www.ncbi.nlm.nih.gov/pubmed/19812666

(5%)(0.1%)

GWAS

Exome

Saitama medical university

Mine the ‘‘Gray Zone’’ of GWA Studies

Saitama medical university

New methods must be developed in order to discover the numerous remaining genes

Use of genome-wide expression data to mine the "Gr... [PLoS Genet. 2010] - PubMed result http://www.ncbi.nlm.nih.gov/pubmed/20532202

Saitama medical university

•Meta-analysis•eQTL•Pathway enrichment

GWAS + XXX

Saitama medical university

Meta-analysis

Genomewide association studies and assessment of t... [N Engl J Med. 2010] - PubMed resulthttp://www.ncbi.nlm.nih.gov/pubmed/20647212

Use of genome-wide expression data to mine the "Gr... [PLoS Genet. 2010] - PubMed result http://www.ncbi.nlm.nih.gov/pubmed/20532202

eQTL

Expression

GWAS

SNP and GWAS enrichments for chromatin states

Discovery and characterization of chromatin states... [Nat Biotechnol. 2010] - PubMed resulthttp://www.ncbi.nlm.nih.gov/pubmed/20657582

Saitama medical university

A functional map of ASD

Functional impact of global rare copy number varia... [Nature. 2010] - PubMed resulthttp://www.ncbi.nlm.nih.gov/pubmed/20531469

Saitama medical university

見えない遺伝率 (SNP, CNV, Rare variants) を探すのと同じで、見えてない遺伝子を探すのも重要

Saitama medical university

見つかるものの機能が何なのか?、は大事

発症機序・病態を理解したいから=> Pathwayとして理解したい=> 疾患同士の繋がりも見たい

現行のGWASの価値の1つはここらへん

Saitama medical university

ブログったー☆=> d.hatena.ne.jp/ma_ko/20100823/p1

Further Readings

Saitama medical university

続きは Web でそのうち!!

Saitama medical university

•Pharmacogenetics•GWAS of Cancers•線形和による遺伝率の改善

今日は話せなかったこと

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http://www.everystockphoto.com/photo.php?imageId=3021422

Take home messages

http://www.everystockphoto.com/photo.php?imageId=2095855

GWAS で見えてない遺伝要因がある (しかも大きい)Rare variants が残りの大半を説明できるのか?Biological な理解を進めるための Wet と Dry.

http://www.everystockphoto.com/photo.php?imageId=238810

Thank you

http://www.everystockphoto.com/photo.php?imageId=2433714

got questions?

Saitama medical university

Common / Low / Rare

Uncovering the roles of rare variants in common di... [Nat Rev Genet. 2010] - PubMed resulthttp://www.ncbi.nlm.nih.gov/pubmed/20479773