nba 100824
Post on 20-Jun-2015
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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
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