Dec.19
13:00 〜 13:10

Dec.20Opening Remarks

Session 3

Functional non-coding RNA (2)Hidetoshi Inoko(Chair: Tatsushi Toda)

Tokai University, Japan

9:00 〜 9:35

piRNA/rasiRNA: a novel class of functional non-coding RNAs

14

Mikiko C.Siomi
Session 1

Institute for Genome Research
University of Tokushima

Asian Genomic Network(Chair: Hidetoshi Inoko)

13:10 〜 14:10

Lessons learned from studying a single-gene disorder6

9:35 〜 10:10

The regulation of microRNA function by RNA editing

15

Yukio Kawahara, MD, PhD

Lap-Chee Tsui

The Wistar Institute

The University of Hong Kong

14:10 〜 14:45

Sunyoung Kim

7

10:10 〜 10:20

BreakSeoul National University, Korea

Session 4
14:45 〜 15:20

Building Asia Pacific R & D Highway for Genomic Medicine and ClinicalDevelopment

Genome Wide Association Study (GWAS) (1)(Chair: Itsuro Inoue)

8

Ken-ichi Arai

10:20 〜 10:55

Recent Discoveries and New Challenges

16

Augustine Kong

Asia-Pacific IMBN; University of Tokyo; SBI Biotech Co., Ltd.

deCODE Genetics, Sturlugata 8, IS-101 Reykjavik, Iceland

15:20 〜 15:40

Break

10:55 〜 11:30

Josephine Hoh, Ph.D.

17

Yale University

Session 2

Functional non-coding RNA (1)11:30 〜 11:55(Chair: Hiroyuki Mano)

15:40 〜 16:15

Evolution of microRNAs

Genome-wide association studies in Japanese with special reference tonarcolepsy
19
Katsushi Tokunaga

9

University of Tokyo

Eugene Berezikov
Hubrecht Institute, Utrecht, The Netherlands

16:15 〜 16:50

Prediction of microRNA targets

11:55 〜 13:00
10

Lunch

Session 5

Nikolaus Rajewsky(Chair: Katsushi Tokunaga)

Max Delbruck Center for Molecular Medicine, Germany

16:50 〜 17:25

microRNAs in Human Cancer

Genome Wide Association Study (GWAS) (2)11

13:00 〜 13:35

Sweet dreams: finding genes for diabetes and obesity

20Mark McCarthy

Carlo M. Croce M.D.

Oxford Centre for Diabetes, Endocrinology and Metabolism
the Wellcome Trust Centre for Human Genetics, University of Oxford

The Ohio State University, Comprehensive Cancer Center

13:35 〜 14:00

Multistage genome-wide association study of type 2 diabetes mellitus in
Japanese population.
21
Masato Kasuga
Kobe University Graduate School of Medicine

Dec.19
Session 6

Resequencing and Comprehensive Candidate Genes Analysis of Human Diseases (1)(Chair: Shoji Tsuji)

14:00 〜 14:35

14:35 〜 15:10

Large-Scale Identification and Characterization of Developmental Brain
22
Disease Genes

Session 1 Asian Genomic Network (Chair: Hidetoshi Inoko)

Guy A. Rouleau

Lessons learned from studying a single-gene disorder

Centre for the Study of Brain Disease, CHUM Research Centre, Notre-Dame Hospital, Montreal, QC

Lap-Chee Tsui (The University of Hong Kong)

Causes of regulatory variation in the human genome

23

6

Sunyoung Kim (Seoul National University, Korea)

7

Building Asia Pacific R & D Highway for Genomic Medicine and ClinicalDevelopment

8

Emmanouil Dermitzakis
Wellcome Trust Sanger Institute15:10 〜 15:20

Session 7

Break

Ken-ichi Arai (Asia-Pacific IMBN; University of Tokyo; SBI Biotech Co., Ltd.)Resequencing and Comprehensive Candidate Genes Analysis of Human Diseases (2)Session 2. Functional non-coding RNA (1) (Chair: Hiroyuki Mano)(Chair: Shoji Tsuji)

15:20 〜 15:55

The Cancer Genome Atlas

24

Daniela S. Gerhard
NCI/NIH, USA

15:55 〜 16:30

Array-based high-throughput sequencing of leukemia genome
Hiroyuki Mano, M.D., Ph.D.
Jichi Medical University

Evolution of microRNAs
Eugene Berezikov (Hubrecht Institute, Utrecht, The Netherlands)

Prediction of microRNA targets
25

Closing remarks
Shoji Tsuji
The University of Tokyo

10

Nikolaus Rajewsky (Max Delbruck Center for Molecular Medicine, Germany)

microRNAs in Human Cancer
Carlo M. Croce M.D. (The Ohio State University, Comprehensive Cancer Center)

16:30 〜 16:35

9

11

Dec.19

13：10 〜 14：10

Dec.19Lap-Chee Tsui ●Vice-Chancellor and President, The University of Hong Kong

Lessons learned fromstudying a single-gene
disorderSunyoung Kim

14：10 〜 14：45●Seoul National University, Korea

The Human Genome Project and theadvances in genomic technologies have madethe cloning of the genes for single-gene disorders relatively easy. There are, however, a few

lessons that can be learned from our study of cystic fibrosis, which is a common single gene disorder in the
Caucasian population. The gene was mapped by family analysis to the long arm of human chromosome 7 andisolated on the basis of its chromosome localization. It is now well established that CFTR functions as acAMP-regulated chloride channel in the secretory epithelium but more recent studies show that it may haveadditional activities. Over 1,300 mutations have been identified in the CFTR gene. Although the most frequent
CFTR mutation accounting for 70% of the mutant alleles, comprehensive mutation analysis fail to identify themutations in all CF patients. In addition, while there is good correlation between certain clinical presentation
and CFTR genotype, severity of CF disease could not be predicted by CFTR genotype alone. It is thought thatmodifier genes and environmental factors are important. While attempts are being made to define the molecular bases of the genetic modifiers, including the use of animal models, it is also found that mutations in CFTR
could cause other diseases, which are now sometimes referred as “CF-related diseases”. Taken altogether, it
can be said that there is really no simple ‘single gene’ disorders. In addition, our experience re-emphasizes
the importance of patient sample and clinical data collection, both of which are crucial to success of study. It isalso essential to combine basic science and clinical research, and, to engage in interdisciplinary collaborations.
While working on CF, it occurred to me and my colleague, Dr Steve Scherer, that the genomic resources andtechnologies accumulated in my laboratory could be used for large-scale genome analysis and study of otherdiseases. This latter work will be discussed in the context of the Toronto Center for Applied Genomics.

http://www.hku.hk/vcoffice/menu/biography.htm

6

1. Asian Genomic Network

1. Asian Genomic Network

7Dec.19

14：45 〜 15：20

Ken-ichi Arai

Dec.19●Founding President, Asia-Pacific IMBN; Special Professor, LSBM,
RCAST & Professor Emeritus, University of Tokyo; President and CEO,SBI Biotech Co., Ltd.

Building Asia Pacific R & D
Highway for Genomic
Medicine and ClinicalDevelopment

Eugene Berezikov

15：40 〜 16：15●Hubrecht Institute, Utrecht, The Netherlands

Evolution of microRNAs
In the old paradigm where

MicroRNAs are a large class of non-coding regulatory RNAs that are involved in almost every aspect of a“necessity triggers invention”, thecell life, from cell proliferation to differentiation to apoptosis. The roles of miRNAs in development andfrontier race had been the competi-disease are increasingly recognized. We have used massively parallel sequencing technology for discovery andtion for limited resources such as

expression profiling of miRNAs in various model organisms, including nematodes, fish, human and primates.

land and raw materials. In the new

In all the investigated species we found numerous novel miRNA candidate genes that often are not phyloge-

paradigm where “innovation creates

netically conserved and usually expressed at lower levels compared to conserved miRNAs. We also discov-necessity”, the frontier race has been the competition for resources of unlimited value such as science &ered that vertebrate genomes contain mirtrons - miRNAs derived from introns and processed by splicing

technology through discovery & innovation. This is achieved through collaborative network of researchers.

machinery instead of Drosha excision. Similar to canonical miRNAs some mirtrons are well-conserved whilest

Translation of discovery into new products by creating new industry is an important agenda. In 21 century,

others are species-specific. Our findings suggest that along with highly conserved ancient miRNAs there are

Asia become the focal point of growth in biotechnology and new centers of biomedical research as well as

many evolving miRNA candidate genes. We propose that such miRNAs may contribute to evolutionary novelty

bioindustry emerged throughout Asia. I would like to discuss several issues such as;

through diversification of gene regulatory networks. We also hypothesize that miRNA candidate genes that

1. Network Bio-research Centers in Asia such as BioPolis of Singapore, BioNexus of Malaysia, BIOTEC ofhave not yet evolved a function, when disregulated, may still be associated with disease like cancer.

Thailand, SIBS of Shanghai, BioMax of Seoul, Academia Sinica/NHRI of Taiwan, OIST of Japan etc.
2. Build Common International Hub in Asia by collaboration of A-IMBN, eIMBL, EMBO, ICGEB and
FAOBMB/IUBMB and to create A-IMBL (Asian EMBL), and to launch Nature A-IMBN Research News
3. Share Common Biotechnology Platform in Asia by building translational research centers for genomic
medicine. Networking biomedical centers for multinational clinical trials.
4. Build R & D Highway in Asia by building support system for bioventures (VCs, incubators) and bypromoting university-industry collaboration
5. Organize Regulatory Environment & Infrastructure in Asia to deal with IP issues, safety evaluation bybuilding FDA/CDC like network in Asia.
I would like to share the view of Ms. Keiko Oishi (CMIC Co., Ltd) regarding “Opportunities for Asiancollaboration and perspectives of developing multinational clinical trials in Asia.”

http://www.niob.knaw.nl/researchpages/berezikov

8

1. Asian Genomic Network

2. Functional non-coding RNA (1)9Dec.19

16：15 〜 16：50

Nikolaus Rajewsky

Dec.19●Max Delbruck Center for Molecular Medicine, Germany

Prediction of microRNAtargets

Carlo M. Croce M.D.

16：50 〜 17：25●The John W. Wolfe Chair in Human Cancer Genetics
Department of Molecular Virology, Immunology andMedical Genetics, The Ohio State University,
Comprehensive Cancer CentermicroRNAs in Human Cancer
MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A
and 3B
MicroRNAs (miRNAs) are small, noncoding RNAs that regulate expression of many genes. Recent studies
suggest roles of miRNAs in carcinogenesis. We and others have shown that expression profiles of miRNAs
are different in lung cancer vs. normal lung, although the significance of this aberrant expression is poorly
understood. Among the reported down-regulated miRNAs in lung cancer, the miRNA (miR)-29 family (29a,29b and 29c) has intriguing complementarities to the 3'-UTRs of DNA methyltransferase (DNMT)3A and -3B(de novo methyltransferases), two key enzymes involved in DNA methylation, that are frequently up-regulated
in lung cancer and associated with poor prognosis. We investigated whether miR-29s could target DNMT3A
and -B and whether restoration of miR-29s could normalize aberrant patterns of methylation in non-small-celllung cancer. We show that expression of miR-29s is inversely correlated to DNMT3A and -3B in lung cancer
tissues, and that mir-29s directly target both DNMT3A and -3B. The enforced expression of miR-29s in lungcancer cell lines restores normal patterns of DNA methylation, induces re-expression of methylation-silenced
tumor suppressor genes, such as FHIT and WWOX, and inhibits tumorigenicity in vitro and in vivo. Thesefindings support a role of miR-29s in epigenetic normalization of NSCLC, providing a rationale for the development of miRNA-based strategies for the treatment of lung cancer.

http://medicine.osu.edu/mvimg

10

2. Functional non-coding RNA (1)2. Functional non-coding RNA (1)11Dec.20
Session 3 Functional non-coding RNA (2) (Chair: Tatsushi Toda)

piRNA/rasiRNA: a novel class of functional non-coding RNAs

14

Mikiko C.Siomi (Institute for Genome Research
University of Tokushima)

The regulation of microRNA function by RNA editing

15

Yukio Kawahara, MD, PhD (The Wistar Institute)
Session 4 Genome Wide Association Study (GWAS) (1) (Chair: Itsuro Inoue)

Recent Discoveries and New Challenges

16

Augustine Kong (deCODE Genetics, Sturlugata 8, IS-101 Reykjavik, Iceland)
Josephine Hoh, Ph.D. (Yale University)

17

Genome-wide association studies in Japanese with special reference tonarcolepsy

19

Katsushi Tokunaga (University of Tokyo)
Session 5 Genome Wide Association Study (GWAS) (2) (Chair: Katsushi Tokunaga)

Sweet dreams: finding genes for diabetes and obesity

20Mark McCarthy(Oxford Centre for Diabetes, Endocrinology and Metabolism
the Wellcome Trust Centre for Human Genetics, University of Oxford)

Multistage genome-wide association study of type 2 diabetes mellitus in
Japanese population.

21

Masato Kasuga (Kobe University Graduate School of Medicine)
Session 6 Resequencing and Comprehensive Candidate Genes Analysis of Human Diseases (1) (Chair: Shoji Tsuji)

Large-Scale Identification and Characterization of Developmental Brain Disease Genes 22
Guy A. Rouleau (Centre for the Study of Brain Disease, CHUM Research Centre, Notre-Dame Hospital, Montreal, QC)

Causes of regulatory variation in the human genome

23

Emmanouil Dermitzakis (Wellcome Trust Sanger Institute)
Session 7 Resequencing and Comprehensive Candidate Genes Analysis of Human Diseases (2) (Chair: Shoji Tsuji)

The Cancer Genome Atlas

24

Daniela S. Gerhard (NCI/NIH, USA)

Array-based high-throughput sequencing of leukemia genome
Hiroyuki Mano, M.D., Ph.D. (Jichi Medical University)25

Dec.20

9：00 〜 9：35

Mikiko C.Siomi

Dec.20

Yukio Kawahara, MD, PhD●Institute for Genome Research
University of TokushimapiRNA/rasiRNA:a novel class of functional
non-coding RNAs

Gene silencing pathways
triggered

by

small

RNAs

are

MicroRNAs (miRNAs)
mediate translational repres-9：35 〜 10：10●The Wistar InstituteThe regulation of microRNA
function by RNA editing

generically called RNA silencing.

sion or degradation of their target mRNA by RNA interference (RNAi), and an increasing line of evidence

RNA interference (RNAi) triggered

indicated that miRNA genes are tightly connected with the pathogenesis of certain human diseases. The levels

by short-interfering RNA (siRNA) of 21- to 23- nucleotide (nt) long is a representative of it. Extensive studies

of individual miRNAs vary under different developmental, cellular, or pathological condition, thus the elucida-on RNA silencing mechanisms revealed that members of the Argonaute family play important roles in thetion of their regulatory mechanisms is essential to the use of these small RNA molecules as future targets forpathways. In Drosophila, the Argoanute family, defined by the presence of PAZ and PIWI domains, consists ofdrug development as well as for the diagnosis of certain human diseases.

five members, which includes AGO1, AGO2, AGO3, Piwi, and Aubergine. One of our goals is to understand

Although miRNAs are single-stranded, 19- to 22-nucleotide molecules, each is generated from a longthe functional differences among the fly Argonaute members in RNA silencing. Previously we have shown thatprimary transcript (pri-miRNA) that consists of an imperfect short dsRNA region and a loop. Pri-miRNAs are

AGO1 and AGO2 in Drosophila function in gene silencing through specific binding with miRNA and siRNA,

sequentially processed by the nuclear Drosha-DGCR8 complex to ~60-70nt intermediates (pre-miRNAs) andrespectively. siRNA-loaded AGO2 functions in RNAi as Silcer, directly responsible for cleaving a target

then by the cytoplasmic Dicer-TRBP complex to mature miRNAs.

completely complementary to siRNA. miRNA-associated AGO1 is thought to repress translation of target

We and other groups have recently provided a line of evidence that certain pri-miRNAs are subject to RNA

mRNAs without cleaving them, but AGO1 also possesses Slicer activity as does AGO2. Piwi, Aubergine, andediting that converts adenosine to inosine in dsRNA regions, and highlighted the multiple roles of this modifi-

AGO3 (the PIWI proteins) are specifically associated with a subset of endogenous small RNA, termed Piwi-

cation in the regulation of expression levels and functions of certain miRNAs. RNA editing can alter the fold-interacting RNAs (piRNAs). Unlike miRNAs, piRNAs are 24-30 nt long, only expressed in gonads, andback dsRNA structure of miRNA precursors, thereby affecting their subsequent processing steps. For

function in genome surveillance through association with the PIWI proteins by silencing mobile elements that

instance, the editing of two specific sites of pri-miR-142 RNAs completely suppresses its cleavage by thehave sufficient potency to invade genome by inserting themselves into the DNA elements. Recently, a model

Drosha-DGCR8 complex, while the editing of pri-miR-151 RNAs results in complete blockage of its cleavage

for piRNA biogenesis in Drosophila was proposed. In addition, 3’ end modification of piRNAs in fly ovaries wasby Dicer-TRBP complex and accumulation of edited pre-miR-151 RNAs. By contrast, the editing of certain pri-determined as methylation by mass spectrometric analysis. However, many aspects of piRNA biogenesis andmiRNAs results in the expression of edited mature miRNAs. We found that two adenosine residues bothmodification remain unclear. Our current work is concerning the mechanisms of piRNA biogenesis and modifi-

positioned in the 5’-proximal half “seed sequence” of miR-376 RNAs are highly edited in select tissues. The

cation and the identification of factor(s) required for these processes.

seed sequence is critical for formation of the RNA duplex between target mRNA and miRNA. As expected, theedited miR-376 RNAs indeed silenced a set of genes different from those targeted by the unedited miR-376

References
1) Okamura K et al. Distinct roles for Argonate proteins in small RNA-directed RNA cleavage pathways. Genes Dev. 18: 1655-66.
20042) Miyoshi K et al. Sicer function of Drosophila Argonautes and its involvement in RISC formation. Genes Dev. 19: 2837-2848.
2005

RNAs both in vivo and in vitro, revealing a distinct role of RNA editing in miRNA-mediated gene silencing.
We recently conducted a survey of RNA editing sites in about 250 human pri-miRNAs, revealing that morethan 20% of these pri-miRNAs are edited significantly in vivo. These results indicate that RNA editing has a
big impact on miRNA function and could be a potential therapeutic target for miRNA-associated diseases.

3) Saito K et al. Specific association of Piwi with rasiRNAs derived from retrotransposon and heterochromatic regions in the
Drosophila genome. Genes Dev. 20: 2214-2222. 2006
4) Gunawardane LS et al. A Slicer-mediated mechanism for rasiRNA 5’ end formation in Drosophila. Science 315: 1587-1590.
20075) Saito K et al. Pimet, the Drosophila homolog of HEN1, mediates 2’-O methylation of Piwi-interacting RNAs at their 3’ ends.
Genes Dev. 21: 1603-1608. 2007
6) Nishida K.M et al. Gene silencing mechanisms mediated by Aubergine-piRNA complexes in Drosophila mal gonad. RNA 13:
1911-1922. 2007

http://www.genome.tokushima-u.ac.jp/dgfa/index.html

14

3. Functional non-coding RNA (2)3. Functional non-coding RNA (2)15Dec.20

10：20 〜 10：55

Augustine Kong

Dec.20●deCODE Genetics, Sturlugata 8, IS-101 Reykjavik, Iceland

Recent Discoveries and
New Challenges

Josephine Hoh, Ph.D.

10：55 〜 11：30●Associate Professor,
Yale University,
Department of Epidemiology and Public HealthThrough large scale genome-

Genome-wide association (GWA) approach has become a norm to map the genetic variants that predispose

wide association studies, suscepti-

humans to common, complex diseases. With the advance of genotyping technologies and the reduction of

bility variants that confer risks to complex diseases are identified at a pace that is unprecedented. These

genotyping cost, GWA studies using 500K to 1.8m markers (or SNPs) are underway. In this talk, I focus on

successes often raised new questions and lead to novel challenges. Examples in cancer, diabetes, cardiovas-

designs for the optimal GWA studies. When time permits, I will present a latest work of applying a GWA case-cular diseases, atrial fibrillation, restless legs syndrome, pigmentation, glaucoma and other complex traits,

control study to a rare disease.

will be used to highlight some of the interesting results and problems.

Risch and Zhang [1] have demonstrated the substantial increase in power obtained by selecting the affected
sibling who expresses the higher end of a distribution of a quantitative trait and the unaffected sibling having
the lower end in the trait spectrum. The principle of extreme discordant sibpair analysis was extended in the
AMD GWA study for case-control selection [2, 3]. Drusen size was used as a quantitative trait measure forwhich all cases had the extreme size of drusen and controls none or only a few small drusen. Controls also
were matched to cases as much as possible for known risk factors as siblings presumably share the sameenvironment. This strategy was estimated to reduce genotyping by 10 to 40 fold [1].
To date, the most efficient use of controls is reported in a large GWA study on seven diseases in that eachcase group was contrasted to the same control group [4]. The GWA studies conducted in Iceland by DeCode
Genetics have also used various subsets selected from one big population control cohort. Such practices may
be expected to be adopted in most future GWA studies.
1. Risch, N. and H. Zhang, Extreme discordant sib pairs for mapping quantitative trait loci in humans. Science, 1995. 268 (5217):
p. 1584-9.
2. Klein, R.J., et al., Complement factor H polymorphism in age-related macular degeneration. Science, 2005. 308 (5720): p.385-9.
3. Dewan, A., et al., HTRA1 promoter polymorphism in wet age-related macular degeneration. Science, 2006. 314 (5801): p.98992.
4. Consortium, W.T.C.C., Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls.
Nature, 2007. 447 (7145): p.661-78.
5. Williams, S.M., et al., Problems with genome-wide association studies. Science, 2007. 316 (5833): p.1840-2.
6. Easton, D.F., et al., Genome-wide association study identifies novel breast cancer susceptibility loci. Nature, 2007. 447 (7148):
p.1087-93.
7. Gudbjartsson, D.F., et al., Variants conferring risk of atrial fibrillation on chromosome 4q25. Nature, 2007. 448 (7151): p.3537.
8. Hakonarson, H., et al., A genome-wide association study identifies KIAA0350 as a type 1 diabetes gene. Nature, 2007. 448(7153): p.591-4.
9. Moffatt, M.F., et al., Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature, 2007.
448 (7152): p.470-3.
10. Sladek, R., et al., A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature, 2007. 445 (7130): p.8815.
11. Thorleifsson, G., et al., Common sequence variants in the LOXL1 gene confer susceptibility to exfoliation glaucoma. Science,
2007. 317 (5843): p. 1397-400.
12. Shriner, D., et al., Problems with genome-wide association studies. Science, 2007. 316 (5833): p.1840-2.
13. Couzin, J. and J. Kaiser, Genome-wide association. Closing the net on common disease genes. Science, 2007. 316 (5826): p.820-

16

4. Genome Wide Association Study (GWAS) (1)4. Genome Wide Association Study (GWAS) (1)17

Dec.20

10：55 〜 11：30

Dec.20Katsushi Tokunaga

2.

Genome-wide association

14. McPherson, R., et al., A common allele on chromosome 9 associated with coronary heart disease. Science, 2007. 316 (5830):
p.1488-91.
15. Zeggini, E., et al., Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science,
2007. 316 (5829): p.1336-41.
16. Scott, L.J., et al., A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science,
2007. 316 (5829): p.1341-5.
17. Saxena, R., et al., Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science, 2007. 316(5829): p.1331-6.
18. Frayling, T.M., et al., A common variant in the FTO gene is associated with body mass index and predisposes to childhood andadult obesity. Science, 2007. 316 (5826): p.889-94.
19. Duerr, R.H., et al., A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science, 2006. 314(5804): p.1461-3.

studies (GWAS) using new
high-throughput SNP typing
technologies have successfully
identified susceptibility genes

11：30 〜 11：55●Department of Human Genetics, Graduate School of
Medicine, University of Tokyo

Genome-wide association
studies in Japanese withspecial reference tonarcolepsy

to several common diseases.
We have been participating in several GWAS efforts in the Japanese population. First, we typed 389 unrelated
healthy Japanese by GeneChip Human Mapping 500K Array and investigated the data cleaning criteria bymeans of log QQ p-value plot in quasi-case-control studies. The preferable criteria were found to be: SNP callrate > 95%, confidence score = 0.5 in BRLMM algorism, Hardy-Weinberg’s equilibrium test p-value > 0.001,
and minor allele frequency > 5% or 1%.
Human narcolepsy is a typical sleep disorder with an incidence of about 0.15% in Japanese and affected bymultiple genetic and environmental factors. A HLA class II gene (DQB1*0602) is a well-established susceptibility gene, whereas the other genes are yet to be identified.

We previously carried out a GWAS fornarcolepsy using 23,000 microsatellite markers, and reported several candidate regions as well as a newresistance gene (Kawashima et al. Am. J. Hum. Genet. 2006). Now, we performed GWAS using the 500K
Array in 222 narcoleptics and 389 controls, and detected some 30 candidate SNPs.

Then, the second

screening was performed using a different sample set with 159 narcoleptics and 190 controls. At least one–7

SNP showed a replicated association with a combined odds ratio of 1.79 (p = 4.4 x 10 ). The subsequent highdensity association mapping surrounding the SNP showed that this SNP is primarily associated with thedisease. This SNP is located closely to two genes and the risk allele was associated with lower mRNA levelsof the genes. Interestingly, both genes were reported to have certain functions relevant to sleep regulation.
We are also responsible for Human SNP Typing Center for the Applied Genomics Initiatives supported by
MEXT, Japan. Thus, we established the 500K Array database of 450 healthy Japanese and completed GWAS
typing for multiple system atrophy and panic disorder. At present, we are producing the control data using
GeneChip Array 6.0 and performing the GWAS typing for other diseases.
Another effort in our typing center is to establish a new multiplex SNP typing technology, which is suitablefor high-density association studies for narrowing-down analyses of candidate regions. We developed a new
method named DigiTag2 (Nishida et al. Anal. Biochem. 2007), which enables us to perform 32-plex or 96-plex
SNP typing with high conversion rates and accuracy without specific instruments.

http://www.humgenet.m.u-tokyo.ac.jp/

18

4. Genome Wide Association Study (GWAS) (1)4. Genome Wide Association Study (GWAS) (1)19

Dec.20

13：00 〜 13：35

Mark McCarthy

Dec.20●Oxford Centre for Diabetes, Endocrinology and Metabolism; andthe Wellcome Trust Centre for Human Genetics, University of
Oxford, Oxford, UK

Masato Kasuga

Sweet dreams: finding genes
Until recently, progress infor diabetes and obesity
identification of the genetic

the main threats to humanvariants influencing predisposition to common forms of diabetes and obesity has been slow. This is in marked

healthcontrast to the large number of genes implicated in rare monogenic forms of both conditions. However, recent

century. The total number ofadvances in genetics, genomics and informatics have transformed the situation, and researchers are now able

people with diabetes world-

to undertake well-powered scans designed to detect association signals across the entire genome.

wide

Diabetes mellitus is one of
in

the

was

twenty-firstestimated

13：35 〜 14：00●Division of Diabetes, Metabolism and Endocrinology,
Department of Internal Medicine,
Kobe University Graduate School of Medicine

Multistage genome-wide
association study of type 2
diabetes mellitus in
Japanese population.

at

For type 2 diabetes, the six genome-wide association studies so far performed (all in samples of Northbetween 151 million and 171 million in 2000 and is projected to increase to 221 million in 2010 and to 366

European origin) have extended the number of loci harbouring common variants implicated in diabetes-

million in 2030. Needless to say, the increase in the number of people with diabetes will be accompanied by ansusceptibility into double figures. Amongst the novel loci identified by this process include variants in/aroundincrease in the number of those with diabetic complications such as nephropathy, retinopathy, neuropathy, andgenes which encode beta-cell zinc transporters (SLC30A8) and putative regulators of beta-cell massatherosclerosis. Type 2 diabetes accounts for more than 90% of cases of diabetes worldwide. The development(CDKN2A/B and CDKAL1). One of these new-found loci, mapping to the fat mass and diabetes associatedof this common form of diabetes results from complex interactions between environmental and genetic(FTO) gene, influences individual risk of type 2 diabetes through a primary effect on fat mass, making this thefactors. It is important to identify the susceptibility genes to type 2 diabetes, to understand the pathogenesis

first common variant known to influence weight and individual risk of obesity.

of this disease and to develop new approaches to its prevention and treatment.

These findings offer two main avenues for clinical translation. First, the identification of new pathways

The recent progress in human genomic science and technology has allowed the undertaking of genome-

involved in disease predisposition - for example, those influencing zinc transport and islet regeneration in thewide association studies with comprehensive single nucleotide polymorphism (SNP) typing. As part of thecase of type 2 diabetes - offers opportunities for development of novel therapeutic and preventative

Millennium Genome Project of Japan, we performed a multistage genome-wide association study of theapproaches. Second, with continuing efforts to identify additional genetic variants, it may become possible tocommon form of type 2 diabetes mellitus with a total of 1612 cases and 1424 controls and with 100,000 SNPs

use patterns of predisposition to tailor individual management of these conditions.

from the standard Japanese polymorphisms (JSNP) database (http://snp.ims.u-tokyo.ac.jp/index_ja.html)

However, it is important to realise that the variants so far identified explain only a small proportion ofgenerated by this project. Successful genotyping results were obtained for 82,343 autosomal SNPs by theoverall susceptibility to these conditions (well below 10 percent), and cannot explain the degree of familial

multiplex PCR-based Invader assay, and 10 SNPs in seven genes showed significant association (P < 0.05).

aggregation which is routinely seen in epidemiological studies. A range of complementary approaches is

Most of these genes previously have not been associated with diabetes in any population. The lowest P value

currently being adopted, by our own group and others, to identify additional type 2 diabetes susceptibility loci,of 2.2 × 10

and to characterise those already found. To find further loci implicated in diabetes and obesity, we are: (a)gene, we examined additional known polymorphisms as well as those revealed by sequencing of the gene in 24

combining data from multiple genome-wide scans, and performing very large-scale replication studies, so as toJapanese subjects. We found that a SNP in “Gene A” showed the lowest P value of 6.7 × 10

increase the power to detect variants of smaller effect; (b) undertaking genome-wide surveys of structural

1.49; 95% confidence interval = 1.34 to 1.66). Among control subjects, the homeostasis model assessment of–12

was obtained for a SNP in “Gene A”. Given that three of the 10 positive SNPs resided in this–13

(odds ratio =variants; and (c) initiating targeted deep resequencing efforts to trap low frequency, intermediate penetrance

β cell function (HOMA-β) was significantly lower (P = 0.0024) in homozygotes for the risk allele of thisvariants that may have escaped attention by classical linkage and association approaches. To characterise thepolymorphism than in individuals with the other two genotypes, suggesting that this allele may be associatedloci already found, we are resequencing the genomic intervals of interest in large patient cohorts, and planningwith impairment of insulin secretion.

large-scale fine-mapping. Finally, we have begun to translate these new discoveries into information of

Our data thus implicated “Gene A” as a susceptibility gene for type 2 diabetes. The identification of thisrelevance to improved clinical management of diabetes and obesity, by focusing on the epidemiological, physi-

genes, as well as other 6 genes in our study may provide insight into the pathogenesis of type 2 diabetes as

ological and pharmacological consequences of the susceptibility variants.

well as a basis for the development of new therapeutic agents.

20

5. Genome Wide Association Study (GWAS) (2)5. Genome Wide Association Study (GWAS) (2)21Dec.20

14：00 〜 14：35

Dec.201

Guy A. Rouleau
1
Julie Gauthier
1
Amelie Piton
2
Fadi Hamdan1
Yan Yang
1
Dan Spiegelman
1
Edouard Henrion
3Marie-Pierre Dubé
4
Pejmun.Haghighi
4
Salvatore Carbonetto
4
Phil Barker
5
Christian Néri
6
Pierre Drapeau●1 Centre for the Study of Brain Disease, CHUM
Research Centre, Notre-Dame Hospital, Montreal,
QC
2 Division of Medical Genetics, Hopital SainteJustine, Montreal, QC
3 Université de Montréal - CRICM
4 McGill University
5 INSERM
6 Université de Montreal, Department of Pathology
and Cellular Biology, Montreal, QC

Large-Scale Identification
And Characterization Of
Developmental Brain
Disease Genes

Emmanouil Dermitzakis

The recent comparative
analysis of the human genome

14：35 〜 15：10●Wellcome Trust Sanger Institute

Causes of regulatory variation in the human genome

has revealed a large fraction of functionally constrained non-coding DNA in mammalian genomes. However,
our understanding of the function of non-coding DNA is very limited. In this talk I will present recent analysis
in my group and collaborators that aims at the identification of functionally variable regulatory regions in thehuman genome by correlating SNPs and copy number variants with gene expression data. I will also bepresenting some analysis on inference of trans regulatory interactions and evolutionary consequences of gene
expression variation.

Schizophrenia (SCZ) and autism(AUT) are common, devastating
and poorly treated mental disorders.

Converging

evidencesuggests that genetically disrupted
synaptogenesis

andsynaptic

plasticity during development may underlie the pathogenesis of such brain disorders. We therefore hypothesize that a significant fraction of SCZ and AUT cases are a result of frequent novel mutations in many different
genes involved in synapse formation and function. Our strategy is to identify the underlying synaptic genetic
factors predisposing to SCZ and AUT by using a new, two-step strategy: first the direct re-sequencing of 1000
genes coding for proteins which regulate an entire brain-specific “machine”, the synapse, in a large number ofpatients, and secondly evaluating the functional effects of disease-related variants of these genes in several
animal models. This will allow us to identify the most promising mutations for future functional genomics
analyses, including transgenic mouse models. In contrast to the all too few mutations discovered to date, we
expect to identify a significant number of genes directly causing or increasing the susceptibility to SCZ and
AUT.

www.sanger.ac.uk/Teams/Team16

22

6. Resequencing and Comprehensive Candidate Genes Analysis of Human Diseases (1)6. Resequencing and Comprehensive Candidate Genes Analysis of Human Diseases (1)23Dec.20

15：20 〜 15：55

Daniela S. Gerhard

Dec.20●NCI/NIH, USA

Hiroyuki Mano, M.D., Ph.D.

The Cancer Genome Atlas
Somatic mutations in the
genome of cancer cells likely
play an essential role in themalignant transformation mecha-

15：55 〜 16：30●Division of Functional Genomics, Jichi
Medical University

Array-based high-throughput
sequencing of leukemia
genomenism, as is already evident in acute myeloid leukemia (AML) cases with the activating mutations in RUNX1,
NPM1, KIT, or NRAS gene. Since a normal karyotype without apparent chromosome abnormalities is identified in the leukemic blasts for >50% of AML cases, sequence alterations in such genome are presumably yet
to be identified.
To discover cancer-promoting mutations in the AML genome, we here developed a large-scale resequencing "wafer" in a collaboration with Perlegen Sciences Inc., which enables the sequence determination
at >nine million nucleotides. Oligonucleotide probes on the wafer were designed to analyze coding regions aswell as splicing signals for the exon/intron boundary among ~5,600 human genes, (1) which are already known
to be mutated in human cancers, and (2) the products of which are involved in DNA repair system, chromosome regulation, redox regulation, intracellular signal transduction, protein kinases, transcriptional factors,
cell cycle regulation, and apoptosis.
For the detection of somatic mutations in AML, we prepared, from a total of twenty AML cases, CD34positive hematopoietic progenitors (“leukemic fraction”) as well as paired CD4-positive normal T-cells(“control fraction”). As the first phase sequencing, genomic DNA of each leukemic fraction was hybridized
with the sequencing wafer, leading to the discovery of a total of >9,000 non-synonymous mutations among>3000 genes on the wafer. We then proceeded to the second phase of the project; another sequencing wafer
was constructed only to determine such non-synonymous mutations, and was subjected to hybridization with aleukemic fraction or with a paired control fraction. Surprisingly, most of the “mutations” identified in theanalysis of leukemic fractions were also present on the genome of the control fractions. Therefore, most ofsuch "mutations" are likely rare polymorphism in the AML genome.
One of the bona fide mutations discovered in the second phase project turned out to lead to a novel aminoacid substitution in a non-receptor-type protein tyrosine kinase. Interestingly, this mutated tyrosine kinase
was shown to acquire a transforming potential. A forced expression of this mutated kinase abrogates cytokinedependency from a hematopoietic cell line, and also substantially inhibit differentiation of blood cells.
Our strategy is thus potent in discovering somatic mutations in cancer genome in a high-throughput
manner.

24

7. Resequencing and Comprehensive Candidate Genes Analysis of Human Diseases (2)7. Resequencing and Comprehensive Candidate Genes Analysis of Human Diseases (2)25