is the recent genetic progress useful for the prediction of … · 2014. 9. 30. · mody6, neurod1....

http://www.hinnovic.org/2008/05/

From Genomics to T2D and Obesity Biomarkers

Is the recent genetic progress useful for the prediction of common diseases?

Nabila Bouatia-Naji, PhDResearch Associate, INSERM

CNRSUMR8090, Institut Pasteur de Lille, France

[email protected]

France UK Canada Denmark CollaborationRob SladekGhislain RocheleauJohan RungStephane CauchiChristian DinaChristine Cavalcanti-ProençaDavid SerreAmélie BonnefondMarjo-Riitta JarvelinDavid J. BaldingDavid MeyreConstantin PolychronakosOluf Pedersen Torben HansenGuillaume CharpentierSamy HadjadjClaire Lévy-MarchalBeverley BalkauMichel MarreJean TichetMarion MarchandJérôme DelplanqueSophie Gallina

ANR-06-PHYSIO-037-02

EURODIA LSHM-CT-2006-518153

Funding

Declare no conflict of interest

N Bouatia-Naji, 10th Dec 2009, Paris

MAGIC investigatorsJosée Dupuis*, Claudia Langenberg*, Inga Prokopenko*, Richa Saxena*, Nicole Soranzo*, Anne U Jackson, Eleanor Wheeler, Nicole L Glazer, Nabila Bouatia-Naji, Anna L Gloyn, Cecilia M Lindgren, Reedik Mägi, Andrew P Morris, Joshua Randall, Toby Johnson, Paul Elliott, Denis Rybin, Gudmar Thorleifsson, ValgerdurSteinthorsdottir, Peter Henneman, Harald Grallert, Abbas Dehghan, Jouke Jan Hottenga, Christopher S Franklin, Pau Navarro, KijoungSong, Anuj Goel, John R B Perry, Josephine M Egan, Taina Lajunen, Niels Grarup, Thomas Sparsø, Alex Doney, Benjamin F Voight, Heather M Stringham, Man Li, Stavroula Kanoni, Peter Shrader, Christine Cavalcanti-Proença, Meena Kumari, Lu Qi, Nicholas J Timpson, Christian Gieger, Carina Zabena, Ghislain Rocheleau, Erik Ingelsson, Ping An, Jeffrey O’Connell, Jian'an Luan, Amanda Elliott, Steven A McCarroll, Felicity Payne, Rosa Maria Roccasecca, François Pattou, Praveen Sethupathy, Kristin Ardlie, YavuzAriyurek, Beverley Balkau, Philip Barter, John P Beilby, Yoav Ben-Shlomo, Rafn Benediktsson, Amanda J Bennett, Sven Bergmann, Murielle Bochud, Eric Boerwinkle, Amélie Bonnefond, Lori L Bonnycastle, Knut Borch-Johnsen, Yvonne Böttcher, Eric Brunner, Suzannah J Bumpstead, Guillaume Charpentier, Yii-Der Ida Chen, Peter Chines, Robert Clarke, Lachlan J M Coin, Matthew N Cooper, Marilyn Cornelis, Gabe Crawford, Laura Crisponi, Ian N M Day, Eco de Geus, Jerome Delplanque, Christian Dina, Michael R Erdos, Annette C Fedson, Antje Fischer-Rosinsky, Nita G Forouhi, Caroline S Fox, Rune Frants, Maria Grazia Franzosi, Pilar Galan, Mark O Goodarzi, Jürgen Graessler, Christopher J Groves, Scott Grundy, Rhian Gwilliam, Ulf Gyllensten, Samy Hadjadj, Göran Hallmans, Naomi Hammond, Xijing Han, Anna-Liisa Hartikainen, Neelam Hassanali, Caroline Hayward, Simon C Heath, Serge Hercberg, Christian Herder, Andrew A Hicks, David R Hillman, Aroon D Hingorani, Albert Hofman, Jennie Hui, Joe Hung, Bo Isomaa, Paul R V Johnson, Torben Jørgensen, Antti Jula, Marika Kaakinen, Jaakko Kaprio, Y Antero Kesaniemi, Mika Kivimaki, Beatrice Knight, SeppoKoskinen, Peter Kovacs, Kirsten Ohm Kyvik, G Mark Lathrop, Debbie A Lawlor, Olivier Le Bacquer, Cécile Lecoeur, Yun Li, ValeriyaLyssenko, Robert Mahley, Massimo Mangino, Alisa K Manning, María Teresa Martínez-Larrad, Jarred B McAteer, Laura J McCulloch, Ruth McPherson, Christa Meisinger, David Melzer, David Meyre, Braxton D Mitchell, Mario A Morken, Sutapa Mukherjee, Silvia Naitza, Narisu Narisu, Matthew J Neville, Ben A Oostra, Marco Orrù, Ruth Pakyz, Colin N A Palmer, Giuseppe Paolisso, Cristian Pattaro, Daniel Pearson, John F Peden, Nancy L. Pedersen, Markus Perola, Andreas F H Pfeiffer, Irene Pichler, Ozren Polasek, Danielle Posthuma, Simon C Potter, Anneli Pouta, Michael A Province, Bruce M Psaty, Wolfgang Rathmann, Nigel W Rayner, Kenneth Rice, Samuli Ripatti, Fernando Rivadeneira, Michael Roden, Olov Rolandsson, Annelli Sandbaek, Manjinder Sandhu, Serena Sanna, AvanAihie Sayer, Paul Scheet, Laura J Scott, Udo Seedorf, Stephen J Sharp, Beverley Shields, Gunnar Sigurðsson, Erik J G Sijbrands, Angela Silveira, Laila Simpson, Andrew Singleton, Nicholas L Smith, Ulla Sovio, Amy Swift, Holly Syddall, Ann-Christine Syvänen, Toshiko Tanaka, Barbara Thorand, Jean Tichet, Anke Tönjes, Tiinamaija Tuomi, André G Uitterlinden, Ko Willems van Dijk, Mandy van Hoek, Dhiraj Varma, Sophie Visvikis-Siest, Veronique Vitart, Nicole Vogelzangs, Gérard Waeber, Peter J Wagner, Andrew Walley, G Bragi Walters, Kim L Ward, Hugh Watkins, Michael N Weedon, Sarah H Wild, Gonneke Willemsen, Jaqueline C M Witteman, John W G Yarnell, Eleftheria Zeggini, Diana Zelenika, Björn Zethelius, Guangju Zhai, Jing Hua Zhao, M Carola Zillikens, DIAGRAM Consortium, GIANT Consortium, Global BPgen Consortium, Ingrid B Borecki, Ruth J F Loos, Pierre Meneton, Patrik K E Magnusson, David M Nathan, Gordon H Williams, Andrew T Hattersley, Kaisa Silander, Veikko Salomaa, George Davey Smith, Stefan R Bornstein, Peter Schwarz, Joachim Spranger, Fredrik Karpe, Alan R Shuldiner, Cyrus Cooper, George V Dedoussis, Manuel Serrano-Ríos, Andrew D Morris, Lars Lind, Lyle J Palmer, Frank B Hu, Paul W Franks, Shah Ebrahim, Michael Marmot, W H Linda Kao, James S Pankow, Michael J Sampson, Johanna Kuusisto, Markku Laakso, Torben Hansen, Oluf Pedersen, Peter Paul Pramstaller, H Erich Wichmann, Thomas Illig, Igor Rudan, Alan F Wright, Michael Stumvoll, Harry Campbell, James F Wilson, Anders Hamsten on behalf of Procardisconsortium, Richard N Bergman, Thomas A Buchanan, Francis S Collins, Karen L Mohlke, Jaakko Tuomilehto, Timo T Valle, David Altshuler, Jerome I Rotter, David S Siscovick, Brenda W J H Penninx, Dorret Boomsma, Panos Deloukas, Timothy D Spector, Timothy M Frayling, Luigi Ferrucci, Augustine Kong, Unnur Thorsteinsdottir, Kari Stefansson, Cornelia M van Duijn, Yurii S Aulchenko, Antonio Cao, Angelo Scuteri, David Schlessinger, Manuela Uda, Aimo Ruokonen, Marjo-Riitta Jarvelin, Dawn M Waterworth, Peter Vollenweider, Leena Peltonen, Vincent Mooser, Goncalo R Abecasis, Nicholas J Wareham, Robert Sladek, Philippe Froguel, Richard M Watanabe, James B Meigs, Leif Groop, Michael Boehnke†, Mark I McCarthy†, Jose C Florez†, and Inês Barroso† N Bouatia-Naji, 10th Dec 2009, Paris

Diabetes Current and Predicted Prevalence Around the World

WHO (http://www.who.int/diabetes)N Bouatia-Naji, 10th Dec 2009, Paris

DT2

Sedentary occupation

Lack of exercise

Nutrition

In utero

Hypertension

Nephropathy Retinopathy

CVD

Neuropathy

Obesity

Type 2 Diabetes: Complex Disease with Severe and Concomitant Health Complications


MODY Genes involved in pancreatic beta-cell function>2% of T2D cases

Glucokinase

MODY1, HNF4αMODY2, GlucokinaseMODY3, HNF1αMODY4, IPF-1 MODY5, HNF1β MODY6, NeuroD1


DT2Gene 4

Gene 3

Gene 5

Gene 13

Gene 9

Gene 12

Gene 11

Gene 8Gene 7

Gene 10Gene 6

Gene 2 Gene 14

Gene 1 Gene n

Small Effects

Type 2 Diabetes : Complex Genetic Disease Heritability ~ 30 to 40%

Lack of Physical Activity Nutrition

Obesity

Environment


T2D Gene List until Early 2007…

Provided by Oluf Pedersen

3) High DensityGenotyping Arrays

1) Human genomeSequence Project

2) Haplotype maps

Genomics Milestones toward Genome Wide Association Studies

2006

2007

2001-04 2005

4) Genome-WideAssociation Studies (GWAS)


T2D Genes List Increased from GWAS Two Years Later (Early 2009)


Sladek et al., Nature 2007 (T2D)Bouatia-Naji et al., Science 2008 (Fasting Glucose)Bouatia-Naji et al., Nat Genet 2009 (Fasting Glucose)

Pancreatic Profile

GWAS odds ratios for BMI/Obesity represented by the closest gene to the associated SNP marker (N= 20)

Dina et al 2007

Obesity Genes List Increased from GWAS (Early 2009)Brain Profile

Meyre et al., Nat Genet 2009 (Obesity)


Nat Rev Genet. 2008 Nov;9(11):819-30

Genes to be identified

T2D Genes Obesity Genes


What Have We Done In the Last Months in T2D Field?

Large Meta-analyses Within Consortia Approach

Large Homogeneous Multistage Approach

MAGICDIAGRAMFrench / Canadian Collaboration

Zeggini et al. NG 2008

Voight et al, in preparation

Dupuis et al 2009, in pressSaxena et al 2009, in pressSoranzo et al, submitted


Rung et al, Nat Genet 2009

Rung et al, Nat Genet, 2009

Multistage approach: maximum cost effective power


•62 SNPs show association (based on inflexion point at p=7 x 10-4)•tested in Stage 3 cohort from Denmark•3,334 cases + 4,364 controls•in addition to association for TCF7L2,•5 SNPs reach genome-wide significance

Multistage Approach Findings

N Bouatia-Naji, 10th Dec 2009, Paris Rung et al, Nat Genet, 2009

Multistage approach: first insulin resistance locus identified using GWAS

Rung et al, Nat Genet, 2009N Bouatia-Naji, 10th Dec 2009, Paris




MAGICDIAGRAMFrench / Canadian Collaboration

Rung et al, Nat Genet 2009 Dupuis et al 2009, in pressSaxena et al 2009, in pressSoranzo et al, submitted




OR (95%CI) p‐value Power

up to 43,370 cases

Novel loci and 101,150 controls

CENTD2 1.14 (1.11‐1.17) 1.4 x 10‐22 0,73BCL11A 1.08 (1.06‐1.10) 2.9 x 10‐15 0,77KCNQ1 1.08 (1.06‐1.10) 2.8 x 10‐13 0,76ZBED3 1.08 (1.06‐1.11) 2.8 x 10‐12 0,60KLF14 1.07 (1.05‐1.10) 2.2 x 10‐10 0,53PRC1 1.07 (1.05‐1.09) 2.4 x 10‐10 0,30

TP53INP1 1.06 (1.04‐1.09) 9.9 x 10‐10 0,31ZFAND6 1.06 (1.04‐1.08) 2.4 x 10‐9 0,27HMGA2 1.10 (1.07‐1.14) 3.6 x 10‐9 0,37HNF1A 1.07 (1.05‐1.10) 2.4 x 10‐8 0,09CHCHD9 1.11 (1.07‐1.15) 2.8 x 10‐8 0,12

Known lociIRS1 1.11 (1.08‐1.13) 5.4 x 10‐20 0,98

MTNR1B 1.09 (1.06‐1.11) 7.8 x 10‐15 0,82

T2D Gene


Case Control Consortium Approach DIAGRAM: 30 Confirmed Susceptibility Genes





DIAGRAMFrench / Canadian Collaboration

Rung et al, Nat Genet 2009

MAGIC

Dupuis et al 2009, in pressSaxena et al 2009, in press




Quantitative Traits Approach: understand the physiology and discover new T2D susceptibility genes

PopulationN

Controls T2D

QTG6PC2 variantsPhysiological glucose variation

MTNR1B variants

Hyperglycemia and T2D


9 novel FG loci identified, including 3 new T2D susceptibility loci (boxed)

G6PC2

GCK

MTNR1B

GCKR DGKBPROX1

ADCY5SLC2A2 GLIS3

ADRA2AMADD

FADS1

CRY2

FAM148BSLC30A8 TCF7L2

Dupuis et al, MAGIC, Nat Genet (in press)

MAGIC: Meta-Analyses of Glucose and Insulin related traits Consortium

Fasting glucose study follow-up


GCKRIGF1

MAGIC: Insulin Resistance traits

With IRS1, IGF1 is a 2nd Insulin resistance locus identified using GWAS

Dupuis*, et al for MAGIC Nat Genet (in press)


MAGIC: 2h glucose levels after glucose challenge

First GWAS for 2h glucose GIPR: an incretin effect locus, ADCY5 a new T2D

Saxena et al, MAGIC, Nat Genet (in press)


Important progress in the genetic basis of T2D….

…What about the predictionpower of these new markers?


Limited predictive power for the newly identifiedT2D loci

N=19, Sparso et al Diabetologia 2009


Limited predictive power for the newly identified T2D loci, compared to clinical factors

N=12, Lyssenko et al NEJM 2008

Slightly improved predictive power for individuals with family history of T2D, (Meigs et al. NEJM 2008, Lyssenko et al NEJM 2008)


Lessons from other common diseasesInternational Schizophrenia Consortium, Nature 2009


We know more about T2D genetics but…


T2D

T2DRisk Genes

Epigenetics

Family Habits

Improve the target: young at high risk

Young offspring at high risk: more appropriate to prediction and prevention


Summary


• Progress in the genetics of metabolic disorders has been made thanks to GWAS T2D (insulin secretion default) and obesity (brain and food intake default)

• In addition to large case control consortia, multistage stage approach proved to be efficient and provided the first insulin resistance loci

• The study of quantitative traits related to T2D, individually and within consortia: helping to understand physiology and identify new T2D loci (MTNR1B, ADCY5)

• Predictive power is low because of the small proportion of variance explained (missing heritability is still important)

• Target the appropriate sub-population (young at high risk) combining both clinical and genetic markers

http://www.hinnovic.org/2008/05/

Questions are welcome!


is the recent genetic progress useful for the prediction of … · 2014. 9. 30. · mody6, neurod1....

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