The New Biology: From Science in The New Biology: From Science in the Modern World to the the Modern World to the

Genetics of DiabetesGenetics of Diabetes

Gilbert S. Omenn, M.D., Ph.D.Gilbert S. Omenn, M.D., Ph.D.University of Michigan, Ann Arbor, MI, USAUniversity of Michigan, Ann Arbor, MI, USA

SuperCourse of Science ConferenceSuperCourse of Science Conference 6 January 20096 January 2009

Bibliotheca Alexandrina, EgyptBibliotheca Alexandrina, Egypt

A Call for Renewal of Science in A Call for Renewal of Science in Muslim CountriesMuslim Countries

Our Muslim forefathers first held up the torch of Our Muslim forefathers first held up the torch of rationality, tolerance, and advancement of rationality, tolerance, and advancement of knowledge throughout the Dark Ages of knowledge throughout the Dark Ages of medieval Europe. [astronomy, math, chemistry]medieval Europe. [astronomy, math, chemistry]

Ibn Al-Haytham (10Ibn Al-Haytham (10thth C) laid down rules for the C) laid down rules for the scientific method of observation, experiment, scientific method of observation, experiment, and search for truth. Ibn Al-Nafis (13and search for truth. Ibn Al-Nafis (13 thth C) C) emphasized respect for contrarian views to be emphasized respect for contrarian views to be tested with evidence. Then came Taqlid.tested with evidence. Then came Taqlid.

Science requires freedom to enquire, challenge, Science requires freedom to enquire, challenge, think, and envision the unimagined.think, and envision the unimagined.

--Ismail Serageldin, SCIENCE 8-08-08--Ismail Serageldin, SCIENCE 8-08-08

Education is the most powerful weapon which you can use to change the world.

Nelson

Mandela

The Bibliotheca AlexandrinaThe Bibliotheca Alexandrina

A beacon and compass for science, education, A beacon and compass for science, education, and peace in the Muslim world and the broader and peace in the Muslim world and the broader developing worlddeveloping world

An institution with a stunning legacy, magnificent An institution with a stunning legacy, magnificent architecture, a splendid leader, fully digitalized architecture, a splendid leader, fully digitalized resources, and remarkable, diverse initiatives, resources, and remarkable, diverse initiatives, including—among many others---the including—among many others---the SuperCourse of Science.SuperCourse of Science.

A leading force for cooperation and collaboration A leading force for cooperation and collaboration among equals between North and South.among equals between North and South.

Europe: Investing in IntelligenceEurope: Investing in Intelligence

“ “Research and innovation are the main Research and innovation are the main keys to Europe’s development. They are keys to Europe’s development. They are also the most efficient way to respond to also the most efficient way to respond to the challenges set by Asia’s large the challenges set by Asia’s large emerging economies and to lay the emerging economies and to lay the foundation for sustainable development for foundation for sustainable development for the entire planet.”the entire planet.”

---Nicolas Sarkozy---Nicolas Sarkozy 14 May, 200814 May, 2008

FRONTIER SCIENCE AND GRAND FRONTIER SCIENCE AND GRAND CHALLENGES: INVESTING IN HIGH-CHALLENGES: INVESTING IN HIGH-

POTENTIAL INDIVIDUALS AND HIGH-POTENTIAL INDIVIDUALS AND HIGH-PAYOFF SCIENTIFIC FIELDSPAYOFF SCIENTIFIC FIELDS

Gilbert S. OmennGilbert S. Omenn

University of MichiganUniversity of Michigan

French Presidency of the EUFrench Presidency of the EU

Symposium Celebrating Frontier ScienceSymposium Celebrating Frontier Science

Paris, 7 October, 2008Paris, 7 October, 2008

Kudos to the EU on the Launch of the Kudos to the EU on the Launch of the Frontiers of Science ProgramFrontiers of Science Program

Investments in young scientists and their Investments in young scientists and their individual investigator-initiated projectsindividual investigator-initiated projects

Sufficient funding to make a differenceSufficient funding to make a difference

High standardsHigh standards

The “Ideas Program”, complementary to The “Ideas Program”, complementary to the 7the 7thth Framework cooperative networks Framework cooperative networks

Congratulations to those honored todayCongratulations to those honored today

The rest of the world has noticed!The rest of the world has noticed!

Grand Challenges for S&T and SocietyGrand Challenges for S&T and Society

1.1. Pursue the unknowns in each scientific Pursue the unknowns in each scientific discipline from math to biology to discipline from math to biology to education.education.

2.2. Mobilize multidisciplinary research and Mobilize multidisciplinary research and development for food security, energy, development for food security, energy, health, green chemistry.health, green chemistry.

3.3. Combine S&T with political will and social Combine S&T with political will and social purpose to overcome poverty and hunger, purpose to overcome poverty and hunger, scarcity of water, and climate change, for scarcity of water, and climate change, for sustainable economic development.sustainable economic development.

--G.S. Omenn, SCIENCE 15 Dec 2006--G.S. Omenn, SCIENCE 15 Dec 2006

Obama Statement on ScienceObama Statement on Science

Saturday December 13 announcement of Saturday December 13 announcement of Presidential Science and Technology Adviser Presidential Science and Technology Adviser John Holdren, Co-Chairs of President’s John Holdren, Co-Chairs of President’s Committee of Advisers on Science and Committee of Advisers on Science and Technology (PCAST) genetics pioneers Harold Technology (PCAST) genetics pioneers Harold Varmus and Eric Lander, and ecologist Jane Varmus and Eric Lander, and ecologist Jane LubchencoLubchenco

Affirmation of the importance of scienceAffirmation of the importance of science

Commitment to integrity of review of scientific Commitment to integrity of review of scientific issues—expect support for stem cell research, issues—expect support for stem cell research, teaching of evolution, and control of greenhouse teaching of evolution, and control of greenhouse gases/climate change.gases/climate change.

U.N. MILLENIUM DEVELOPMENT GOALSU.N. MILLENIUM DEVELOPMENT GOALS

These goals for peace, security, development, human rights These goals for peace, security, development, human rights and fundamental freedoms (1990 to 2015) are people-and fundamental freedoms (1990 to 2015) are people-centered, time-bound, and measurable. centered, time-bound, and measurable.

1.1. Eradicate extreme poverty (<$1/day; 1 billion people) Eradicate extreme poverty (<$1/day; 1 billion people) and hunger--by 50%and hunger--by 50%2.2. Achieve universal primary education for boys and girlsAchieve universal primary education for boys and girls3.3. Promote gender equality and empower womenPromote gender equality and empower women4.4. Reduce child mortality rate before age 5 by 67% Reduce child mortality rate before age 5 by 67% 5.5. Improve maternal health--reduce mortality ratio by 75%Improve maternal health--reduce mortality ratio by 75%6.6. Combat HIV/AIDS, malaria and other diseases---begin to Combat HIV/AIDS, malaria and other diseases---begin to reverse incidence and spreadreverse incidence and spread7.7. Ensure environmental sustainabiity--50% reduction in Ensure environmental sustainabiity--50% reduction in those without safe drinking waterthose without safe drinking water8. Develop a global partnership for development8. Develop a global partnership for development

GRAND CHALLENGES IN GLOBAL INFECTIOUS GRAND CHALLENGES IN GLOBAL INFECTIOUS DISEASES (7 Goals, 14 Challenges)—Gates FoundationDISEASES (7 Goals, 14 Challenges)—Gates Foundation

Improve childhood vaccines (3)Improve childhood vaccines (3)

Create new vaccines (3)Create new vaccines (3)

Control insects that transmit agents of Control insects that transmit agents of disease (2)disease (2)

Improve nutrition to promote health (1)Improve nutrition to promote health (1)

Improve drug treatment of infectious Improve drug treatment of infectious diseases (1)diseases (1)

Cure latent and chronic infection (2) Cure latent and chronic infection (2)

Measure health status accurately and Measure health status accurately and economically (2)economically (2)

It’s a New World in Life SciencesIt’s a New World in Life SciencesNew Biology---New TechnologyNew Biology---New TechnologyGenome Expression MicroarraysGenome Expression MicroarraysComparative Genomics, Epigenetics, Comparative Genomics, Epigenetics,

miRNA Gene RegulationmiRNA Gene RegulationProteomics, incl alternative splice isoformsProteomics, incl alternative splice isoformsBioinformaticsBioinformaticsSystems BiologySystems Biology

Path to predictive, personalized, preventive (P3) healthcare

Biology as an Information Science: Biology as an Information Science: Historical MilestonesHistorical Milestones

The molecule of inheritance is DNA, not protein: 1944The molecule of inheritance is DNA, not protein: 1944The Watson-Crick double-helix model of DNA permits The Watson-Crick double-helix model of DNA permits transcription and replication and mutations: 1953transcription and replication and mutations: 195346, not 48, human chromosomes: 195646, not 48, human chromosomes: 1956The triplet code for proteins demonstrated: 1960 The triplet code for proteins demonstrated: 1960 The principle of “unity in diversity” applies to all living The principle of “unity in diversity” applies to all living things---at all levels from molecules to cells to organ things---at all levels from molecules to cells to organ functions to ecosystemsfunctions to ecosystemsSystems biology combines the digital code of genetics Systems biology combines the digital code of genetics with environmental and behavioral inputs and with environmental and behavioral inputs and perturbations (Leroy Hood)perturbations (Leroy Hood)Latest: Synthetic Biology (George Church)Latest: Synthetic Biology (George Church)

The DNA Pioneers

The Historic Weekend of Feb 15-16, 2001

Eric Lander

Ari Patrinos

J. Craig Venter and Francis Collins

U.S. Leaders of the Human Genome Project

Protein DNA

Avalanche of Genomic InformationAvalanche of Genomic InformationThe International HapMap Consortium aims to The International HapMap Consortium aims to genotype 1 million SNPs from 270 individuals.genotype 1 million SNPs from 270 individuals.Direct associations of individual SNP alleles with Direct associations of individual SNP alleles with disease phenotypes (including linkage disease phenotypes (including linkage disequilibrium, LD) are more powerful than disequilibrium, LD) are more powerful than linkage-based indirect association analyses.linkage-based indirect association analyses.dbSNP has >10 million validated SNPs.dbSNP has >10 million validated SNPs.Haplotype structures can be obtained via Haplotype structures can be obtained via genome-wide LD, haplotype blocks (1 KB to 1 genome-wide LD, haplotype blocks (1 KB to 1 MB), and haplotype-tagging SNPs, respecting MB), and haplotype-tagging SNPs, respecting recombination hotspots and variable LD.recombination hotspots and variable LD.

ESTIMATED COSTS OF GENOTYPINGESTIMATED COSTS OF GENOTYPING

When Human Genome sequence published in When Human Genome sequence published in 2001, along with 10M common SNPs identified, 2001, along with 10M common SNPs identified, proposed case/control studies of 1000 + 1000 proposed case/control studies of 1000 + 1000 participants with 20B genotypes @ $0.50 had cost participants with 20B genotypes @ $0.50 had cost estimate of $10B. estimate of $10B.

HapMap brought cost of 300,000 tagging SNPs @ HapMap brought cost of 300,000 tagging SNPs @ $0.003 to $2M per common disease (5000x $0.003 to $2M per common disease (5000x decrease in 4 years).decrease in 4 years).

Now we have even more powerful analyses with Now we have even more powerful analyses with “next-generation sequencing of the genome”“next-generation sequencing of the genome”

Computational muscle: “Skate where the puck is Computational muscle: “Skate where the puck is gonna be” (Gretzky) in planning big studiesgonna be” (Gretzky) in planning big studies

A Golden Age for the A Golden Age for the Public Health SciencesPublic Health Sciences

Sequencing and analyzing the human Sequencing and analyzing the human genome is generating genetic information genome is generating genetic information that must be linked with information that must be linked with information about:about:• Nutrition and metabolismNutrition and metabolism• Lifestyle behaviorsLifestyle behaviors• Diseases and medications Diseases and medications • Microbial, chemical, physical exposuresMicrobial, chemical, physical exposures

Every discipline of public health sciences Every discipline of public health sciences neededneeded..

NIH National Centers for Biomedical Computing

Informatics for IntegratingBiology and the Bedside (i2b2)Isaac Kohane, PI

Center for Computational Biology(CCB) Arthur Toga, PI

Multiscale Analysis of Genomicand Cellular Networks (MAGNet)Andrea Califano, PI

National Alliance for MedicalImaging Computing (NA-MIC)Ron Kikinis, PI

The National Center ForBiomedical Ontology (NCBO)Mark Musen, PI

Physics-Based Simulation ofBiological Structures (SIMBIOS)Russ Altman, PI

National Center for Integrative Biomedical Informatics (NCIBI) Brian D. Athey, PI

Multi- and Interdisciplinary Research will be Multi- and Interdisciplinary Research will be Required to Solve the “Puzzle” of Complex Required to Solve the “Puzzle” of Complex

Diseases and Conditions—such as DiabetesDiseases and Conditions—such as Diabetes

GenesBehaviorDiet/NutritionInfectious agentsEnvironment Society???

44,000 Faculty3500 Universities

174 Countries

Supercourse Mirror SitesSupercourse Mirror Sites

42 Mirrored Sites,MOH Egypt, Sudan, China, Mongolia, Russia

East-West Collaboration

A.Husseini (Birzeit University, West A.Husseini (Birzeit University, West Bank): “Diabetes in the Arab World”, Bank): “Diabetes in the Arab World”,

from the SuperCoursefrom the SuperCourse

Prevalence Estimates of Diabetes in selected Prevalence Estimates of Diabetes in selected

Arab Countries > 20 Years old in the Year 2025Arab Countries > 20 Years old in the Year 2025 Dev Countries/World/Tunisia/Oman/Saudi Arabia/Dev Countries/World/Tunisia/Oman/Saudi Arabia/EgyptEgypt

                                                 Prevalence Estimates of Diabetes in selected Arab Countries > 20 Years in the year 2025

Genetics of Diabetes and Its Genetics of Diabetes and Its

Complications: Layers of ComplexityComplications: Layers of Complexity

Craig L. Hanis, Ph.D., University of Texas at Houston; delivered at Univ Pittsburgh,

23 October, 2001

#1 ranked “Genetics and Diabetes” lecture at www.pitt.edu/~super1/

Rising Interest in the Genetics of Rising Interest in the Genetics of Diabetes and Its ComplicationsDiabetes and Its Complications

0

50

100

150

200

250

300

350Publications

1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000

A Brief History of the Genetics A Brief History of the Genetics of Diabetesof Diabetes

Nightmare

Headache

Heterogeneity

Complexity

Interactions

Linkage

Disequilibrium

Complex InheritanceComplex Inheritance

Model Free Linkage ApproachesModel Free Linkage Approaches– Affected PairsAffected Pairs

Concordant Sib PairsConcordant Sib Pairs

Discordant Sib PairsDiscordant Sib Pairs

Association Based MappingAssociation Based Mapping– Transmission Disequilibrium TestingTransmission Disequilibrium Testing

Parent - Offspring Trios (pairs)Parent - Offspring Trios (pairs)– Traditional AssociationsTraditional Associations

SNP-based mappingSNP-based mapping

Fine MappingFine Mapping

Ultimately a search for association Ultimately a search for association of disease with single-nucleotide of disease with single-nucleotide polymorphisms (SNP)polymorphisms (SNP)Criteria for selecting samplesCriteria for selecting samples– Affected/UnaffectedAffected/Unaffected– Segregating/Non-segregatingSegregating/Non-segregating– Haplotype DeterminationHaplotype Determination

enhanced by pedigrees?enhanced by pedigrees?

Type 2 Diabetes in 3 Ethnic GroupsType 2 Diabetes in 3 Ethnic Groups

0%10%20%30%40%50%60%70%

Prevalence

35-44 45-54 55-64 65-74 75+

Age Category

Pima Indians Starr County USPHS

Genome-Wide Association (GWA) Studies Genome-Wide Association (GWA) Studies GWA studies represent a systematic search with nucleic GWA studies represent a systematic search with nucleic acid probes (chips) for variants in the genome acid probes (chips) for variants in the genome statistically associated with particular diseases or traits.statistically associated with particular diseases or traits.““Next-generation sequencing” is replacing chip arrays.Next-generation sequencing” is replacing chip arrays.Only 2% of the DNA codes for protein products, so few Only 2% of the DNA codes for protein products, so few of these variants actually occur in such coding genes, of these variants actually occur in such coding genes, but they may still influence regulation of gene function.but they may still influence regulation of gene function.Tremendous investment and output past several yearsTremendous investment and output past several years

has transformed the genetic side of molecular has transformed the genetic side of molecular epidemiology, but neglected non-genetic variablesepidemiology, but neglected non-genetic variablesVariants give clues to unsuspected genes and pathways Variants give clues to unsuspected genes and pathways potentially involved in diseases like diabetes mellitus.potentially involved in diseases like diabetes mellitus.

I focus rest of the lecture on genomics and diabetes, as a I focus rest of the lecture on genomics and diabetes, as a bridge to the WHO course starting today on bridge to the WHO course starting today on Epidemiology of Diabetes.Epidemiology of Diabetes.

First GWA Studies for T2DMFirst GWA Studies for T2DM

In 2007, five GWA studies were reported: In 2007, five GWA studies were reported: They replicated earlier evidence for three genome They replicated earlier evidence for three genome

variants: TCF7L2, PPARG, and KCNJ11.variants: TCF7L2, PPARG, and KCNJ11.They identified at least six additional variants in or They identified at least six additional variants in or

near these loci: SLC30A8, IGF2BP2, FTO, near these loci: SLC30A8, IGF2BP2, FTO, HHEX-IDE, CDKAL1, CDKN2A-CDKN2B.HHEX-IDE, CDKAL1, CDKN2A-CDKN2B.

Only one (SLC30A8) is a likely functional variant at Only one (SLC30A8) is a likely functional variant at the protein level.the protein level.

Variants in FTO are associated also with body Variants in FTO are associated also with body mass index.mass index.

Interpretation of GWA Studies of Interpretation of GWA Studies of Type 2 DiabetesType 2 Diabetes

These studies are unbiased by previous These studies are unbiased by previous hypotheses of predisposing geneshypotheses of predisposing genes

The results are limited by modest effects and The results are limited by modest effects and need for stringent statistical thresholds and very need for stringent statistical thresholds and very large sample sizes.large sample sizes.

The largest allelic OR for any established variant The largest allelic OR for any established variant is <= 1.35 for TCF7L2; at least nine others (now is <= 1.35 for TCF7L2; at least nine others (now about 20) have OR 1.1-1.2.about 20) have OR 1.1-1.2.

The aggregate attributable risk is <10 percent.The aggregate attributable risk is <10 percent.

Meta-Analysis of GWA Data for Meta-Analysis of GWA Data for Susceptibility Loci for Type 2 DiabetesSusceptibility Loci for Type 2 Diabetes

[[Zeggini et al, Nature Genetics 2008]Zeggini et al, Nature Genetics 2008]

Common variants at multiple loci have modest Common variants at multiple loci have modest but reproducible association with risk of T2DM.but reproducible association with risk of T2DM.Three studies combined (DGI, FUSION, Three studies combined (DGI, FUSION, WTCCC): 10,128 individuals of European WTCCC): 10,128 individuals of European descent; 2.2 million SNPs genotyped/extended descent; 2.2 million SNPs genotyped/extended with imputed SNPs from haplotype variationwith imputed SNPs from haplotype variationUsed both Affy 500K and Illumina 317K chipsUsed both Affy 500K and Illumina 317K chipsTried to replicate findings analysis for 11 Tried to replicate findings analysis for 11 variants with p<10-5 with 53,975 samplesvariants with p<10-5 with 53,975 samplesFound at least six more previously unknown loci: Found at least six more previously unknown loci: JAZF1, CDC123-CAMK1D, TSPAN8-LGR5, JAZF1, CDC123-CAMK1D, TSPAN8-LGR5, THADA, ADAMTS9, NOTCH2. The first three THADA, ADAMTS9, NOTCH2. The first three are probably associated with insulin release.are probably associated with insulin release.

Complementary Strategy: GWA Studies of Complementary Strategy: GWA Studies of Risk Factors for T2 DiabetesRisk Factors for T2 Diabetes[Mohlke et al, Hum Mol Genetics 2008][Mohlke et al, Hum Mol Genetics 2008]

Classic genetic epidemiology studies estimate Classic genetic epidemiology studies estimate genetic effects explain 25% of variance for 20 genetic effects explain 25% of variance for 20 measures of cardiovascular function, 51% for measures of cardiovascular function, 51% for five anthropologic measures, and 40%s for 38 five anthropologic measures, and 40%s for 38 blood tests, including cholesterol and blood tests, including cholesterol and metabolism.metabolism.They reviewed GWA studies of >200,000 SNPs They reviewed GWA studies of >200,000 SNPs that reported at least one SNP exceeding that reported at least one SNP exceeding statistical significance threshold of p<5x10-8 for statistical significance threshold of p<5x10-8 for cholesterol and lipid levels, obesity, myocardial cholesterol and lipid levels, obesity, myocardial infarction, or coronary heart disease.infarction, or coronary heart disease.

Cholesterol, Lipoproteins, LipidsCholesterol, Lipoproteins, Lipidsand CRP and CRP [Mohlke et al, Hum Mol Genetics 2008][Mohlke et al, Hum Mol Genetics 2008]

Glucokinase regulator (GCKR) initially Glucokinase regulator (GCKR) initially associated with triglyceridesassociated with triglyceridesThen with HDL-C, LDL-C, TG and 11 additional Then with HDL-C, LDL-C, TG and 11 additional previously reported SNP variants and 7 new locipreviously reported SNP variants and 7 new lociSNPs near SORT1-PSRC1-CELSR2 loci were SNPs near SORT1-PSRC1-CELSR2 loci were associated with LDL-C; a SNP explained 58-associated with LDL-C; a SNP explained 58-86% of the inter-individual variability in transcript 86% of the inter-individual variability in transcript levels for these three neighboring genes.levels for these three neighboring genes.7 variants are associated with C-reactive protein 7 variants are associated with C-reactive protein levels, including CRP itself, APOE, leptin levels, including CRP itself, APOE, leptin receptor, and HNF1 homeobox A (HNF1A).receptor, and HNF1 homeobox A (HNF1A).

Fat Mass and Obesity GenesFat Mass and Obesity Genes

A 2005 review cited 127 gene candidates and 253 A 2005 review cited 127 gene candidates and 253 quantitative trait loci reported from linkage studies quantitative trait loci reported from linkage studies of obesity. Hardly any were confirmed.of obesity. Hardly any were confirmed.

In 2007 two independent GWA studies identified In 2007 two independent GWA studies identified obesity-associated variants in the first intron of the obesity-associated variants in the first intron of the FTO gene; now replicated many times. FTO FTO gene; now replicated many times. FTO encodes a 2-oxoglutarate-dependent nucleic acid encodes a 2-oxoglutarate-dependent nucleic acid demethylase whose relation to obesity or BMI is demethylase whose relation to obesity or BMI is not yet understood.not yet understood.

Informative HeterogeneityInformative Heterogeneity

The initial association of FTO with diabetes was The initial association of FTO with diabetes was not replicated in several well-powered GWA not replicated in several well-powered GWA studies.studies.

Whether or not FTO turns up in T2DM GWA Whether or not FTO turns up in T2DM GWA studies depends entirely on the inclusion criteria studies depends entirely on the inclusion criteria for cases—if obese individuals are excluded, as for cases—if obese individuals are excluded, as in the GWA studies above, FTO is not in the GWA studies above, FTO is not associated; if they are included, FTO is associated; if they are included, FTO is associated (indirectly) with T2DM.associated (indirectly) with T2DM.

Obesity and MC4R (chromosome 18q21)Obesity and MC4R (chromosome 18q21)

Two recent large GWA studies for obesity-Two recent large GWA studies for obesity-related traits identified associated SNPs near the related traits identified associated SNPs near the melanocortin-4 receptor (MC4R) gene. This melanocortin-4 receptor (MC4R) gene. This receptor is a major target in drug development receptor is a major target in drug development for obesity. Mutations in MC4R can produce a for obesity. Mutations in MC4R can produce a rare extreme form of childhood obesity.rare extreme form of childhood obesity.BMI, insulin resistance, and waist circum-BMI, insulin resistance, and waist circum-ference were associated with these variants 188 ference were associated with these variants 188 kb downstream of MC4R. What is actually kb downstream of MC4R. What is actually happening with these allelic substitutions is happening with these allelic substitutions is unknown, but under investigation.unknown, but under investigation.Together FTO and MC4R account for only 1.2 Together FTO and MC4R account for only 1.2 kg/m2 variation in BMI in adults.kg/m2 variation in BMI in adults.

Other Quantitative Metabolic VariablesOther Quantitative Metabolic Variables

For fasting glucose level, there are For fasting glucose level, there are common sequence variants in glucokinase common sequence variants in glucokinase (GCK) promoter and in islet-specific (GCK) promoter and in islet-specific glucose-6-phosphatase, catalytic 2 glucose-6-phosphatase, catalytic 2 (G6PC2).(G6PC2).

Uric acid levels are associated with Uric acid levels are associated with variants at solute carrier/glucose variants at solute carrier/glucose transporter SLC2A9.transporter SLC2A9.

Surprisingly, none for high blood pressure Surprisingly, none for high blood pressure or systolic or diastolic blood pressures.or systolic or diastolic blood pressures.

Evidence for Association of T2DM with Several Traits on Chromosome 9p21: SNPs in 10,128 GWA samples. Arrows =

locations of SNPs. Black bars = recombination hotspots. Genes and transcripts at the bottom.

Stature/Height—Heritability >0.8Stature/Height—Heritability >0.8[Sanna et al and Lettre et al, Nature Genetics 2008][Sanna et al and Lettre et al, Nature Genetics 2008]

Body mass index comprises height and weight Body mass index comprises height and weight measures.measures.Several rare mutations are definitely associated with Several rare mutations are definitely associated with height in Mendelian syndromesheight in Mendelian syndromesCommon variants in transcription factor HMGA2 are Common variants in transcription factor HMGA2 are associated with height in the general population.associated with height in the general population.GWA studies from Finland and Sardinia reveal an GWA studies from Finland and Sardinia reveal an association of osteoarthritis-associated locus GDF5-association of osteoarthritis-associated locus GDF5-UQCC---perhaps through bone growth [Sanna et al]UQCC---perhaps through bone growth [Sanna et al]With six populations, 10 additional loci have now been With six populations, 10 additional loci have now been associated [Lettre et al], and the two above confirmed; associated [Lettre et al], and the two above confirmed; however, together they (and others) account for just 2 however, together they (and others) account for just 2 percent of population variation in height. They do expand percent of population variation in height. They do expand our ideas of biological regulation of height.our ideas of biological regulation of height.

Classic Approach of Detecting Classic Approach of Detecting Large-Effect Rare MutationsLarge-Effect Rare Mutations

Three of the T2DM-associated variant loci were Three of the T2DM-associated variant loci were actually discovered through analysis of the actually discovered through analysis of the heterogeneity of the disorderheterogeneity of the disorderRare Mendelian mutants of KCNJ11, WFS1, and Rare Mendelian mutants of KCNJ11, WFS1, and HNF1B can cause diabetes, including Maturity-HNF1B can cause diabetes, including Maturity-Onset Diabetes of the Young. These variants Onset Diabetes of the Young. These variants have been confirmed repeatedly by GWA.have been confirmed repeatedly by GWA.Their potential pathways relevant to diabetes Their potential pathways relevant to diabetes biology are shown in next slide.biology are shown in next slide.Rare or small-effect loci may still be clues to Rare or small-effect loci may still be clues to underlying pathophysiology and targets to treat.underlying pathophysiology and targets to treat.Copy-number variants are also missed in GWA Copy-number variants are also missed in GWA studies.studies.

Processes involved in genetic predisposition to type 2 diabetes, based on the best candidates within each signal and human

physiological studies. Most genes implicated in diabetes susceptibility act through effects on beta-cell function or mass.

[McCarthy and Hattersly, 2008]

Resources to Keep up with FieldResources to Keep up with Field

U.S. NIH (NCI-NHGRI) maintain an ongoing U.S. NIH (NCI-NHGRI) maintain an ongoing catalog of published genome-wide association catalog of published genome-wide association studiesstudiesThere are many databases of gene sequences There are many databases of gene sequences and variants, and protein variants to assist in and variants, and protein variants to assist in annotation of the potential biological roles of annotation of the potential biological roles of variants in or near mapped genes.variants in or near mapped genes.Statistical compendia for tests and adjustments Statistical compendia for tests and adjustments for bias due to selection, misclassification, and for bias due to selection, misclassification, and population stratification are established; see population stratification are established; see McCarthy et al, Nature Reviews/Genetics 2008.McCarthy et al, Nature Reviews/Genetics 2008.GWAS Graphical User Interface: graphical GWAS Graphical User Interface: graphical browser [Chen et al, Bioinformatics 2008]browser [Chen et al, Bioinformatics 2008]

Special Challenges & Opportunities in Special Challenges & Opportunities in Muslim CountriesMuslim Countries

Nearly all GWA studies have been Nearly all GWA studies have been performed on Causasians of European performed on Causasians of European origins.origins.It is very likely that different variants will be It is very likely that different variants will be important in African and Asian important in African and Asian populations, so population-based studies populations, so population-based studies of the kind recently initiated here for of the kind recently initiated here for cardiomyopathy would be expected to cardiomyopathy would be expected to yield interesting and useful findings.yield interesting and useful findings.

General Challenges and Opportunities for General Challenges and Opportunities for Diabetes EpidemiologistsDiabetes Epidemiologists

This explosion of new findings about potential This explosion of new findings about potential genetic predispositions to Type 2 Diabetes, and genetic predispositions to Type 2 Diabetes, and analogous findings for T1 Diabetes, explains analogous findings for T1 Diabetes, explains only a modest aggregate proportion of risk only a modest aggregate proportion of risk explained by the genetic variants (<10%).explained by the genetic variants (<10%).More and larger GWA and re-sequencing More and larger GWA and re-sequencing studies will find more variants, probably of studies will find more variants, probably of smaller and smaller effect.smaller and smaller effect.The big effects are almost surely to be found The big effects are almost surely to be found among non-genetic variables (environmental, among non-genetic variables (environmental, behavioral, dietary), as in our early diagram---behavioral, dietary), as in our early diagram---and in gene-environment interactions.and in gene-environment interactions.

KEY COMPONENTS OF THE KEY COMPONENTS OF THE VISIONVISION

An avalanche of genomic information: validated An avalanche of genomic information: validated SNPs, haplotype blocks, candidate genes/alleles, SNPs, haplotype blocks, candidate genes/alleles, proteins, & metabolites--associated with disease riskproteins, & metabolites--associated with disease risk Powerful computational methodsPowerful computational methods Effective linkages with better environmental and Effective linkages with better environmental and behavioral datasets for eco-genetic analysesbehavioral datasets for eco-genetic analyses Credible privacy and confidentiality protectionsCredible privacy and confidentiality protections Breakthrough tests, vaccines, drugs, behaviors, Breakthrough tests, vaccines, drugs, behaviors, and regulatory actions to reduce health risks and and regulatory actions to reduce health risks and cost-effectively treat patients in the US and globally.cost-effectively treat patients in the US and globally.

Getting Ahead of the Science: Getting Ahead of the Science: Personalized GenomicsPersonalized Genomics

23andme.com is a company in California, 23andme.com is a company in California, offering:offering:Disease Risks: premature—genome Disease Risks: premature—genome variants associated with various diseases, variants associated with various diseases, but very little of the attributable risk knownbut very little of the attributable risk knownAncestry testing: Good—Haplotypes tied Ancestry testing: Good—Haplotypes tied to population origins (Africa, Europe, Asia)to population origins (Africa, Europe, Asia)Geneology/family roots: Good, using Y Geneology/family roots: Good, using Y chromosome and mitochondrial DNAchromosome and mitochondrial DNA

Synthetic Biology, an Emerging FieldSynthetic Biology, an Emerging Field

Interdisciplinary science and engineering to design and build Interdisciplinary science and engineering to design and build novel biological functions and systems to:novel biological functions and systems to:Gain insights into what makes life tick, constructing genetic Gain insights into what makes life tick, constructing genetic circuits to achieve what nature evolved over eonscircuits to achieve what nature evolved over eonsDevelop powerful biotechnologies by integrating biological Develop powerful biotechnologies by integrating biological components, circuits and replicating organismscomponents, circuits and replicating organisms

Applications:Applications:Engineered microorganisms that produce drugsEngineered microorganisms that produce drugsBiosensors for detecting abnormalities and diseasesBiosensors for detecting abnormalities and diseasesMicroorganisms that convert renewable resources into Microorganisms that convert renewable resources into energy carriersenergy carriersMicroorganisms to remediate hazardous material Microorganisms to remediate hazardous material contaminated sites—”environmental biotechnology”contaminated sites—”environmental biotechnology”

Safety regimens will be critical.Safety regimens will be critical.

Engineering Life: Building a FAB for BiologyEngineering Life: Building a FAB for Biology

The BIO FAB Group: David Baker, George Church, Jim Collins, Drew Endy, Joseph Jacobson, Jay Keasling, Paul Modrich, Christina Smolke and Ron Weiss (Scientific American 2006)

BIOLOGICAL COMPONENTS are the basis of an approach to biotechnology modeled on electronics engineering.

Principles and practices learned from engineering successes, especially standardization of parts and automation of processes can help transform biotechnology and “genetic engineering” from a specialized craft into a mature industry.

Pierre Teilhard de ChardinPierre Teilhard de Chardin

1881-19551881-1955

The future belongs to those who give the The future belongs to those who give the

next generation hope.next generation hope.

““There are those There are those who look at who look at things the way things the way they are, and they are, and ask, why?... ask, why?...

I dream of I dream of things that never things that never were, and ask, were, and ask, why not?” why not?”

--Robert F. --Robert F. Kennedy (1968)Kennedy (1968)