1. Advances in human genomics research have identified over 800 genetic loci associated with common diseases like type 2 diabetes through genome-wide association studies and candidate gene studies. 2. Further research has found that most type 2 diabetes genes identified play a role in pancreatic beta-cell function, and that both frequent and rare genetic variants contribute to disease risk. 3. Integrating human genomics with metabolic medicine offers advantages for personalized healthcare, including identifying new drug targets, predicting drug responses and side effects, improving clinical trial design, and enabling more optimized long-term patient care.

1. From Human Genomics to Personalized Metabolic Medicine [email_address] CNRS 8199-University Lille 2 Pasteur Institute, Lille, France

3. TCF7L2 Exploration of Linkage Peaks ENPP1* HNF4A* ADIPOQ* CAPN10* PPARG KCNJ11 HNF1B WFS1 Biological Candidates Gene Studies HNF1A* CDKN2A/2B IGF2BP2 CDKAL1 HHEX/IDE SLC30A8 KCNQ1 IRS1 TSPAN8/LGR5 ADAMTS9 NOTCH2 CDC123/CAMK1D THADA JAZF1 GWAS for T2D DGKB/TMEM195 MTNR1B GCKR GCK ADCY5 PROX1 GWAS for T2D-related traits Mean Increased Risk for T2D SNPs = 10 to 40% Genes/loci associated with T2D

4. Most T2D genes found by GWAS are suggested to play a role in pancreatic  -cell function

5. The BMI/Obesity Gene map BMI Childhood Obesity Waist MC4R FTO TMEM18 NEGR1 SEC16B ETV5 BDNF FAIM2 SH2B1 KCTD15 GNPDA2 MTCH2 NRXN3 TFAP2B MSRA LYPLAL1 NPC1 MAF PTER GPRC5B RBJ MAP2K5 FANCL QPCTL TNNI3K LRRN6C FLJ35779 SLC39A8 TMEM160 CADM2 PRKD1 LRP1B MTIF3 ZNF608 RPL27A NUDT3 PTBP2 RSPO3 VEGFA TBX15-WARS2 NFE2L3 GRB14 DNM3-PIGC ITPR2-SSPN LY86 HOXC13 ADAMTS9 ZNRF3-KREMEN1 NISCH-STAB1 CPEB4

6. Central Nervous System Adipose Tissue FTO MC4R POMC PCSK1 LEPR ENPP1 NPC1 PRL BDNF TRKB SIM1 TMEM18 KCTD15 SH2B1 NEGR1 GNPDA2 NRXN3 LEP LEPR MAF PRL, ENPP1 NEGR1 Obesity is a neuro (endocrine) disorder

7. From the frequent variants/frequent disease theory to the rare variants/frequent disease hypothesis Allele frequency Effect size ENPP1 PPARG KCNJ11 CAPN10 HNF4A HNF1A “ Rare but common” variants with strong effects on physiology Frequent DNA variants (SNP) only explain modest part of the heritability “ Rare” variants: Copy Number Variations (GSV) and point mutations

8. Walters et al, nature, 4th of February, 2010 The screening of children with extreme obesity identify rare CNV

9. Walters et al, nature, 2010 The effect of the chromosome 16p 11.2 microdeletion on obesity is age-dependent 25 kg/m 2 Morbid obesity Obesity The increased risk for Morbid Obesity is 4300%

10. Rare but Common potent mutations

13. Whole Genome Sequencing identifies mutations increasing disease risk and modulating response to various drugs

14. The evaluation of the interaction of the environment with the clinical genome allows a comprehensive health assessment

15. Genomics and System Medicine can bring an optimized Metabolic/CV disease care The Personalized Medicine shift challenge