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Whole Genome Association Studies Overview Professor Torben A. Kruse Department of Biochemistry, Pharmacology og Genetic

DSGE 3. april 2008. Whole Genome Association Studies Overview Professor Torben A. Kruse Department of Biochemistry, Pharmacology og Genetics Odense University Hospital og Human MicroArray Centre OUH / SDU. Mendelian - Monogenic. Specific variation, GENE A . DISEASE A. Multifactoriel.

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Whole Genome Association Studies Overview Professor Torben A. Kruse Department of Biochemistry, Pharmacology og Genetic

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  1. DSGE 3. april 2008 Whole Genome Association Studies Overview Professor Torben A. Kruse Department of Biochemistry, Pharmacology og Genetics Odense University Hospital og Human MicroArray Centre OUH / SDU

  2. Mendelian - Monogenic Specific variation, GENE A DISEASE A

  3. Multifactoriel Variant GENE A + Variant GENE B + Variant GENE C + Environmental factor F SYGDOM A Variant GENE A + Variant GENE D + Variant GENE E + Environmental factor G SYGDOM A

  4. Monogenic disorders - the extremes of variation

  5. STRATEGIES FOR IDENTIFICATION OF DISEASE GENES • Extended families - linkage analysis major gene • Affected sibpair analysis • Shared segment analysis • Association studies minor gene • Cytogenetics

  6. 1980’s Development of DNA-markers

  7. T. Alitalo et al Am.Jour.Hum.Genet 1988

  8. Genohype seduction • >1000 Mendelian disease genes identified • Some major biological pathways/mechanisms identified • Human Genome Sequence

  9. Few generations Many generations IBD mapping Shared segment Linkage disequilibrium Association

  10. GWA in isolated population, Faroe Islands: Bipolar affective disorder, H. Ewald et al 1999 Schizophrenia, H.Ewald et al 2002 Autism, M Lauritzen et al 2006 Panic disorder, A. Wang et al 2006 GWA in outbread population at Human MicroArray Centre: Rhinitis (hayfever), allergy: Ass.prof. Charlotte Brasch-Andersen Bone mass: Claus Brasen, MD Depression symptomatology: Assoc.prof Lene Christiansen Hand grip strength: Assoc.prof Lene Christiansen

  11. Genome-wide association (GWA) has been facilitated by the advent of:

  12. SNP typing 1988: 1 SNP in 100 sec (240 genotypes/day) 2008: 1 SNP in 0.001 sec

  13. GENOME-WIDE ASSOCIATION • Technology: • Affymetrix: random; 500K, 1000K • Illumina: “haplotype tagging”; 300K, 550K, 1000K • Perlegen: “haplotype tagging” (Affy-like technology): 200-300K ht SNPs, 800K ht+singleton SNPs

  14. Diabetes mellitus (h2=0.6-1.0) Schizophrenia (h2=0.7) Perinatal disorders COPD (h2=0.6) Self-inflicted injury Unipolar depression (h2=0.5) Dementia (h2=0.4) Lung cancer Cerebrovascular disease Osteoarthritis Alcohol abuse (h2=0.4) Road traffic accidents Major causes of disability(Dalys, Murray & Lopez, 1996) Ischaemic heart disease (h2=0.3-0.6) Congenital anomalies (h2=0.5-0.8)

  15. Alleles A B C D... Genes CD/CV hypothesis Genetic architecture of disease • Common disease/ common variant model(Lander, 1996; Reich & Lander 2001) • genetic risk for common diseases due to high frequency alleles

  16. CD/CV hypothesis • Alzheimer disease APOE (4, 2) (0.15, 0.05-0.1) (OR=3, 0.5) • AIDS CCR5 (32-BP) (0.09) (RR=0.65-<0.1) • Type 1 diabetes mellitus DQB1*0201-DRB1*03/ DQB1*0302-DRB1*0401 (0.05) (RR=20) IL12B 3’UTR allele 1 (0.79) (RR<1.5) • Type 2 diabetes mellitus PPARG Pro12Ala (0.85, RR=1.25) CAPN10 112/121 (0.03-0.29) (RR 3-5) • Venous thrombosis F5 R506Q (0.02-0.08) (RR=4-5)

  17. Ankylosing spondylitis HLA-B*2702,04,05 (0.09) (OR=170) • Breast cancer BRCA2 N372H (0.22-0.29) (RR=1.31) • Prostate cancer ELAC2 S217L (0.30) (RR=1.3) • Neural tube defect PDGFRA H1/H2 haplos. (0.23)(RR=1.3) • Crohn’s disease NOD2 3020insC (0.04) (RR=2) • Haemolytic anaemia G6PD V68M/N126D (A-) (~0.20 Africa) HBB E6K (HbC) (0.09 W.Africa) • Haemochromatosis HFE C282Y (0.05) (RR=26) CD/CV hypothesis

  18. GWA STUDIES identify common risk variants….

  19. Conclusions: • Some new genes are identified • SNPs show very modest effects • Only partial overlap between SNPs identified in different GWAs (same phenotype) • No evidence for stronger association to sub-phenotypes

  20. Conclusions cont. • Several associations outside transcriptional units • Identified SNPs only explain a small fraction of genetic contribution (power?? model??)

  21. Multilocus/multiallele hypothesis many disease alleles at many loci the rule(common and rare diseases) recent allelic diversity predominates over old Genes A B C D E F G H I J K L…. Alleles

  22. Mendelian subsets of common disorders - allelic and locus heterogeneity • Ischaemic heart LDLR > 735 alleles disease APOB >2 [R3500Q 1:500] • Alzheimer disease APP, PS1, PS2 all multi-allelic • Breast cancer BRCA1 > 865 alleles BRCA2 > 450 alleles • Chronic obstructive CFTR > 963 alleles (DF508) pulmonary disease PI (20 alleles, PI*Z 1-2%) • Colorectal cancer MSH2, MLH1 all multi-allelic • Haemolytic anaemia HBB > 100 alleles

  23. Is GWA the end of things ?………..No • *Tagging approach with SNPs (incl. imputation 3 mio HapMap SNPs) • - Current GWA formats can identify common variants (>5-10%) with OR’s > 1.1 (in sufficiently powered samples) • - GWA will not identify rare variants (<1-5%) • Copy Number Variations CNV • Epigenetics: e.g. methylation patterns • Genetic Genomics: link with mRNA expression) • *Technological developments: • - Genome-wide sequencing techniques*: • - 454, Solexa, ABI • *Machines > € 500 K; Currently >30 million base pairs per run

  24. Genetics in perspective Proportion of cases attributable to smoking • 90% of lung cancer • 90% of larynx cancer • 30-70% bladder cancer • 80% of chronic bronchitis • 12.5% of coronary artery disease Vineis et al. (2001) • High familial risk (S >30) • Low familial risk (S < 3) diagnosis counselling prediction prevention biological insights

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