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Genome wide association studies of complex traits in outbred and isolated populations CM van Duijn

Genome wide association studies of complex traits in outbred and isolated populations CM van Duijn Genetic Epidemiology Unit Erasmus MC, Rotterdam, The Netherlands. Topics. To what extend do isolates differ from outbred populations ?

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Genome wide association studies of complex traits in outbred and isolated populations CM van Duijn

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  1. Genome wide association studies of complex traits in outbred and isolated populations CM van Duijn Genetic Epidemiology Unit Erasmus MC, Rotterdam, The Netherlands

  2. Topics • To what extend do isolates differ from outbred populations ? • What is the role of isolates in gene wide association studies ?

  3. Population dynamics in isolates Founder effect Genetic drift

  4. Genetic Research in Isolated Populations (GRIP) program • Recent genetically isolated population in the South-West of the Netherlands • At least 150 founders in 1750 • Substantial population growth, with minimal new immigration until last decades • Genealogical data Rotterdam GRIP

  5. Comparison of genetic variability GRIP, Iceland, CEPH Mean number of alleles CEPH > Iceland > GRIP 10.059 > 7.623 > 7.240 (p<0.01) Mean heterozygosity CEPH > Iceland > GRIP 0.768 > 0.758 > 0.757 (p<0.05) Inbreeding Pardo et al, Ann Hum Genet 2005

  6. Pedigree of the GRIP population What is the effect of isolation on genome?

  7. 0.046 0.0483 0.0068 0 0 0 0 0 Expected fluctuations alleles proportions by allele frequency P * Probability loss of allele Probability allele proportion is > 5P0* Probability allele proportion is > 10P0* 0 0.954 0.026 0.0001 0.615 0.02 0.001 0.0083 0 0.01 0 0 0.025 0 0 0.05 0 0 0.1 0 0 0.25 0 0 0.5 P0*: Allele proportion original population Pardo et al, Ann Hum Genet 2005

  8. Gene Gene Gene Gene Protein Protein Protein Protein Gene Protein Complex disease Protein Protein Gene Protein Gene Gene Rare mutations in an outbred population

  9. Gene Gene Gene Gene Protein Protein Protein Protein Gene Protein Complex disease Protein Protein Gene Protein Gene Gene Rare mutations in an isolated population

  10. Gene Gene Gene Gene Protein Protein Protein Protein Gene Protein Complex disease Protein Protein Gene Protein Gene Gene Common mutations in an isolated population

  11. Comparison of linkage disequilibrium of recently isolated populations • Antioquia, Colombia ((ANT) • Ashkenazi (ASH) • Azores (AZO) • Central Valley of Costa Rica (CR) • GRIP population Netherlands (NL) • Early settlement Finland (FIC) • Finnish subisolate of Kuusamo (FIK) • Finland nationwide (FIP) • Newfoundland (NFL) • Afrikaner (SAF) • Province of Nuoro in Sardiana (SAR) • Caucasian general population (CAU) Service et al, Nature Genet 2006

  12. Linkage disequilibrium units (LDU) for chromosome 22 Service et al, Nature Genet 2006

  13. To what extend do isolates differ from outbred populations? • Have a reduced variability for rare genetic variants • May show extended linkage disequilibrium • Are often characterised by consanguinity

  14. Topics • To what extend do isolates differ from outbred populations ? • What is the role of isolates in gene wide association studies ?

  15. Finding genes in isolates • Rare variants Became very prevalent or disappeared Linkage is most powerful approach • Multiple common variants Will be found also in isolated populations Association is most powerful approach

  16. Finding genes in isolates • Rare variants with major effects Linkage: example Alzheimer disease • Multiple common variants Association: eye colour

  17. Pedigree Alzheimer’s disease (AD) • 111 probable late onset (75 ± 5.3 years) Alzheimer patients • 103 patients were connected based on genealogy • Genome wide screen with 420 micro-satelilite markers (Perkin Elmer)

  18. Results genome wide screen Liu et al, AJHG in press

  19. Haplotype analysis chromosome 3

  20. Finding genes in isolates • From linkage to association? • From association to linkage?

  21. Genome wide association analysis Population • 200 distantly related individuals Phenotype • Cognitive function Genotyping • Affymetrix 250K SNP array Data Analysis • Single SNP association: Type 1 error (p): nominal and permutation tests

  22. Genome wide analysis Stroop test in 200 individuals (ERF)

  23. Chromosome 10 region rs17129622 rs11185978 rs7071717 Learning 0.23 0.36 0.30 Recall 0.55 0.60 0.67 Recognition 0.48 0.60 0.71 Stroop 0.00003 0.00002 0.000005 TMT-B 0.00023 0.01 0.01 Semantic Fluency 0.10 0.05 0.04 Phonological Fluency 0.002 0.001 0.01 Block Test 0.80 0.61 0.90 Total evidence 7*10-13 9*10-13 3*10-14 Adjusted p-value 0.02 0.01 0.002 CYP2C19 - CYP2C9 Liu et al, AJHG in press

  24. Finding genes in isolates • Rare variants with major effects Linkage: example Alzheimer disease • Multiple common variants Association: eye colour

  25. Genetics of eye color • Co-dominant trait • Brown dominates over green, green over blue • Strong association for blue/nonblue eye color was found with three OCA2 SNPs (Duffy et al. 2007)

  26. OCA2 and eye colour 3-SNP haplotype was observed with a frequency of 0.905 in those with blue eyes and 0.095 in those with brown eyes Duffy et al, AJHG 2007, 80:241-252

  27. GWA in 192 participants of GRIP (Affymetrix 250k) • Significant association (p=1.2×10-9) to the OCA2 region at chromosome 15q13.1 • Adjusted for multiple testing by 100 genome-wide permutations

  28. Rotterdam Study • Population-based study: outbred Caucasian population • 12,000 subjects aged 55 + years who have been followed for 15 years • Sampling DNA, RNA, serum/plasma • Screening for major diseases and risk factors ever 5 years • Genome wide association: Affymetrix 500K

  29. GWA analysis in 481 persons of the Rotterdam study

  30. Linkage of OCA2 to eye color in 4 families GRIP Family 14 LOD=1.6 Family 7 LOD=1.4 Family 5 LOD=1.1 Family 12 LOD=1.1 Overall LOD 3000 relatives = 22.0

  31. Finding genes in isolates • From linkage to association • From association to linkage • Powerful replication

  32. Diseases studied in GRIP Neuropsychiatric Cardiovascular Parkinson disease Hemochromatosis Alzheimer's disease Diabetes type 2 Stroke/ White Matter Disease Hypertension Multiple Sclerosis Pre-eclampsia ADHD Fertility: PCOS Depression Atherosclerosis Anxiety Hyperlipidemia

  33. Diseases studied in GRIP • Ophthalmologic Macular degeneration • Glaucoma • Auto-immune Type 1 diabetes • Bone Osteoporosis • Osteoarthritis • Rheumatoid arthritis • Lung COPD • Pharmacology Response antihypertensives

  34. Cardiovascular assessments Plaques, intima media thickness, pulsewave velocity

  35. Ophthalmologic studies Age related macular degeneration Glaucoma

  36. Neuropsychiatric testing

  37. Thanks !

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