NGS and complex genetics

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1 NGS and complex genetics Robert Kraaij Genetic Laboratory Department of Internal Medicine

2 Gene Hunting Rotterdam Study and GWAS Next Generation Sequencing

3 Gene Hunting

4 Mendelian gene hunting: linkage Gregor Mendel ( ) Linkage analysis

5 Simple Disease vs Complex Disease Simple Disease severe phenotype early onset rare Mendelian inheritance e.g.: cystic fibrosis, osteogenesis imperfecta Complex Disease mild phenotype late onset common complex inheritance e.g.: diabetes, asthma, osteoporosis Mutations (< 1%) Polymorphisms (> 1%)

6 AGGAGTCTGACTGACCATTGGACTAGGGGATTGACCAGTAGGCTGCGATTCGGATGCGGATTGACGATTAAAAAGGATTACGATTAGCTGT GACGTGCAGGATGCTGCGATGCTGGACTGAACGCCCCCCGGGCTTCTTTATTAGCTGCTGACGTGCCAGATGCTGACGTGCAGTGCGGCTG ACGGTGCTTACCTGGATCGGATGCTACCAGTCGATCGATCGATCGTAGCGTAGCGTATGCTAGCTAGTGATCGATGCTAGTAGCTAGCTAG Single Nucleotide CTGATCGATCATCGATCGTAGCTAGCTAGCTAGCTAGCTGATCGATCGATGCTAGCTAGCTAGCTAGTCATCTGTGGTGGGGGGTTAAATG CGATTGCCGCTAGCTAGAACAAAATAGCGGTATTTTGGGGAGTCTGACTGACCATTGGACTAGGGGATTGACCAGTAGGCTGCGATTCGGA TGCGGATTGACGATTAAAAAGGATTACGATTAGCTGTGACGTGCAGGATGCTGCGATGCTGGACTGAACGCCCCCCGGGCTTCTTTATTAG Polymorphism? CTGCTGACGTGCCAGATGCTGACGTGCAGTGCGGCTGACGGAGTCTGACTGACCATTGGACTAGGGGATTGACCAGTAGGCTGCGATTCGG ATGCGGATTGACGATTAAAAAGGATTACGATTAGCTGTGACGTGCAGGATGCTGCGATGCTGGACTGAACGCCCCCCGGGCTTCTTTATTA GCTGCTGACGTGCCAGATGCTGACGTGCAGTGCGGCTGACGGTGCTTACCTGGATCGGATGCTACCAGTCGATCGATCGATCGTAGCGTAG CGTATGCTAGCTAGTGATCGATGCTAGTAGCTAGCTAGCTGATCGATCATCGATCGTAGCTAGCTAGCTAGCTAGCTGATCGATCGATGCT AGCTAGCTAGCTAGTCATCTGTGGTGGGGGGTTAAATGCGATTGCCGCTAGCTAGAACAAAATAGCGGTATTTTGGGGAGTCTGACTGACC ATTGGACTAGGGGATTGACCAGTAGGCTGCGATTCGGATGCGGATTGACGATTAAAAAGGATTACGATTAGCTGTGACGTGCAGGATGCTG CGATGCTGGACTGAACGCCCCCCGGGCTTCTTTATTAGCTGCTGACGTGCCAGATGCTGACGTGCAGTGAGGAGTCTGACTGACCATTGGA CTAGGGGATTGACCAGTAGGCTGCGATTCGGATGCGGATTGACGATTAAAAAGGATTACGATTAGCTGTGACGTGCAGGATGCTGCGATGC TGGACTGAACGCCCCCCGGGCTTCTTTATTAGCTGCTGACGTGCCAGATGCTGACGTGCAGTGCGGCTGACGGTGCTTACCTGGATCGGAT GCTACCAGTCGATCGATCGATCGTAGCGTAGCGTATGCTAGCTAGTGATCGATGCTAGTAGCTAGCTAGCTGATCGATCATCGATAACCGG ATAAGGGCTAGCTAGCTGATCGATCGATGCTAGCTAGCTAGCTAGTCATCTGTGGTGGGGGGTTAAATGCGATTGCCGCTAGCTAGAACAA AATAGCGGTATTTTGGCGGCTGACGGTGCTTACCTGGATCGGATGCTACCAGTCGATCGATCGATCGTAGCGTAGCGTATGCTAGCTAGTG ATCGATGCTAGTAAGGAGTCTGACTGACCATTGGACTAGGGGATTGACCAGTAGGCTGCGATTCGGATGCGGATTGACGATTAAAAAGGAT TACGATTAGCTGTGACGTGCAGGATGCTGCGATGCTGGACTGAACGCCCCCCGGGCTTCTTTATTAGCTGCTGACGTGCCAGATGCTGACG TGCAGTGCGGCTGACGGTGCTTACCTGGATCGGATGCTACCAGTCGATCGATCGATCGTAGCGTAGCGTATGCTAGCTAGTGATCGATGCT AGTAGCTAGCTAGCTGATCGATCATCGATCGTAGCTAGCTAGCTAGCTAGCTGATCGATCGATGCTAGCTAGCTAGCTAGTCATCTGTGGT GGGGGGTTAAATGCGATTGCCGCTAGCTAGAACAAAATAGCGGTATTTTGGAGGAGTCTGACTGACCATTGGACTAGGGGATTGACCAGTA GGCTGCGATTCGGATGCGGATTGACGATTAAAAAGGATTACGATTAGCTGTGACGTGCAGGATGCTGCGATGCTGGACTGAACGCCCCCCG GGCTTCTTTATTAGCTGCTGACGTGCCAGATGCTGACGTGCAGTGCGGCTGACGGTGCTTACCTGGATCGGATGCTACCAGTCGATCGATC GATCGTAGCGTAGCGTATGCTAGCTAGTGATCGATGCTAGTAGCTAGCTAGCTGATCGATCATCGATCGTAGCTAGCTAGCTAGCTAGCTG ATCGATCGATGCTAGCTAGCTAGCTAGTCATCTGTGGTGGGGGGTTAAATGCGATTGCCGCTAGCTAGAACAAAATAGCGGTATTTTGGGC TAGCTAGCTGATCGATCATCGATCGTAGCTAGCTAGCTAGCTAGCTGATCGATCGATGCTAGCTAGCTAGCTAGTCATCTGTGGTGGGGGG TTAAATGCGATTGCCGCTAGCTAGAACAAAATAGCGGTATTTTGGGGTGCTTACCTGGATCGGATGCTACCAGTCGATCGATCGATCGTAG CGTAGCGTATGCTAGCTAGTGATCGATGCTAGTAGCTAGCTAGCTGATCGATCATCGATCGTAGCTAGCTAGCTAGCTAGCTGATCGATCG ATGCTAGCTAGCTAGCTAGTCATCTGTGGTGGGGGGTTAAATGCGATTGCCGCTAGCTAGAACAAAATAGCGGTATTTTGGAGGAGTCTGA CTGACCATTGGACTAGGGGATTGACCAGTAGGCTGCGATTCGGATGCGGATTGACGATTAAAAAGGATTACGATTAGCTGTGACGTGCAGG ATGCTGCGATGCTGGACTGAACGCCCCCCGGGCTTCTTTATTAGCTGCTGACGTGCCAGATGCTGACGTGCAGTGCGGCTGACGGTGCTTA CCTGGATCGGATGCTACCAGTCGATCGATCGATCGTAGCGTAGCGTATGCTAGCTAGTGATCGATGCTAGTAGCTAGCTAGCTGATCGARK

7 AGGAGTCTGACTGACCATTGGACTAGGGGATTGACCAGTAGGCTGCGATTCGGATGCGGATTGACGATTAAAAAGGATTACGATTAGCTGT GACGTGCAGGATGCTGCGATGCTGGACTGAACGCCCCCCGGGCTTCTTTATTAGCTGCTGACGTGCCAGATGCTGACGTGCAGTGCGGCTG ACGGTGCTTACCTGGATCGGATGCTACCAGTCGATCGATCGATCGTAGCGTAGCGTATGCTAGCTAGTGATCGATGCTAGTAGCTAGCTAG Re-sequencing CTGATCGATCATCGATCGTAGCTAGCTAGCTAGCTAGCTGATCGATCGATGCTAGCTAGCTAGCTAGTCATCTGTGGTGGGGGGTTAAATG CGATTGCCGCTAGCTAGAACAAAATAGCGGTATTTTGGGGAGTCTGACTGACCATTGGACTAGGGGATTGACCAGTAGGCTGCGATTCGGA TGCGGATTGACGATTAAAAAGGATTACGATTAGCTGTGACGTGCAGGATGCTGCGATGCTGGACTGAACGCCCCCCGGGCTTCTTTATTAG CTGCTGACGTGCCAGATGCTGACGTGCAGTGCGGCTGACGGAGTCTGACTGACCATTGGACTAGGGGATTGACCAGTAGGCTGCGATTCGG ATGCGGATTGACGATTAAAAAGGATTACGATTAGCTGTGACGTGCAGGATGCTGCGATGCTGGACTGAACGCCCCCCGGGCTTCTTTATTA GCTGCTGACGTGCCAGATGCTGACGTGCAGTGCGGCTGACGGTGCTTACCTGGATCGGATGCTACCAGTCGATCGATCGATCGTAGCGTAG CGTATGCTAGCTAGTGATCGATGCTAGTAGCTAGCTAGCTGATCGATCATCGATCGTAGCTAGCTAGCTAGCTAGCTGATCGATCGATGCT AGCTAGCTAGCTAGTCATCTGTGGTGGGGGGTTAAATGCGATTGCCGCTAGCTAGAACAAAATAGCGGTATTTTGGGGAGTCTGACTGACC ATTGGACTAGGGGATTGACCAGTAGGCTGCGATTCGGATGCGGATTGACGATTAAAAAGGATTACGATTAGCTGTGACGTGCAGGATGCTG CGATGCTGGACTGAACGCCCCCCGGGCTTCTTTATTAGCTGCTGACGTGCCAGATGCTGACGTGCAGTGAGGAGTCTGACTGACCATTGGA CTAGGGGATTGACCAGTAGGCTGCGATTCGGATGCGGATTGACGATTAAAAAGGATTACGATTAGCTGTGACGTGCAGGATGCTGCGATGC TGGACTGAACGCCCCCCGGGCTTCTTTATTAGCTGCTGACGTGCCAGATGCTGACGTGCAGTGCGGCTGACGGTGCTTACCTGGATCGGAT GCTACCAGTCGATCTATCGATCGTAGCGTAGCGTATGCTAGCTAGTGATCGATGCTAGTAGCTAGCTAGCTGATCGATCATCGATAACCGG ATAAGGGCTAGCTAGCTGATCGATCGATGCTAGCTAGCTAGCTAGTCATCTGTGGTGGGGGGTTAAATGCGATTGCCGCTAGCTAGAACAA AATAGCGGTATTTTGGCGGCTGACGGTGCTTACCTGGATCGGATGCTACCAGTCGATCGATCGATCGTAGCGTAGCGTATGCTAGCTAGTG ATCGATGCTAGTAAGGAGTCTGACTGACCATTGGACTAGGGGATTGACCAGTAGGCTGCGATTCGGATGCGGATTGACGATTAAAAAGGAT TACGATTAGCTGTGACGTGCAGGATGCTGCGATGCTGGACTGAACGCCCCCCGGGCTTCTTTATTAGCTGCTGACGTGCCAGATGCTGACG TGCAGTGCGGCTGACGGTGCTTACCTGGATCGGATGCTACCAGTCGATCGATCGATCGTAGCGTAGCGTATGCTAGCTAGTGATCGATGCT AGTAGCTAGCTAGCTGATCGATCATCGATCGTAGCTAGCTAGCTAGCTAGCTGATCGATCGATGCTAGCTAGCTAGCTAGTCATCTGTGGT GGGGGGTTAAATGCGATTGCCGCTAGCTAGAACAAAATAGCGGTATTTTGGAGGAGTCTGACTGACCATTGGACTAGGGGATTGACCAGTA GGCTGCGATTCGGATGCGGATTGACGATTAAAAAGGATTACGATTAGCTGTGACGTGCAGGATGCTGCGATGCTGGACTGAACGCCCCCCG GGCTTCTTTATTAGCTGCTGACGTGCCAGATGCTGACGTGCAGTGCGGCTGACGGTGCTTACCTGGATCGGATGCTACCAGTCGATCGATC GATCGTAGCGTAGCGTATGCTAGCTAGTGATCGATGCTAGTAGCTAGCTAGCTGATCGATCATCGATCGTAGCTAGCTAGCTAGCTAGCTG ATCGATCGATGCTAGCTAGCTAGCTAGTCATCTGTGGTGGGGGGTTAAATGCGATTGCCGCTAGCTAGAACAAAATAGCGGTATTTTGGGC TAGCTAGCTGATCGATCATCGATCGTAGCTAGCTAGCTAGCTAGCTGATCGATCGATGCTAGCTAGCTAGCTAGTCATCTGTGGTGGGGGG TTAAATGCGATTGCCGCTAGCTAGAACAAAATAGCGGTATTTTGGGGTGCTTACCTGGATCGGATGCTACCAGTCGATCGATCGATCGTAG CGTAGCGTATGCTAGCTAGTGATCGATGCTAGTAGCTAGCTAGCTGATCGATCATCGATCGTAGCTAGCTAGCTAGCTAGCTGATCGATCG ATGCTAGCTAGCTAGCTAGTCATCTGTGGTGGGGGGTTAAATGCGATTGCCGCTAGCTAGAACAAAATAGCGGTATTTTGGAGGAGTCTGA CTGACCATTGGACTAGGGGATTGACCAGTAGGCTGCGATTCGGATGCGGATTGACGATTAAAAAGGATTACGATTAGCTGTGACGTGCAGG ATGCTGCGATGCTGGACTGAACGCCCCCCGGGCTTCTTTATTAGCTGCTGACGTGCCAGATGCTGACGTGCAGTGCGGCTGACGGTGCTTA CCTGGATCGGATGCTACCAGTCGATCGATCGATCGTAGCGTAGCGTATGCTAGCTAGTGATCGATGCTAGTAGCTAGCTAGCTGATCGARK

8 AGGAGTCTGACTGACCATTGGACTAGGGGATTGACCAGTAGGCTGCGATTCGGATGCGGATTGACGATTAAAAAGGATTACGATTAGCTGT GACGTGCAGGATGCTGCGATGCTGGACTGAACGCCCCCCGGGCTTCTTTATTAGCTGCTGACGTGCCAGATGCTGACGTGCAGTGCGGCTG ACGGTGCTTACCTGGATCGGATGCTACCAGTCGATCGATCGATCGTAGCGTAGCGTATGCTAGCTAGTGATCGATGCTAGTAGCTAGCTAG CTGATCGATCATCGATCGTAGCTAGCTAGCTAGCTAGCTGATCGATCGATGCTAGCTAGCTAGCTAGTCATCTGTGGTGGGGGGTTAAATG CGATTGCCGCTAGCTAGAACAAAATAGCGGTATTTTGGGGAGTCTGACTGACCATTGGACTAGGGGATTGACCAGTAGGCTGCGATTCGGA TGCGGATTGACGATTAAAAAGGATTACGATTAGCTGTGACGTGCAGGATGCTGCGATGCTGGACTGAACGCCCCCCGGGCTTCTTTATTAG Human Genome Project CTGCTGACGTGCCAGATGCTGACGTGCAGTGCGGCTGACGGAGTCTGACTGACCATTGGACTAGGGGATTGACCAGTAGGCTGCGATTCGG ATGCGGATTGACGATTAAAAAGGATTACGATTAGCTGTGACGTGCAGGATGCTGCGATGCTGGACTGAACGCCCCCCGGGCTTCTTTATTA GCTGCTGACGTGCCAGATGCTGACGTGCAGTGCGGCTGACGGTGCTTACCTGGATCGGATGCTACCAGTCGATCGATCGATCGTAGCGTAG Re-sequencing (dbsnp) CGTATGCTAGCTAGTGATCGATGCTAGTAGCTAGCTAGCTGATCGATCATCGATCGTAGCTAGCTAGCTAGCTAGCTGATCGATCGATGCT AGCTAGCTAGCTAGTCATCTGTGGTGGGGGGTTAAATGCGATTGCCGCTAGCTAGAACAAAATAGCGGTATTTTGGGGAGTCTGACTGACC HapMap Project ATTGGACTAGGGGATTGACCAGTAGGCTGCGATTCGGATGCGGATTGACGATTAAAAAGGATTACGATTAGCTGTGACGTGCAGGATGCTG CGATGCTGGACTGAACGCCCCCCGGGCTTCTTTATTAGCTGCTGACGTGCCAGATGCTGACGTGCAGTGAGGAGTCTGACTGACCATTGGA CTAGGGGATTGACCAGTAGGCTGCGATTCGGATGCGGATTGACGATTAAAAAGGATTACGATTAGCTGTGACGTGCAGGATGCTGCGATGC TGGACTGAACGCCCCCCGGGCTTCTTTATTAGCTGCTGACGTGCCAGATGCTGACGTGCAGTGCGGCTGACGGTGCTTACCTGGATCGGAT GCTACCAGTCGATCTATCGATCGTAGCGTAGCGTATGCTAGCTAGTGATCGATGCTAGTAGCTAGCTAGCTGATCGATCATCGATAACCGG ATAAGGGCTAGCTAGCTGATCGATCGATGCTAGCTAGCTAGCTAGTCATCTGTGGTGGGGGGTTAAATGCGATTGCCGCTAGCTAGAACAA ~ 12 million common DNA polymorphisms AATAGCGGTATTTTGGCGGCTGACGGTGCTTACCTGGATCGGATGCTACCAGTCGATCGATCGATCGTAGCGTAGCGTATGCTAGCTAGTG ATCGATGCTAGTAAGGAGTCTGACTGACCATTGGACTAGGGGATTGACCAGTAGGCTGCGATTCGGATGCGGATTGACGATTAAAAAGGAT TACGATTAGCTGTGACGTGCAGGATGCTGCGATGCTGGACTGAACGCCCCCCGGGCTTCTTTATTAGCTGCTGACGTGCCAGATGCTGACG in human genome TGCAGTGCGGCTGACGGTGCTTACCTGGATCGGATGCTACCAGTCGATCGATCGATCGTAGCGTAGCGTATGCTAGCTAGTGATCGATGCT AGTAGCTAGCTAGCTGATCGATCATCGATCGTAGCTAGCTAGCTAGCTAGCTGATCGATCGATGCTAGCTAGCTAGCTAGTCATCTGTGGT GGGGGGTTAAATGCGATTGCCGCTAGCTAGAACAAAATAGCGGTATTTTGGAGGAGTCTGACTGACCATTGGACTAGGGGATTGACCAGTA GGCTGCGATTCGGATGCGGATTGACGATTAAAAAGGATTACGATTAGCTGTGACGTGCAGGATGCTGCGATGCTGGACTGAACGCCCCCCG GGCTTCTTTATTAGCTGCTGACGTGCCAGATGCTGACGTGCAGTGCGGCTGACGGTGCTTACCTGGATCGGATGCTACCAGTCGATCGATC Hypothesis: GATCGTAGCGTAGCGTATGCTAGCTAGTGATCGATGCTAGTAGCTAGCTAGCTGATCGATCATCGATCGTAGCTAGCTAGCTAGCTAGCTG ATCGATCGATGCTAGCTAGCTAGCTAGTCATCTGTGGTGGGGGGTTAAATGCGATTGCCGCTAGCTAGAACAAAATAGCGGTATTTTGGGC TAGCTAGCTGATCGATCATCGATCGTAGCTAGCTAGCTAGCTAGCTGATCGATCGATGCTAGCTAGCTAGCTAGTCATCTGTGGTGGGGGG Common Variant Common Disease TTAAATGCGATTGCCGCTAGCTAGAACAAAATAGCGGTATTTTGGGGTGCTTACCTGGATCGGATGCTACCAGTCGATCGATCGATCGTAG CGTAGCGTATGCTAGCTAGTGATCGATGCTAGTAGCTAGCTAGCTGATCGATCATCGATCGTAGCTAGCTAGCTAGCTAGCTGATCGATCG ATGCTAGCTAGCTAGCTAGTCATCTGTGGTGGGGGGTTAAATGCGATTGCCGCTAGCTAGAACAAAATAGCGGTATTTTGGAGGAGTCTGA CTGACCATTGGACTAGGGGATTGACCAGTAGGCTGCGATTCGGATGCGGATTGACGATTAAAAAGGATTACGATTAGCTGTGACGTGCAGG ATGCTGCGATGCTGGACTGAACGCCCCCCGGGCTTCTTTATTAGCTGCTGACGTGCCAGATGCTGACGTGCAGTGCGGCTGACGGTGCTTA CCTGGATCGGATGCTACCAGTCGATCGATCGATCGTAGCGTAGCGTATGCTAGCTAGTGATCGATGCTAGTAGCTAGCTAGCTGATCGARK

9 AGGAGTCTGACTGACCATTGGACTAGGGGATTGACCAGTAGGCTGCGATTCGGATGCGGATTGACGATTAAAAAGGATTACGATTAGCTGT GACGTGCAGGATGCTGCGATGCTGGACTGAACGCCCCCCGGGCTTCTTTATTAGCTGCTGACGTGCCAGATGCTGACGTGCAGTGCGGCTG ACGGTGCTTACCTGGATCGGATGCTACCAGTCGATCGATCGATCGTAGCGTAGCGTATGCTAGCTAGTGATCGATGCTAGTAGCTAGCTAG CTGATCGATCATCGATCGTAGCTAGCTAGCTAGCTAGCTGATCGATCGATGCTAGCTAGCTAGCTAGTCATCTGTGGTGGGGGGTTAAATG CGATTGCCGCTAGCTAGAACAAAATAGCGGTATTTTGGGGAGTCTGACTGACCATTGGACTAGGGGATTGACCAGTAGGCTGCGATTCGGA TGCGGATTGACGATTAAAAAGGATTACGATTAGCTGTGACGTGCAGGATGCTGCGATGCTGGACTGAACGCCCCCCGGGCTTCTTTATTAG CTGCTGACGTGCCAGATGCTGACGTGCAGTGCGGCTGACGGAGTCTGACTGACCATTGGACTAGGGGATTGACCAGTAGGCTGCGATTCGG ATGCGGATTGACGATTAAAAAGGATTACGATTAGCTGTGACGTGCAGGATGCTGCGATGCTGGACTGAACGCCCCCCGGGCTTCTTTATTA GCTGCTGACGTGCCAGATGCTGACGTGCAGTGCGGCTGACGGTGCTTACCTGGATCGGATGCTACCAGTCGATCGATCGATCGTAGCGTAG CGTATGCTAGCTAGTGATCGATGCTAGTAGCTAGCTAGCTGATCGATCATCGATCGTAGCTAGCTAGCTAGCTAGCTGATCGATCGATGCT AGCTAGCTAGCTAGTCATCTGTGGTGGGGGGTTAAATGCGATTGCCGCTAGCTAGAACAAAATAGCGGTATTTTGGGGAGTCTGACTGACC ATTGGACTAGGGGATTGACCAGTAGGCTGCGATTCGGATGCGGATTGACGATTAAAAAGGATTACGATTAGCTGTGACGTGCAGGATGCTG CGATGCTGGACTGAACGCCCCCCGGGCTTCTTTATTAGCTGCTGACGTGCCAGATGCTGACGTGCAGTGAGGAGTCTGACTGACCATTGGA CTAGGGGATTGACCAGTAGGCTGCGATTCGGATGCGGATTGACGATTAAAAAGGATTACGATTAGCTGTGACGTGCAGGATGCTGCGATGC TGGACTGAACGCCCCCCGGGCTTCTTTATTAGCTGCTGACGTGCCAGATGCTGACGTGCAGTGCGGCTGACGGTGCTTACCTGGATCGGAT GCTACCAGTCGATCTATCGATCGTAGCGTAGCGTATGCTAGCTAGTGATCGATGCTAGTAGCTAGCTAGCTGATCGATCATCGATAACCGG ATAAGGGCTAGCTAGCTGATCGATCGATGCTAGCTAGCTAGCTAGTCATCTGTGGTGGGGGGTTAAATGCGATTGCCGCTAGCTAGAACAA AATAGCGGTATTTTGGCGGCTGACGGTGCTTACCTGGATCGGATGCTACCAGTCGATCGATCGATCGTAGCGTAGCGTATGCTAGCTAGTG ATCGATGCTAGTAAGGAGTCTGACTGACCATTGGACTAGGGGATTGACCAGTAGGCTGCGATTCGGATGCGGATTGACGATTAAAAAGGAT TACGATTAGCTGTGACGTGCAGGATGCTGCGATGCTGGACTGAACGCCCCCCGGGCTTCTTTATTAGCTGCTGACGTGCCAGATGCTGACG TGCAGTGCGGCTGACGGTGCTTACCTGGATCGGATGCTACCAGTCGATCGATCGATCGTAGCGTAGCGTATGCTAGCTAGTGATCGATGCT AGTAGCTAGCTAGCTGATCGATCATCGATCGTAGCTAGCTAGCTAGCTAGCTGATCGATCGATGCTAGCTAGCTAGCTAGTCATCTGTGGT GGGGGGTTAAATGCGATTGCCGCTAGCTAGAACAAAATAGCGGTATTTTGGAGGAGTCTGACTGACCATTGGACTAGGGGATTGACCAGTA GGCTGCGATTCGGATGCGGATTGACGATTAAAAAGGATTACGATTAGCTGTGACGTGCAGGATGCTGCGATGCTGGACTGAACGCCCCCCG GGCTTCTTTATTAGCTGCTGACGTGCCAGATGCTGACGTGCAGTGCGGCTGACGGTGCTTACCTGGATCGGATGCTACCAGTCGATCGATC GATCGTAGCGTAGCGTATGCTAGCTAGTGATCGATGCTAGTAGCTAGCTAGCTGATCGATCATCGATCGTAGCTAGCTAGCTAGCTAGCTG ATCGATCGATGCTAGCTAGCTAGCTAGTCATCTGTGGTGGGGGGTTAAATGCGATTGCCGCTAGCTAGAACAAAATAGCGGTATTTTGGGC TAGCTAGCTGATCGATCATCGATCGTAGCTAGCTAGCTAGCTAGCTGATCGATCGATGCTAGCTAGCTAGCTAGTCATCTGTGGTGGGGGG TTAAATGCGATTGCCGCTAGCTAGAACAAAATAGCGGTATTTTGGGGTGCTTACCTGGATCGGATGCTACCAGTCGATCGATCGATCGTAG CGTAGCGTATGCTAGCTAGTGATCGATGCTAGTAGCTAGCTAGCTGATCGATCATCGATCGTAGCTAGCTAGCTAGCTAGCTGATCGATCG ATGCTAGCTAGCTAGCTAGTCATCTGTGGTGGGGGGTTAAATGCGATTGCCGCTAGCTAGAACAAAATAGCGGTATTTTGGAGGAGTCTGA CTGACCATTGGACTAGGGGATTGACCAGTAGGCTGCGATTCGGATGCGGATTGACGATTAAAAAGGATTACGATTAGCTGTGACGTGCAGG ATGCTGCGATGCTGGACTGAACGCCCCCCGGGCTTCTTTATTAGCTGCTGACGTGCCAGATGCTGACGTGCAGTGCGGCTGACGGTGCTTA CCTGGATCGGATGCTACCAGTCGATCGATCGATCGTAGCGTAGCGTATGCTAGCTAGTGATCGATGCTAGTAGCTAGCTAGCTGATCGARK

10 DNA differences cause phenotype differences

11 Twin studies demonstrate heritability Heritable diseases and traits: Diabetes Breast cancer Osteoarthrosis Menopause Height Infidelity Entrepreneurship Paget s Disease Depression Eye color Osteoporosis Longevity Eye diseases Etc. Rheumatoid arthritis Lung cancer BMI Weight Menarche cholesterol Uric acid Ankylosing spondylitis Myocardial Infarction Skin colour Stroke Smoking behaviour Etc.

12 Complex Genetics Simple Complex Genome wide Families Genome wide Populations linkage association

13 Rotterdam Study and GWAS

14 ERGO : The Rotterdam Study A single-centre, prospective population-based cohort study, started 1990 Base-line cohort = 7,983 men and women of age 55 yrs In 2007: 4 Follow-up measurements: ~1500 per subject each time Ethnically homogeneous: 99% Caucasian Computerized GP + pharmacy monitoring Study determinants and prevalence/incidence of chronic and disabling disease in the elderly: CVD, Neurodegenerative Disease, Endocrine diseases, Locomotor disease (osteoporosis, osteoarthritis), Eye End 2004: coronary heart disease stroke fractures maculopathy dementia ~ DNA samples available: 1990: ERGO base-line/ RSI: n=7, : ERGO plus/ RSII: n=3,000 (55+) 2004: ERGO young/ RSIII: 3,500 (45+)

15 RSI: ERGO Baseline Age N = 6000; Illumina 550K RSI-1 RSI-2 RSI-3 RSI-4 GWAS Data available: JAN 2008 RSII: ERGO PLUS Age N = 2500; Illumina 550K RSII-1 RSII-2 MAY 2009 RSIII: ERGO Young Age N = 2800; Illumina 610K RSIII-1 JUL 2009 ERF (isolate) Age N = 2600; Illumina 317K ERF APRIL 2009 Generation R Age 5-15 N = 6000; Illumina 610K GenR-1 NOV 2009

16 Genome-Wide Association Study (GWAS) DNA collection: e.g cases vs controls DATA ANALYSIS (e.g., PLINK): Illumina Affymetrix AA AB BB Each dot is one SNP in, e.g, 2000 subjects AA BB AB AA BB AB. AB SNP 1 SNP 2 SNP 3. SNP 550, X Chromosomes Select SNPs (p-value, frequency) REPLICATION in other cohorts! Meta-Analysis of all data

17 LUMBAR SPINE BMD 5 x 10 8 Rotterdam Study ERF Study Twins UK decode Genetics Framingham Study N=5,000 Rivadeneira et al., Nat Genet., 2009

18 LUMBAR SPINE BMD LRP5 5 x 10 8 Rotterdam Study ERF Study Twins UK decode Genetics Framingham Study N=6,200 Rivadeneira et al., Nat Genet., 2009

19 LUMBAR SPINE BMD LRP5 5 x 10 8 Rotterdam Study ERF Study Twins UK decode Genetics Framingham Study N=8,500 Rivadeneira et al., Nat Genet., 2009

20 LUMBAR SPINE BMD RANK L 1p36 MHC C6ôrf10 OPG LRP5 5 x 10 8 Rotterdam Study ERF Study Twins UK decode Genetics Framingham Study N=15,000 Rivadeneira et al., Nat Genet., 2009

21 LUMBAR SPINE BMD RANK L 1p36 C6ôrf10 OPG LRP5 SP7 5 x 10 8 Rotterdam Study ERF Study Twins UK decode Genetics Framingham Study N=19,125 Rivadeneira et al., Nat Genet., 2009

22 allowing unprecedented leap in discoveries with > 800 studies on 150 human traits published to date

23 and that is definitively the case for our group in Rotterdam!! Publications: Nat Genet: 24 The Lancet: 6 Nature: 4 NEJM: 2 JAMA: 2... ~ 100 papers N = 12,000 N = 6,000 children Other consortia / isolated efforts

24 What are next steps after the success of GWAS? Unanswered Questions: Causative SNP? Causative gene? Mechanism? Biologic Pathways? Limited explained variance per trait/disease: dark matter The Hunt for Genetic Dark Matter : More common variants Not-yet-assessed common variants Rare (less frequent) variants (<5%, <1%) Copy Number Variations (CNV) Gene-gene interaction: (limited power) Gene-environment interaction: (limited power, standardization) Epi-genetics: methylation patterns of DNA

25 Next Generation Sequencing

26 The Human Genome Project Bill Clinton Tony Blair Craig Venter Francis Collins * 26 Juni 2000: Press conference Bill Clinton & Tony Blair: "working draft, 95% gesequenced * 14 april 2003: finished: 99% gesequenced. >>Cheaper and Faster!! Costs: $ 2.7 miljard (instead of $ 3 billion estimated costs) Timing: (instead of 2005)

27 Next Generation Sequencing Illumina HiSeq flowcells per machine 2 x 100 bp reads 8 days 100 Gb per flowcell

28 Future plans - GWAS on 2500 vertebral fracture cases from GENOMOS collection - GWAS parents Generation R => imprinting - Custom array LOCOMOTOR CHIP with already 50,000 candidate samples in GENOMOS collection - GWAS / 1000 GENOMES (Metabo-,Immuno- chips copncept) - Rare CNVs - Prioritization strategies (bioinformatics, eqtls, animal models) - Sequencing leads (regional, whole exome, whole genome) - Whole genome sequencing Rotterdam Study and Generation R individuals ~ 30,000 individuals

29 EU-BBMRI-NL: Dutch Genome Project : Trio design Full genome Sequence of 250 trios Caucasians with GWAS data, spread over NL Rotterdam Study => 34 trios ERF (Brabant), LifeLines (Groningen), Leiden Longevity Study Netherlands Twin Register (A dam/nl) Currently run at BGI

30 Possibilities Exome sequencing (CHARGE-S) Promising but the focus is not identifying the real variant underlying GWAS Proof of principle of involvement of gene identified by GWAS signal Targeted sequencing identified loci (CHARGE-S) Whole-genome sequencing (BB-MRI, RS individuals) Low pass sequencing Deep sequencing at Complete Genomics

31 Setup Illumina Compute Isilon storage 180 TB raw ~120 TB redundant Erasmus MC network Dell compute 128 cores 6 GB/core

32 Acknowledgements CHARGE

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