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LP/J

LP/J. KK/HlJ. PL/J. P H A R M A C O G E N E T I C A N A L Y S I S O F T H E C A R D I O V A S C U L A R R E S P O N S E I N I N B R E D M I C E. Medical Genetics Corinne Berthonneche, Fanny Schüpfer, Fabienne Maurer,

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LP/J

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  1. LP/J KK/HlJ PL/J P H A R M A C O G E N E T I C A N A L Y S I S O F T H E C A R D I O V A S C U L A R R E S P O N S E I N I N B R E D M I C E • Medical Genetics • Corinne Berthonneche, Fanny Schüpfer, Fabienne Maurer, • Bastian Peter, Micha Hersch, Sven Bergmann, Jacqui Beckmann • Internal Medicine • Thierry Pedrazzini • Pharmacology and Cardiology / DKF UNIBE • Hugues Abriel • Computer Science and Engineering • Eleazar Eskin (UCLA)

  2. P R O J E C T • atenolol • (β-adrenergic receptor blocker) • isoproterenol • (β-adrenergic receptor agonist)

  3. euthanasy tissues plasma ECG urine SBP and HR recording training phase SBPHR CONTROL or ISOPROTERENOL or ATENOLOL 0 7 14 days osmotic mini-pump implantation for continuous and controlled drug delivery n=10 mice per condition and per strain SBP : Systolic Blood Pressure HR : Heart Rate P R O T O C O L

  4. control atenolol iso low dose iso high dose strain 1 strain 2 P R O T O C O L … strain n n=10 mice per condition and per strain 23 strains total > 1000 mice

  5. P H E N O T Y P E S

  6. P H E N O T Y P E S - S U M M A R Y • all phenotypes and responses to drug treatments are highly heritable (h2>0.7) • ctr measurements are consistent with data from other studies • responses to drug exposure are trait-, drug-, and dose-specific • responses are significantly more pronounced under β-stimulation than β-blockade • there is compartmental and strain-specific cardiac sensitivity to iso, with atria responding at lower concentrations than ventricles in the majority of the strains • there is little concordance between strain similarity based on the phenotypes and genotypic relatedness computed from genomic SNP profiles. • « cardiovascular phenotypes are unlikely to segregate according to global phylogeny, but rather be governed by smaller, local differences in the genetic architecture of the various strains »

  7. P H E N O T Y P E S - S U M M A R Y • all phenotypes and responses to drugtreatments are highlyheritable (h2>0.7) • ctrmeasurements are consistent with data fromotherstudies • responses to drugexposure are trait-, drug-, and dose-specific • responses are significantly more pronouncedunderβ-stimulation thanβ-blockade • thereiscompartmental and strain-specificcardiacsensitivity to iso, withatriarespondingatlower concentrations thanventricles in the majority of the strains • thereislittle concordance betweenstrainsimilaritybased on the phenotypes and genotypicrelatednesscomputedfromgenomic SNP profiles. • cardiovascularphenotypes are unlikely to segregateaccording to global phylogeny, but ratherbegoverned by smaller, local differences in the genetic architecture of the variousstrains

  8. pharmacokinetics (+ metabolites) plasma; urine non invasive measurements • tissues • heart • liver ECG heart rate systolic blood pressure 1 mouse • transcriptional analyses • proteomics • etc... P R O T O C O L microarrays RNA-seq G W A s

  9. Efficient mixed-model association (EMMA) corrects for population structure and genetic relatedness in model organism association mapping

  10. pointwise -log10p-values -> 6000 SNPs at p≤10–6 and 283 SNPs with p<10–10 chromosomes BW t-test 38 strains ca 100’000 SNPs

  11. BW t-test BW EMMA p=3.8x10-6 explains 39% of the genetic variance component “ Although the strongest signals for the body weight after applying the mixed model are not genome-wide significant, they are concentrated in a region around 114 Mb in chromosome 8. This region almost exactly falls into the LOD peak of a previously known body weight QTL Bwq3. ”

  12. BW t-test 38 strains BW EMMA p=3.8x10-6 explains 39% of the genetic variance component LW t-test 34 strains LW EMMA p=1.2x10-9 explains 59% of the genetic variance component

  13. G E N O M E - W I D E A S S O C I A T I O N • 18 phenotypes • 4 conditions (ctr, ate, iso1, iso10 ) • 88’263 SNPs across 22 strains ( Broad1 SNP dataset !) • 2 statistical tests (REMLt and LRT) • -> 144 scans

  14. A N I L L U S T R A T I O N O F E M M A R E S U L T S GW AS C A N S F O R V W I

  15. I S O P R O T E R E N O L - I N D U C E D C A R D I A C H Y P E R T R O P H Y Mice challenged by daily IP injections of 50 mg/kg isoproterenol for 1 wk PW posterior wall thickness MCSA mean cardiac myocyte cross-sectional area adapted from: Zarrinpashneh et al. AMPKα2 counteracts the development of cardiac hypertrophy induced by isoproterenol. BBRC 376:677-681, 2008

  16. R E S U L T S VWI (ratio VW/BWE)

  17. REMLt LRT 8 8 ctr 6 6 4 4 2 2 0 0 8 8 ate 6 6 4 4 2 2 0 0 8 8 iso1 6 6 4 4 2 2 0 0 8 iso10 6 4 4 2 2 0 0 1 3 5 7 9 1 3 5 7 9 2 4 6 8 10 12 14 16 18 X 2 4 6 8 10 12 14 16 18 X 11 13 15 17 19 11 13 15 17 19 T O P 1 0 0 0 H I T S 32 « loci » with unadjusted p < 10-5

  18. 10 1 2 3 4 8 chr3 81-85 Mb / ctr REMLt chr3 86-90 Mb / ctr REMLt chr4 94.8 Mb / iso1 REMLt chr7 75-77 Mb / ate REMLt 6 4 2 0 5 6 7 8 chr1 11.5-12.5 Mb / ate LRT chr1 38.5-39.5 Mb / ate LRT chr2 130-132 Mb / ate LRT chr2 117-118 Mb / iso1 REMLt 9 10 11 12 chr4 151-153 Mb / iso10 REMLt chr10 110-111 Mb / iso1 REMLt chr1 94.5-95.5 Mb / iso10 REMLt chr2 119-121 Mb / iso10 REMLt 13 14 15 16 chr5 104-105 Mb / iso10 REMLt chr6 76-77 Mb / iso10 LRT chr5 127-129 Mb / ate REMLt chr9 65-66 Mb / ate REMLt

  19. 10 17 18 19 20 8 6 4 2 0 21 22 23 24 25 26 27 28 29 30 31 32 chr7 16-17 Mb / iso1 REMLt chr6 125-126 Mb / iso1 REMLt chr7 24.5-25.5 Mb / iso1 REMLt chr4 72-73.5 Mb / iso10 REMLt chr4 82.5-83.5 Mb / iso10 REMLt chr6 145-146 Mb / iso10 REMLt chr6 5-6 Mb / iso10 REMLt chr18 60.5-61.5 Mb / iso10 LRT chr4 135-136 Mb / ctr LRT chr5 45-46 Mb / iso1 LRT chr5 47-48 Mb / iso1 LRT chr12 101-103 Mb / iso10 LRT chr12 113-114 Mb / iso10 LRT chr6 110-111 Mb / iso10 LRT chr1 3-3.5 Mb / iso10 REMLt chr17 12-13 Mb / iso10 REMLt

  20. Q U A L I T Y C H E C K • 32 loci for VWI(across 4 conditions and 2 statistical tests) • check whether p-values were obtained at positions with full allele sets across the 22 strains • - if yes, check SDP and consistency of results across statistical tests • if not, try to extrapolate a « corrected p-value » from a nearby SNP with a similar SDP and a full allele set (using the publicly available Broad1 and/or the imputed CGD1 SNP datasets) • list putative candidate genes (UCSC genome browser, biblio, etc…)

  21. REMLt LRT 8 8 ctr 6 6 4 4 2 2 0 0 8 8 ate 6 6 4 4 2 2 0 0 8 8 iso1 6 6 4 4 2 2 0 0 8 iso10 6 4 4 2 2 0 0 1 3 5 7 9 1 3 5 7 9 2 4 6 8 10 12 14 16 18 X 2 4 6 8 10 12 14 16 18 X 11 13 15 17 19 11 13 15 17 19 E X A M P L E 1 Q U A L I T Y C H E C K

  22. 6 4 -log10pEMMA 2 0 E X A M P L E 1 Q U A L I T Y C H E C K Locus 18 Significance (based on data with full allele set):CORRECT Top hit: position chr 6:125'528'422 alleles (EMMA) # alleles 1 = 17; # alleles 2 = 5 condition / stat iso1, REMLT p-value: 4.07x10-6 unadjusted p-values across conditions ctr REMLt ate REMLt iso1 REMLtiso10 REMLt ctr LRT ate LRT iso1 LRT iso10 LRT 6.2x10-5 3.7x10-54.07x10-6 2.67x10-5 2.77x10-4 2.04x10-4 5.62x10-5 1.63x10-4

  23. vWF intron 6 G G G G G G G G G G G G G G G G A A G G A A A E X A M P L E 1 Q U A L I T Y C H E C K Locus 18 Significance (based on data with full allele set):CORRECT Top hit: position chr 6:125'528'422 alleles (EMMA) # alleles 1 = 17; # alleles 2 = 5 condition / stat iso1, REMLT p-value: 4.07x10-6 Ranking strains by increasing VWI means in the iso1 group:

  24. window: 124-126 Mb 6 4 2 0 vWFintron 6

  25. REMLt LRT 8 8 ctr 6 6 4 4 2 2 0 0 8 8 ate 6 6 4 4 2 2 0 0 8 8 iso1 6 6 4 4 2 2 0 0 8 iso10 6 4 4 2 2 0 0 1 3 5 7 9 1 3 5 7 9 2 4 6 8 10 12 14 16 18 X 2 4 6 8 10 12 14 16 18 X 11 13 15 17 19 11 13 15 17 19 E X A M P L E 2 Q U A L I T Y C H E C K

  26. E X A M P L E 2 Q U A L I T Y C H E C K Locus 9 Significance (based on data with full allele set):INFLATED (but p-values still below 10-5) Top hit 1 : position chr 4:151'355'820 alleles (EMMA) # alleles 1 = 16; # alleles 2 = 5 condition / stat iso1, REMLt p-value: 3.35x10-7 Top hit 2 : position chr 4:152'394'133 alleles (EMMA) # alleles 1 = 17; # alleles 2 = 4 condition / stat iso10, REMLt p-value: 2.31x10-7

  27. 6 iso1 4 -log10pEMMA 2 0 6 iso10 4 -log10pEMMA 2 0 E X A M P L E 2 Q U A L I T Y C H E C K unadjusted p-values across conditions position #1 #2 ctr R ate R iso1 R iso10 Rctr L ate L iso1 L iso10 L 151'355'820 16 52.06x10-5 7.62x10-53.35x10-75.8x10-6 1.29x10-4 3.06x10-4 1.39x10-5 6.05x10-5 152'394'13317 43.13x10-5 2.48x10-44x10-72.31x10-71.66x10-4 6.75x10-4 1.52x10-5 9.93x10-6 151'352'086 16 67.31x10-5 2.85x10-42.87x10-66.66x10-53.02x10-4 7.65x10-4 4.57x10-5 2.74x10-4 152'341'83117 51.17x10-4 8.58x10-44.15x10-68.03x10-64.09x10-4 1.67x10-3 5.59x10-5 7x10-5

  28. chr 4:151'355'820 chr 4:152'394'133 G T T T T T T T T T T T T T T T T G T G G G C C C C C C C C C C C C C C C C C T T C T T chr 4:151'352'086 chr 4:152'341'831 T T T T T T T T T T T T T T T T C C T C C C G G G G G G G G G G G G G G G G G T T G T T unadjusted p-values across conditions position #1 #2 ctr R ate R iso1 Riso10 Rctr L ate L iso1 L iso10 L 151'355'820 16 5 2.06x10-5 7.62x10-53.35x10-75.8x10-6 1.29x10-4 3.06x10-4 1.39x10-5 6.05x10-5 152'394'133 17 4 3.13x10-5 2.48x10-44x10-72.31x10-71.66x10-4 6.75x10-4 1.52x10-5 9.93x10-6 151'352'08616 67.31x10-5 2.85x10-42.87x10-66.66x10-53.02x10-4 7.65x10-4 4.57x10-5 2.74x10-4 152'341'83117 51.17x10-4 8.58x10-44.15x10-68.03x10-64.09x10-4 1.67x10-3 5.59x10-5 7x10-5 E X A M P L E 2 Q U A L I T Y C H E C K iso1 iso10

  29. E X A M P L E 2 Q U A L I T Y C H E C K window: 151-153.5 Mb • very little information on these • Dnajc11 [Hsp40] and Thap3 « interact with Acetaminophen » • Phf13: PHD finger protein • Klhl21: probable substrate-specific adapter of an E3 ubiquitin- protein ligase complex (by similarity); may be expressed in the heart (mouse arrays)

  30. REMLt LRT 8 8 ctr 6 6 4 4 2 2 0 0 8 8 ate 6 6 4 4 2 2 0 0 8 8 iso1 6 6 4 4 2 2 0 0 8 iso10 6 4 4 2 2 0 0 1 3 5 7 9 1 3 5 7 9 2 4 6 8 10 12 14 16 18 X 2 4 6 8 10 12 14 16 18 X 11 13 15 17 19 11 13 15 17 19 E X A M P L E 3 Q U A L I T Y C H E C K

  31. 6 4 -log10pEMMA 2 0 unadjusted p-values across conditions position #1 #2 ctr R ate R iso1 Riso10 R ctr L ate L iso1 L iso10 L 110'702'509 1647.55x10-6 2.38x10-51.59x10-64.2x10-6 1.01x10-4 1.91x10-4 4.16x10-5 6.97x10-5 110'607'85618 42.06x10-5 6.22x10-51.14x10-53.76x10-4 1.58x10-4 3.02x10-4 1.05x10-4 9.53x10-4 E X A M P L E 3 Q U A L I T Y C H E C K Locus 10 Significance (based on data with full allele set): INFLATED Top hit : position chr 10:110'702'509 alleles (EMMA) # alleles 1 = 16; # alleles 2 = 4 condition / stat iso1, REMLt p-value: 1.588x10-6

  32. chr 10:110'607'856 T T T T T T T T T T T T T T T T G T G G T G C C C C C C C C C C C C C C C C T C T C C T G G G G G G G G G G G G G G G G A G A G G A chr 10:110'636'818 C C C C C C C C C C C C C C C C A C A A C A G G G G G G G G G G G G G G G G A G A G G A C C C C C C C C C C C C C C C C C C C A C C G G G G G G G G G G G G G G G G C G C C G G chr 10:110'702'509 T T T T T T T T T T T T T T T T C T C C C C unadjusted p-values across conditions position #1 #2 ctr R ate R iso1 Riso10 R ctr L ate L iso1 L iso10 L 110'702'509 1647.55x10-6 2.38x10-51.59x10-64.2x10-6 1.01x10-4 1.91x10-4 4.16x10-5 6.97x10-5 110'607'85618 42.06x10-5 6.22x10-51.14x10-53.76x10-4 1.58x10-4 3.02x10-4 1.05x10-4 9.53x10-4 E X A M P L E 3 Q U A L I T Y C H E C K iso1

  33. Osbpl8: oxysterol-binding protein-like protein 8 isoform . . . E X A M P L E 3 Q U A L I T Y C H E C K window: 110-111 Mb

  34. NATURE GENETICS VOLUME 40 NUMBER 5 MAY 2008 546 Integrated genomic appraoches implicate osteoglycin (Ogn) in the regulation of left ventricular mass Enrico Petretto1,2,11, Rizwan Sarwar1,11, Ian Grieve1, Han Lu1, Mande K Kumaran1, Phillip J Muckett1, Jonathan Mangion1, Blanche Schroen1, Matthew Benson1, Prakash P Punjabi3, Sanjay K Prasad3, Dudley J Pennell3, Chris Kiesewetter3, Elena S Tasheva4, Lolita M Corpuz4, Megan D Webb4, Gary W Conrad4, Theodore W Kurtz5, Vladimir Kren6,7, Judith Fischer8, Norbert Hubner8, Yigal M Pinto9, Michal Pravenec6,7, Timothy J Aitman1,10 & Stuart A Cook1,3 1Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK. 2Division of Epidemiology, Public Health and Primary Care, Faculty of Medicine, Imperial College, Praed Street, London, W2 1PG, UK. 3National Heart and Lung Institute, Imperial College, Dovehouse Street, London, SW3 6LY, UK. 4Division of Biology, 116 Ackert Hall, Kansas State University, Manhattan, Kansas 66506-4901, USA. 5Department of Laboratory Medicine, University of California, San Francisco, California 94143-0134, USA. 6Institute of Physiology, Czech Academy of Sciences and Centre for Applied Genomics, Vídeská 1083, 142 20 Prague 4, Czech Republic. 7Charles University in Prague, Institute of Biology and Medical Genetics of the First Faculty of Medicine and General Teaching Hospital, Albertov 4, 128 00 Prague 2, Czech Republic. 8Max-Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, Berlin-Buch, 13125, Germany. 9Heart Failure Research Center, Academic Medical Center, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands. 10Section of Molecular Genetics and Rheumatology, Division and Faculty of Medicine, Imperial College, Hammersmith Hospital, Du Cane Road, London, W12 0NN. 11These authors contributed equally to this work. Correspondence to: Timothy J Aitman1,10 (t.aitman@csc.mrc.ac.uk) or Stuart A Cook1,3 (stuart.cook@imperial.ac.uk )

  35. 1 34

  36. ctr iso10

  37. REMLt LRT 8 8 ctr 6 6 4 4 2 2 0 0 8 8 ate 6 6 4 4 2 2 0 0 8 8 iso1 6 6 4 4 2 2 0 0 8 iso10 6 4 4 2 2 0 0 1 3 5 7 9 1 3 5 7 9 2 4 6 8 10 12 14 16 18 X 2 4 6 8 10 12 14 16 18 X 11 13 15 17 19 11 13 15 17 19 E X A M P L E 4 Q U A L I T Y C H E C K

  38. E X A M P L E 4 Q U A L I T Y C H E C K Locus 13 Significance (based on data with full allele set):INFLATED ? Top hit 1 : position chr 5:104'572'764 alleles (EMMA) # alleles 1 = 15; # alleles 2 = 5 condition / stat iso10, REMLt p-value: 8.03x10-7 Top hit 2 : position chr 5:104'515'280 alleles (EMMA) #alleles 1 = 17; # alleles 2 = 4 condition / stat iso10, REMLt p-value: 5.597x10-6

  39. 6 4 -log10pEMMA 2 0 unadjusted p-values across conditions position #1 #2 ctr R ate R iso1 R iso10 Rctr L ate L iso1 L iso10 L 104'572'764 15 53.65x10-4 5.52x10-4 1.64x10-58.03x10-71.09x10-3 1.38x10-3 1.56x10-4 4.08x10-5 104'515'280 17 41.3x10-3 1.14x10-3 9.77x10-55.6x10-62.52x10-3 2.21x10-3 4.12x10-4 9.5x10-5 E X A M P L E 4 Q U A L I T Y C H E C K iso10

  40. C C C C C C C C C C C C C C C C T C T T T chr 5:104‘515‘280 chr 5:104‘572‘764 C C C C C C C C C C C C C C C C T C T T T T unadjusted p-values across conditions position #1 #2 ctr R ate R iso1 R iso10 Rctr L ate L iso1 L iso10 L 104'572'764 1553.65x10-4 5.52x10-4 1.64x10-58.03x10-71.09x10-3 1.38x10-3 1.56x10-4 4.08x10-5 104'515'280 1741.3x10-3 1.14x10-3 9.77x10-55.6x10-62.52x10-3 2.21x10-3 4.12x10-4 9.5x10-5 E X A M P L E 4 Q U A L I T Y C H E C K iso10

  41. E X A M P L E 4 Q U A L I T Y C H E C K window: 104-105 Mb Sparcl1: Protein of the ECM. SPARC-like protein 1, a member of the SPARC family, is downregulated in various tumours. Information is otherwise sparse. BUT : the analogue Sparc (osteonectin) was identified as a cis-eQTL associated with indexed cardiac mass in the rat. There is further experimental evidence for a link between Sparc and cardiac hypertrophy.

  42. NATURE GENETICS VOLUME 40 NUMBER 5 MAY 2008 546 Integrated genomic appraoches implicate osteoglycin (Ogn) in the regulation of left ventricular mass Enrico Petretto1,2,11, Rizwan Sarwar1,11, Ian Grieve1, Han Lu1, Mande K Kumaran1, Phillip J Muckett1, Jonathan Mangion1, Blanche Schroen1, Matthew Benson1, Prakash P Punjabi3, Sanjay K Prasad3, Dudley J Pennell3, Chris Kiesewetter3, Elena S Tasheva4, Lolita M Corpuz4, Megan D Webb4, Gary W Conrad4, Theodore W Kurtz5, Vladimir Kren6,7, Judith Fischer8, Norbert Hubner8, Yigal M Pinto9, Michal Pravenec6,7, Timothy J Aitman1,10 & Stuart A Cook1,3 1Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK. 2Division of Epidemiology, Public Health and Primary Care, Faculty of Medicine, Imperial College, Praed Street, London, W2 1PG, UK. 3National Heart and Lung Institute, Imperial College, Dovehouse Street, London, SW3 6LY, UK. 4Division of Biology, 116 Ackert Hall, Kansas State University, Manhattan, Kansas 66506-4901, USA. 5Department of Laboratory Medicine, University of California, San Francisco, California 94143-0134, USA. 6Institute of Physiology, Czech Academy of Sciences and Centre for Applied Genomics, Vídeská 1083, 142 20 Prague 4, Czech Republic. 7Charles University in Prague, Institute of Biology and Medical Genetics of the First Faculty of Medicine and General Teaching Hospital, Albertov 4, 128 00 Prague 2, Czech Republic. 8Max-Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, Berlin-Buch, 13125, Germany. 9Heart Failure Research Center, Academic Medical Center, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands. 10Section of Molecular Genetics and Rheumatology, Division and Faculty of Medicine, Imperial College, Hammersmith Hospital, Du Cane Road, London, W12 0NN. 11These authors contributed equally to this work. Correspondence to: Timothy J Aitman1,10 (t.aitman@csc.mrc.ac.uk) or Stuart A Cook1,3 (stuart.cook@imperial.ac.uk )

  43. NATURE GENETICS VOLUME 40 NUMBER 5 MAY 2008 546 Supplementary Table 2. Cis-eQTLs detected with FDR ≤ 5%, an absolute fold change > 1.5 at the peak of linkage by parental genotype, and that co-localize with cardiac mass QTLs (i.e., between genetic markers at the extremes of the QTL region as defined in the Rat Genome Database, http://rgd.mcw.edu/) that have been mapped in the SHR or BN strain crosses. Probeset Id Gene Symbol Chr PGW FDR (%) LOD score Fold change 1367562_at Sparc* 10 8.5x10-5 0.6% 7.0 1.6 1376749_at Ogn 17 1.7x10-3 4.1% 6.0 2.7 1383263_at Ogn 17 1.3x10-3 3.2% 6.3 2.5 1368574_at Adra1b◊* 10 1.0x10-6 0.4% 10.2 1.8 1398844_at Txn2◊ 7 6.6x10-5 0.5% 7.6 -1.6 * these genes are located in the same QTL in the rat ◊ these genes are major determinants of cardiac hypertrophy in the mouse There are 76 entries (70 genes) in the original table

  44. ctr iso10

  45. S U M M A R Y Q U A L I T Y C H E C K • Of the 32 loci for VWI with pEMMA<10-5 : • 16 loci based on SNP(s) with full allele sets across the 22 strains • 11 judged as « correct » (p-values are consistent across tests); these hits fall mainly in gene-poor regions • 5 judged as « false positives » (inconsistent data) • 16 loci based on SNP(s) with incomplete allele sets across the 22 strains • at least 10 have inflated p-values • Candidate genes ?

  46. 10 1 2 3 4 8 chr3 81-85 Mb / ctr REMLt chr3 86-90 Mb / ctr REMLt chr4 94.8 Mb / iso1 REMLt chr7 75-77 Mb / ate REMLt 6 CORRECT CORRECT CORRECT INFLATED 4 2 0 5 6 7 8 chr1 11.5-12.5 Mb / ate LRT chr1 38.5-39.5 Mb / ate LRT chr2 130-132 Mb / ate LRT chr2 117-118 Mb / iso1 REMLt CORRECT INFLATED INFLATED ? INFLATED 9 10 11 12 chr4 151-153 Mb / iso10 REMLt chr10 110-111 Mb / iso1 REMLt chr1 94.5-95.5 Mb / iso10 REMLt chr2 119-121 Mb / iso10 REMLt INFLATED but ok INFLATED INFLATED INFLATED ? 13 14 15 16 chr5 104-105 Mb / iso10 REMLt chr6 76-77 Mb / iso10 LRT chr5 127-129 Mb / ate REMLt chr9 65-66 Mb / ate REMLt CORRECT CORRECT CORRECT INFLATED ?

  47. 10 17 18 19 20 8 6 INFLATED but ok CORRECT CORRECT INFLATED ? 4 2 0 21 22 23 24 CORRECT INFLATED ? INFLATED INFLATED ? 25 26 27 28 CORRECT INFLATED FALSE POSITIVE FALSE POSITIVE 29 30 31 32 INFLATED FALSE POSITIVE FALSE POSITIVE FALSE POSITIVE chr7 16-17 Mb / iso1 REMLt chr6 125-126 Mb / iso1 REMLt chr7 24.5-25.5 Mb / iso1 REMLt chr4 72-73.5 Mb / iso10 REMLt chr4 82.5-83.5 Mb / iso10 REMLt chr6 145-146 Mb / iso10 REMLt chr6 5-6 Mb / iso10 REMLt chr18 60.5-61.5 Mb / iso10 LRT chr4 135-136 Mb / ctr LRT chr5 45-46 Mb / iso1 LRT chr5 47-48 Mb / iso1 LRT chr12 101-103 Mb / iso10 LRT chr12 113-114 Mb / iso10 LRT chr6 110-111 Mb / iso10 LRT chr1 3-3.5 Mb / iso10 REMLt chr17 12-13 Mb / iso10 REMLt

  48. I N S U M M A R Y • Issues • POWER • Genome-wide significance ? • Perform QC across all scans • Prioritize candidate genes

  49. N O T E S SDP in Adrb1 in the CV-PGX panel Source: CGD1 imputed SNP panel (MPD)

  50. « L O C I » W I T H p <10-5

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