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LP/J PL/JKK/HlJ 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 Internal Medicine.

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Presentation on theme: "LP/J PL/JKK/HlJ 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 Internal Medicine."— Presentation transcript:

1 LP/J PL/JKK/HlJ 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 Internal Medicine Thierry Pedrazzini Medical Genetics Corinne Berthonneche, Fanny Schüpfer, Fabienne Maurer, Bastian Peter, Micha Hersch, Sven Bergmann, Jacqui Beckmann Pharmacology and Cardiology / DKF UNIBE Hugues Abriel Computer Science and Engineering Eleazar Eskin (UCLA)

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

3 SBP : Systolic Blood Pressure HR : Heart Rate euthanasy tissues plasma days or ISOPROTERENOL or ATENOLOL 0714 SBP and HR recording training phase SBP HR ECG urine CONTROL osmotic mini-pump implantation for continuous and controlled drug delivery n=10 mice per condition and per strain P R O T O C O L

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

5 P H E N O T Y P E S

6 all phenotypes and responses to drug treatments are highly heritable (h 2 >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 » P H E N O T Y P E S - S U M M A R Y

7 all phenotypes and responses to drug treatments are highly heritable (h 2 >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 P H E N O T Y P E S - S U M M A R Y

8 ECG heart rate systolic blood pressure non invasive measurements tissues heart liver  transcriptional analyses  proteomics etc... plasma; urine pharmacokinetics (+ metabolites) 1 mouse 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 BW t-test chromosomes pointwise -log 10 p-values -> 6000 SNPs at p≤10 –6 and 283 SNPs with p<10 –10 38 strains ca 100’000 SNPs

11 BW t-test BW EMMA “ 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. ” p=3.8x10 -6 explains 39% of the genetic variance component

12 BW t-test 38 strains BW EMMA LW t-test 34 strains LW EMMA p=3.8x10 -6 explains 39% of the genetic variance component 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 G W A S C A N S F O R V W I 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

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 adapted from: Zarrinpashneh et al. AMPKα2 counteracts the development of cardiac hypertrophy induced by isoproterenol. BBRC 376:677-681, 2008 PW posterior wall thickness MCSA mean cardiac myocyte cross-sectional area Mice challenged by daily IP injections of 50 mg/kg isoproterenol for 1 wk

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

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

18 1 234 5678 9101112 13141516 chr3 81-85 Mb / ctr REMLtchr3 86-90 Mb / ctr REMLtchr4 94.8 Mb / iso1 REMLtchr7 75-77 Mb / ate REMLt chr1 11.5-12.5 Mb / ate LRTchr1 38.5-39.5 Mb / ate LRTchr2 130-132 Mb / ate LRTchr2 117-118 Mb / iso1 REMLt chr4 151-153 Mb / iso10 REMLtchr10 110-111 Mb / iso1 REMLtchr1 94.5-95.5 Mb / iso10 REMLtchr2 119-121 Mb / iso10 REMLt chr5 104-105 Mb / iso10 REMLtchr6 76-77 Mb / iso10 LRTchr5 127-129 Mb / ate REMLtchr9 65-66 Mb / ate REMLt 10 8 6 4 2 0

19 17 181920 21222324 25262728 29303132 chr7 16-17 Mb / iso1 REMLtchr6 125-126 Mb / iso1 REMLtchr7 24.5-25.5 Mb / iso1 REMLtchr4 72-73.5 Mb / iso10 REMLt chr4 82.5-83.5 Mb / iso10 REMLtchr6 145-146 Mb / iso10 REMLtchr6 5-6 Mb / iso10 REMLtchr18 60.5-61.5 Mb / iso10 LRT chr4 135-136 Mb / ctr LRTchr5 45-46 Mb / iso1 LRTchr5 47-48 Mb / iso1 LRTchr12 101-103 Mb / iso10 LRT chr12 113-114 Mb / iso10 LRTchr6 110-111 Mb / iso10 LRTchr1 3-3.5 Mb / iso10 REMLtchr17 12-13 Mb / iso10 REMLt 10 8 6 4 2 0

20 Q U A L I T Y C H E C K 32 loci for VWI (across 4 conditions and 2 statistical tests) 1.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) 2.list putative candidate genes (UCSC genome browser, biblio, etc…)

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

22 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: positionchr 6:125'528'422 alleles (EMMA)# alleles 1 = 17; # alleles 2 = 5 condition / statiso1, REMLT p-value: 4.07x10 -6 unadjusted p-values across conditions ctr REMLtate REMLtiso1 REMLtiso10 REMLtctr LRTate LRTiso1 LRTiso10 LRT 6.2x10 -5 3.7x10 -5 4.07x10 -6 2.67x10 -5 2.77x10 -4 2.04x10 -4 5.62x10 -5 1.63x10 -4 0 4 6 2 -log 10 p EMMA

23 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: positionchr 6:125'528'422 alleles (EMMA)# alleles 1 = 17; # alleles 2 = 5 condition / statiso1, REMLT p-value: 4.07x10 -6 GGGGGGGGGGGGGGGGAAAAAGG vWF intron 6 Ranking strains by increasing VWI means in the iso1 group:

24 0 4 6 2 vWF intron 6 window: 124-126 Mb

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

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 : positionchr 4:151'355'820 alleles (EMMA)# alleles 1 = 16; # alleles 2 = 5 condition / statiso1, REMLt p-value:3.35x10 -7 Top hit 2 :positionchr 4:152'394'133 alleles (EMMA)# alleles 1 = 17; # alleles 2 = 4 condition / statiso10, REMLt p-value:2.31x10 -7

27 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#2ctr Rate Riso1 Riso10 Rctr Late Liso1 Liso10 L 151'355'82016 5 2.06x10 -5 7.62x10 -5 3.35x10 -7 5.8x10 -6 1.29x10 -4 3.06x10 -4 1.39x10 -5 6.05x10 -5 152'394'13317 4 3.13x10 -5 2.48x10 -4 4x10 -7 2.31x10 -7 1.66x10 -4 6.75x10 -4 1.52x10 -5 9.93x10 -6 0 4 6 2 -log 10 p EMMA 0 4 6 2 iso1 iso10 151'352'08616 6 7.31x10 -5 2.85x10 -4 2.87x10 -6 6.66x10 -5 3.02x10 -4 7.65x10 -4 4.57x10 -5 2.74x10 -4 152'341'83117 51.17x10 -4 8.58x10 -4 4.15x10 -6 8.03x10 -6 4.09x10 -4 1.67x10 -3 5.59x10 -5 7x10 -5

28 E X A M P L E 2 Q U A L I T Y C H E C K iso1iso10 chr 4:151'355'820 unadjusted p-values across conditions position#1#2ctr Rate Riso1 Riso10 Rctr Late Liso1 Liso10 L 151'355'82016 5 2.06x10 -5 7.62x10 -5 3.35x10 -7 5.8x10 -6 1.29x10 -4 3.06x10 -4 1.39x10 -5 6.05x10 -5 152'394'13317 4 3.13x10 -5 2.48x10 -4 4x10 -7 2.31x10 -7 1.66x10 -4 6.75x10 -4 1.52x10 -5 9.93x10 -6 TTTTTTTTTTTTTTGTT G GGGT chr 4:152'394'133 CCCCCCCCCCCCCCTTC C CTTC 151'352'08616 6 7.31x10 -5 2.85x10 -4 2.87x10 -6 6.66x10 -5 3.02x10 -4 7.65x10 -4 4.57x10 -5 2.74x10 -4 152'341'83117 51.17x10 -4 8.58x10 -4 4.15x10 -6 8.03x10 -6 4.09x10 -4 1.67x10 -3 5.59x10 -5 7x10 -5 chr 4:151'352'086 TTTTTTTTTTTTTTCTTCCCCTGGGGGGGGGGGGGGTTGGGTTG chr 4:152'341'831

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

31 E X A M P L E 3 Q U A L I T Y C H E C K 0 4 6 2 -log 10 p EMMA Locus 10 Significance (based on data with full allele set): INFLATED Top hit : positionchr 10:110'702'509 alleles (EMMA)# alleles 1 = 16; # alleles 2 = 4 condition / statiso1, REMLt p-value:1.588x10 -6 unadjusted p-values across conditions position#1#2ctr Rate Riso1 Riso10 Rctr Late Liso1 Liso10 L 110'702'50916 47.55x10 -6 2.38x10 -5 1.59x10 -6 4.2x10 -6 1.01x10 -4 1.91x10 -4 4.16x10 -5 6.97x10 -5 110'607'85618 42.06x10 -5 6.22x10 -5 1.14x10 -5 3.76x10 -4 1.58x10 -4 3.02x10 -4 1.05x10 -4 9.53x10 -4

32 E X A M P L E 3 Q U A L I T Y C H E C K iso1 chr 10:110'702'509 TTTTTTTTTTTTTTTCTCCCCT unadjusted p-values across conditions position#1#2ctr Rate Riso1 Riso10 Rctr Late Liso1 Liso10 L 110'702'50916 47.55x10 -6 2.38x10 -5 1.59x10 -6 4.2x10 -6 1.01x10 -4 1.91x10 -4 4.16x10 -5 6.97x10 -5 110'607'85618 42.06x10 -5 6.22x10 -5 1.14x10 -5 3.76x10 -4 1.58x10 -4 3.02x10 -4 1.05x10 -4 9.53x10 -4 TTTTTTTTTTTTTTTGTGGTGT CCCCCCCCCCCCCCCTCTCCTC GGGGGGGGGGGGGGGAGAGGAG CCCCCCCCCCCCCCCACAACAC GGGGGGGGGGGGGGGAGAGGAG CCCCCCCCCCCCCCCCCCACCC GGGGGGGGGGGGGGGCGCCGGG chr 10:110'607'856 chr 10:110'636'818

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

34 NATURE GENETICS VOLUME 40 NUMBER 5 MAY 2008 546 Integrated genomic appraoches implicate osteoglycin (Ogn) in the regulation of left ventricular mass Enrico Petretto 1,2,11, Rizwan Sarwar 1,11, Ian Grieve 1, Han Lu 1, Mande K Kumaran 1, Phillip J Muckett 1, Jonathan Mangion 1, Blanche Schroen 1, Matthew Benson 1, Prakash P Punjabi 3, Sanjay K Prasad 3, Dudley J Pennell 3, Chris Kiesewetter 3, Elena S Tasheva 4, Lolita M Corpuz 4, Megan D Webb 4, Gary W Conrad 4, Theodore W Kurtz 5, Vladimir Kren 6,7, Judith Fischer 8, Norbert Hubner 8, Yigal M Pinto 9, Michal Pravenec 6,7, Timothy J Aitman 1,10 & Stuart A Cook 1,3 1 Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK. 2 Division of Epidemiology, Public Health and Primary Care, Faculty of Medicine, Imperial College, Praed Street, London, W2 1PG, UK. 3 National Heart and Lung Institute, Imperial College, Dovehouse Street, London, SW3 6LY, UK. 4 Division of Biology, 116 Ackert Hall, Kansas State University, Manhattan, Kansas 66506-4901, USA. 5 Department of Laboratory Medicine, University of California, San Francisco, California 94143-0134, USA. 6 Institute of Physiology, Czech Academy of Sciences and Centre for Applied Genomics, Vídeská 1083, 142 20 Prague 4, Czech Republic. 7 Charles 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. 8 Max-Delbrück Center for Molecular Medicine, Robert-Rössle- Strasse 10, Berlin-Buch, 13125, Germany. 9 Heart Failure Research Center, Academic Medical Center, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands. 10 Section of Molecular Genetics and Rheumatology, Division and Faculty of Medicine, Imperial College, Hammersmith Hospital, Du Cane Road, London, W12 0NN. 11 These authors contributed equally to this work. Correspondence to: Timothy J Aitman 1,10 (t.aitman@csc.mrc.ac.uk) or Stuart A Cook 1,3 (stuart.cook@imperial.ac.uk )

35 34 1

36 ctr iso10

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

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 : positionchr 5:104'572'764 alleles (EMMA)# alleles 1 = 15; # alleles 2 = 5 condition / statiso10, REMLt p-value:8.03x10 -7 Top hit 2 :positionchr 5:104'515'280 alleles (EMMA)#alleles 1 = 17; # alleles 2 = 4 condition / statiso10, REMLt p-value:5.597x10 -6

39 E X A M P L E 4 Q U A L I T Y C H E C K 0 4 6 2 -log 10 p EMMA iso10 unadjusted p-values across conditions position#1#2ctr Rate Riso1 Riso10 Rctr Late Liso1 Liso10 L 104'572'76415 53.65x10 -4 5.52x10 -4 1.64x10 -5 8.03x10 -7 1.09x10 -3 1.38x10 -3 1.56x10 -4 4.08x10 -5 104'515'28017 41.3x10 -3 1.14x10 -3 9.77x10 -5 5.6x10 -6 2.52x10 -3 2.21x10 -3 4.12x10 -4 9.5x10 -5

40 E X A M P L E 4 Q U A L I T Y C H E C K unadjusted p-values across conditions position#1#2ctr Rate Riso1 Riso10 Rctr Late Liso1 Liso10 L 104'572'76415 53.65x10 -4 5.52x10 -4 1.64x10 -5 8.03x10 -7 1.09x10 -3 1.38x10 -3 1.56x10 -4 4.08x10 -5 chr 5:104‘572‘764 CCCCCCCCCCCCCCCTCTTTTC chr 5:104‘515‘280 CCCCCCCCCCCCCCCCTTTTC iso10 104'515'28017 41.3x10 -3 1.14x10 -3 9.77x10 -5 5.6x10 -6 2.52x10 -3 2.21x10 -3 4.12x10 -4 9.5x10 -5

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 Petretto 1,2,11, Rizwan Sarwar 1,11, Ian Grieve 1, Han Lu 1, Mande K Kumaran 1, Phillip J Muckett 1, Jonathan Mangion 1, Blanche Schroen 1, Matthew Benson 1, Prakash P Punjabi 3, Sanjay K Prasad 3, Dudley J Pennell 3, Chris Kiesewetter 3, Elena S Tasheva 4, Lolita M Corpuz 4, Megan D Webb 4, Gary W Conrad 4, Theodore W Kurtz 5, Vladimir Kren 6,7, Judith Fischer 8, Norbert Hubner 8, Yigal M Pinto 9, Michal Pravenec 6,7, Timothy J Aitman 1,10 & Stuart A Cook 1,3 1 Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK. 2 Division of Epidemiology, Public Health and Primary Care, Faculty of Medicine, Imperial College, Praed Street, London, W2 1PG, UK. 3 National Heart and Lung Institute, Imperial College, Dovehouse Street, London, SW3 6LY, UK. 4 Division of Biology, 116 Ackert Hall, Kansas State University, Manhattan, Kansas 66506-4901, USA. 5 Department of Laboratory Medicine, University of California, San Francisco, California 94143-0134, USA. 6 Institute of Physiology, Czech Academy of Sciences and Centre for Applied Genomics, Vídeská 1083, 142 20 Prague 4, Czech Republic. 7 Charles 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. 8 Max-Delbrück Center for Molecular Medicine, Robert-Rössle- Strasse 10, Berlin-Buch, 13125, Germany. 9 Heart Failure Research Center, Academic Medical Center, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands. 10 Section of Molecular Genetics and Rheumatology, Division and Faculty of Medicine, Imperial College, Hammersmith Hospital, Du Cane Road, London, W12 0NN. 11 These authors contributed equally to this work. Correspondence to: Timothy J Aitman 1,10 (t.aitman@csc.mrc.ac.uk) or Stuart A Cook 1,3 (stuart.cook@imperial.ac.uk )

43 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 P GW 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_atTxn2 ◊ 76.6x10 -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 NATURE GENETICS VOLUME 40 NUMBER 5 MAY 2008 546

44 ctr iso10

45 S U M M A R YQ U A L I T Y C H E C K Of the 32 loci for VWI with p EMMA <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 1 234 5678 9101112 13141516 chr3 81-85 Mb / ctr REMLtchr3 86-90 Mb / ctr REMLtchr4 94.8 Mb / iso1 REMLtchr7 75-77 Mb / ate REMLt chr1 11.5-12.5 Mb / ate LRTchr1 38.5-39.5 Mb / ate LRTchr2 130-132 Mb / ate LRTchr2 117-118 Mb / iso1 REMLt chr4 151-153 Mb / iso10 REMLtchr10 110-111 Mb / iso1 REMLtchr1 94.5-95.5 Mb / iso10 REMLtchr2 119-121 Mb / iso10 REMLt chr5 104-105 Mb / iso10 REMLtchr6 76-77 Mb / iso10 LRTchr5 127-129 Mb / ate REMLtchr9 65-66 Mb / ate REMLt 10 8 6 4 2 0 CORRECT INFLATED CORRECT INFLATED INFLATED ? CORRECT INFLATED INFLATED but ok INFLATED INFLATED ? CORRECT

47 17 181920 21222324 25262728 29303132 chr7 16-17 Mb / iso1 REMLtchr6 125-126 Mb / iso1 REMLtchr7 24.5-25.5 Mb / iso1 REMLtchr4 72-73.5 Mb / iso10 REMLt chr4 82.5-83.5 Mb / iso10 REMLtchr6 145-146 Mb / iso10 REMLtchr6 5-6 Mb / iso10 REMLtchr18 60.5-61.5 Mb / iso10 LRT chr4 135-136 Mb / ctr LRTchr5 45-46 Mb / iso1 LRTchr5 47-48 Mb / iso1 LRTchr12 101-103 Mb / iso10 LRT chr12 113-114 Mb / iso10 LRTchr6 110-111 Mb / iso10 LRTchr1 3-3.5 Mb / iso10 REMLtchr17 12-13 Mb / iso10 REMLt 10 8 6 4 2 0 INFLATED ? CORRECT INFLATED but ok INFLATED ? CORRECT INFLATED INFLATED ? CORRECT FALSE POSITIVE INFLATED FALSE POSITIVE

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

51


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