SUPPLEMENTARY INFORMATION. Meta-analyses of genome-wide association studies identify multiple novel loci related to pulmonary function

Transcription

1 SUPPLEMENTARY INFORMATION Meta-analyses of genome-wide association studies identify multiple novel loci related to pulmonary function Dana B. Hancock, 1,29 Mark Eijgelsheim, 2,29 Jemma B. Wilk, 3,29 Sina A. Gharib, 4,5,29 Laura R. Loehr, 1,6 Kristin D. Marciante, 5,7 Nora Franceschini, 6 Yannick M.T.A. van Durme, 2,8 Ting-hsu Chen, 9,10 R. Graham Barr, 11,12,13 Matthew B. Schabath, 14 David J. Couper, 15 Guy G. Brusselle, 2,8 Bruce M. Psaty, 5,6,16,17,18 Cornelia M. van Duijn, 2 Jerome I. Rotter, 19 André G. Uitterlinden, 2,20 Albert Hofman, 2 Naresh M. Punjabi, 21 Fernando Rivadeneira, 2,20 Alanna C. Morrison, 22 Paul L. Enright, 23 Kari E. North, 6,24 Susan R. Heckbert, 7,16,17 Thomas Lumley, 25,30 Bruno H.Ch. Stricker, 2,20,26,27,30 George T. O Connor, 9,10,30 Stephanie J. London 1,28,30 1 Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina; 2 Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands; 3 Departments of Neurology and Medicine, Boston University School of Medicine, Boston, Massachusetts; 4 Center for Lung Biology, University of Washington, Seattle, Washington; 5 Department of Medicine, University of Washington, Seattle, Washington; 6 Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; 7 Cardiovascular Health Research Unit, University of Washington, Seattle, Washington; 8 Department of Respiratory Medicine, Ghent University and Ghent University Hospital, Ghent, Belgium; 9 Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts; 10 The National Heart, Lung, and Blood Institute s Framingham Heart Study, Framingham, Massachusetts; 11 Division of General Medicine, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York; 12 Division of Pulmonary, Allergy and Critical Care, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York; 13 Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York; 14 Risk Assessment, Detection, and Intervention, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida; 15 Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; 16 Department of Epidemiology, University of Washington, Seattle, Washington; 17 Center for Health Studies, Group Health, Seattle, Washington; 18 Department of Health Services, University of Washington, Seattle, Washington; 19 Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California; 20 Department of Internal Medicine, Eramus Medical Center, Rotterdam, The Netherlands; 21 Departments of Medicine and Epidemiology, Johns Hopkins University, Baltimore, Maryland; 22 Human Genetics Center, Division of Epidemiology and Disease Control, University of Texas Health Science Center at Houston, Houston, Texas; 23 College of Public Health, University of Arizona, Tucson, Arizona; 24 Carolina Center for Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, NC; 25 Department of Biostatistics, University of Washington, Seattle, Washington; 26 Netherlands Genomics Initiativesponsored Netherlands Consortium for Healthy Aging, Rotterdam, The Netherlands; 27 Inspectorate of Health Care, The Hague, The Netherlands; 28 Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina; 29 These authors contributed equally to this work; 30 These authors jointly directed this work. 1

2 Supplementary Table 2. Genome-wide significant SNPs (P<5x10-8 ) from meta-analysis of associations with FEV 1 /FVC in all participants and in never smokers from the CHARGE consortium, sorted by GWAS P value. No genome-wide significant associations were observed in ever smokers. CHARGE meta-analysis in all participants CHARGE meta-analysis in never smokers Gene/ Nearest Reference Allele β, perallele FEV 1 /FVC β, perallele FEV 1 /FVC SNP Chr Position SNP type gene allele frequency a (%) P (%) b P c rs Intergenic HHIP T x NS rs Intergenic HHIP G x NS rs Intergenic HHIP C x NS rs Intergenic HHIP G x NS rs Intergenic HHIP G x NS rs Intergenic HHIP G x NS rs Intergenic HHIP G x NS rs Intergenic HHIP T x NS rs Intergenic HHIP G x NS rs Intergenic HHIP C x NS rs Intergenic HHIP C x NS rs Intergenic HHIP G x NS rs Intergenic HHIP G x NS rs Intergenic HHIP G x NS rs Intergenic HHIP G x NS rs Intergenic HHIP G x NS rs Intergenic HHIP G x NS rs Intergenic HHIP G x NS rs Intergenic HHIP C x NS rs Intergenic HHIP C x NS rs Intergenic HHIP C x NS 2

3 rs Intergenic HHIP C x NS rs Intergenic HHIP G x NS rs Intergenic HHIP C x NS rs Intergenic HHIP G x NS rs Intronic GPR126 A x x10-9 rs Intergenic HHIP C x NS rs Intronic GPR126 G x x10-9 rs UTR GPR126 G x x10-8 rs Intergenic HHIP C x NS rs Intronic ADAM19 A x NS rs Intronic GPR126 G x x10-8 rs Intergenic GPR126 C x x10-8 rs Intronic ADAM19 T x NS rs Intergenic HHIP G x NS rs Intergenic GPR126 G x x10-8 rs Intergenic GPR126 C x x10-8 rs Intergenic GPR126 G x x10-8 rs Intronic ADAM19 G x NS rs Intronic ADAM19 G x NS rs Intronic ADAM19 G x NS rs Nonsynonymous ADAM19 T x NS (missense) rs d Intronic GPR126 G x x10-9 rs Intergenic GPR126 A x x10-9 rs Intronic ADAM19 G x NS rs d Intergenic GPR126 G x x10-9 rs d Intronic GPR126 G x x10-9 rs d Intronic GPR126 C x x10-9 rs Intronic GPR126 G x x10-9 rs Intronic GPR126 G x x10-10 rs d Intronic GPR126 G x x10-9 3

4 rs Intronic GPR126 C x x10-9 rs Intronic GPR126 C x x10-10 rs Intronic GPR126 G x NS rs Intronic GPR126 T x x10-9 rs Intronic GPR126 T x x10-10 rs Intronic GPR126 C x x10-9 rs Intronic GPR126 G x x10-9 rs Intronic GPR126 G x x10-10 rs Intronic GPR126 G x x10-10 rs Intronic GPR126 G x x10-8 rs Intronic GPR126 C x x10-9 rs Intronic GPR126 C x x10-8 rs Intronic GPR126 T x x10-9 rs Intronic GPR126 G x x10-9 rs d Intergenic GPR126 C x x10-8 rs Intergenic HHIP T x NS rs Intronic GPR126 G x x10-9 rs Intronic GPR126 G x x10-8 rs Intronic GPR126 G x x10-9 rs Intronic GPR126 C x x10-8 rs Intronic GPR126 G x x10-8 rs Intronic GPR126 C x x10-8 rs Intronic GPR126 C x x10-9 rs Intronic GPR126 G x x10-9 rs Intronic GPR126 T x x10-8 rs d Intergenic GPR126 C x x10-8 rs d Intergenic GPR126 C x x10-8 rs Intronic GPR126 C x x10-9 rs Intronic GPR126 C x x10-9 rs Intronic GPR126 T x x10-9 rs Intronic GPR126 C x x10-9 rs Intronic GPR126 G x x10-8 4

5 rs Intronic GPR126 G x x10-8 rs Intronic GPR126 G x x10-9 rs Nonsynonymous GPR126 A x x10-8 (missense) rs Intronic GPR126 C x x10-10 rs Intronic GPR126 G x x10-9 rs Intronic GPR126 G x x10-9 rs Intergenic GPR126 C x NS rs d Intronic GPR126 G x x10-9 rs Intergenic GPR126 G x x10-8 rs Intronic GPR126 C x x10-8 rs Intronic GPR126 C x NS rs Intergenic GPR126 G x NS rs Intronic GPR126 G x x10-9 rs Nonsynonymous AGER T x NS (missense) rs d Intergenic GPR126 G x x10-8 rs Intronic GPR126 G x NS rs Intronic FAM13A T x NS rs Intronic FAM13A C x NS rs Intronic FAM13A C x NS rs Intronic PTCH1 A x NS rs Intronic FAM13A A x NS rs Intronic GPR126 G x x10-9 rs Intergenic GPR126 G x NS rs d Intergenic GPR126 C x x10-8 rs Intronic PTCH1 A x NS rs Intronic GPR126 G x NS rs d Intergenic GPR126 C x NS rs Intergenic GPR126 T x NS 5

6 rs Intergenic PID1 T x NS rs Intergenic PID1 T x NS rs Intergenic PID1 C x NS rs Intergenic PID1 G x NS rs Intergenic PID1 G x NS rs Intronic PPT2 T x NS rs Intergenic PID1 C x NS rs d Intergenic GPR126 C x NS a Weighted average reference allele frequency for combined cohorts. b β estimates are not given for results that are not significant. c Results with P>5x10-8 were considered not significant. d Opposing β directions were noted for at least one CHARGE cohort in the meta-analysis of all participants. FEV 1 /FVC, forced expiratory volume in one second to forced vital capacity ratio; NS, not significant; UTR, untranslated region 6

7 Supplementary Table 3. Cohort-specific association results for SNPs with the smallest P value from each implicated locus at or near genome-wide significance in CHARGE. Gene/ Nearest gene β, per-allele FEV 1 /FVC (%) or FEV 1 (ml) ARIC CHS FHS RS-I RS-II β, β, β, β, per-allele per-allele per-allele per-allele FEV 1 /FVC FEV 1 /FVC FEV 1 /FVC FEV 1 /FVC (%) or (%) or (%) or (%) or SE FEV 1 (ml) SE FEV 1 (ml) SE FEV 1 (ml) SE FEV 1 (ml) Reference SNP Chr allele Trait SE rs HHIP T FEV 1 /FVC rs GPR126 A FEV 1 /FVC rs ADAM19 A FEV 1 /FVC rs AGER T FEV 1 /FVC rs FAM13A T FEV 1 /FVC rs PTCH1 A FEV 1 /FVC rs PID1 T FEV 1 /FVC rs HTR4 T FEV 1 /FVC rs NPNT A FEV FEV 1, forced expiratory volume in one second; FEV 1 /FVC, forced expiratory volume in one second to forced vital capacity ratio; SE, standard error 7

8 Supplementary Table 4. Genome-wide significant SNPs (P<5x10-8 ) from meta-analysis of associations with FEV 1 in all participants and in ever smokers from the CHARGE consortium, sorted by GWAS P value. No genome-wide significant associations were observed in never smokers. CHARGE meta-analysis in all participants CHARGE meta-analysis in ever smokers Gene/ Nearest Reference Allele β, per-allele β, per-allele SNP Chr Position SNP type gene allele frequency a FEV 1 (ml) P FEV 1 (ml) b P c rs Intergenic NPNT A x x10-9 rs Intronic INTS12 T x x10-9 rs Intergenic FLJ20184 T x NS rs Intergenic NPNT C x x10-9 rs Intergenic NPNT G x x10-9 rs Intergenic NPNT C x x10-9 rs Intergenic NPNT G x x10-9 rs Intronic GSTCD T x x10-9 rs Intronic GSTCD G x x10-8 rs Intronic GSTCD A x x10-8 rs Intronic GSTCD T x x10-8 rs Intronic GSTCD G x x10-8 rs Intronic GSTCD C x x10-8 rs Intronic GSTCD C x x10-8 rs Intronic GSTCD G x x10-9 rs Intronic GSTCD G x x10-9 rs Intronic GSTCD G x x10-9 rs Intronic GSTCD G x x10-8 rs Intronic GSTCD T x x10-8 rs Intronic GSTCD T x x10-9 rs Intronic GSTCD G x x10-9 rs Intronic GSTCD C x x10-9 rs Intronic GSTCD G x x10-9 8

9 rs Intronic GSTCD C x x10-9 rs Intronic GSTCD G x x10-9 rs Intronic GSTCD G x x10-9 rs Intronic GSTCD T x x10-9 rs Intronic GSTCD G x x10-9 rs Intronic INTS12 G x x10-8 rs Intronic INTS12 G x x10-8 rs Intronic INTS12 G x x10-8 rs Intronic GSTCD C x x10-8 rs Intronic GSTCD G x x10-9 rs Intronic GSTCD C x x10-8 rs Intronic GSTCD G x x10-8 rs Intronic GSTCD C x x10-8 rs Intronic GSTCD G x x10-8 rs Intronic GSTCD G x x10-9 rs Intronic FLJ20184 T x NS rs Intronic GSTCD G x x10-8 rs Intronic FLJ20184 G x NS rs Intronic FLJ20184 G x NS rs Intronic FLJ20184 C x NS rs Intronic FLJ20184 C x NS rs Intergenic FLJ20184 G x NS rs Intergenic INTS12 T x NS a Weighted average reference allele frequency for combined cohorts. b β estimates are not given for results that are not significant. c Results with P>5x10-8 were considered not significant. FEV 1, forced expiratory volume in one second; NS, not significant 9

10 Supplementary Table 5. Associations with FEV 1 for SNPs from the top 8 loci implicated for FEV 1 /FVC and associations with FEV 1 /FVC for SNPs from the top 3 loci implicated for FEV 1 in CHARGE. Association results from the CHARGE and SpiroMeta consortia and the corresponding joint meta-analysis are shown. SNPs are grouped together by the nearest gene. P values highlighted in bold exceeded the threshold for significance (P<5x10-8 for the GWAS and joint meta-analysis, P<8.33x10-4 for replication). Gene/ Nearest gene CHARGE GWAS SpiroMeta replication Joint meta-analysis β, per-allele Allele β, per-allele β, per-allele frequency FEV 1 (ml) P a FEV 1 (ml) P FEV 1 (ml) P Reference Allele SNP Chr allele frequency a Associations with FEV 1 for SNPs from the top 8 loci implicated for FEV 1 /FVC rs HHIP T x x x10-9 rs HHIP T x x x10-7 rs GPR126 A x x x10-3 rs GPR126 A x x x10-5 rs GPR126 T x x x10-5 rs GPR126 A x x x10-3 rs ADAM19 A x x x10-7 rs ADAM19 T x x x10-7 rs AGER b T x x x10-2 rs PPT2 b T x x x10-1 rs FAM13A T x x x10-1 rs FAM13A A x x x10-2 rs PTCH1 A x x x10-1 rs PTCH1 A x x x10-1 rs PID1 T x x x10-3 rs PID1 T x x x10-3 rs HTR4 T x x x10-9 rs HTR4 T x x x10-8 Associations with FEV 1 /FVC for SNPs from the top 3 loci implicated for FEV 1 rs NPNT c A x x x10-4 rs NPNT c C x x x10-5 rs INTS12 c T x x x

11 rs INTS12 c T x x x10-3 rs FLJ20184 c T x x x10-3 rs FLJ20184 c T x x x10-4 rs GSTCD c T x x x10-3 rs GSTCD c A x x x10-4 rs TSPYL4 d A x x x10-3 rs NT5DC1 d A x x x10-3 rs ADCY2 A x x x10-2 rs ADCY2 T x x x10-2 a Weighted average coded allele frequency for combined cohorts. b AGER and PPT2 SNPs are considered to represent one locus given their correlations. c NPNT, INTS12, FLJ20184, and GSTCD SNPs are considered to represent one locus given their correlations. d TSPYL4 and NT5DC1 SNPs are considered to represent one locus given their correlations. FEV 1 /FVC, forced expiratory volume in one second to forced vital capacity ratio; FEV 1, forced expiratory volume in one second 11

12 a. b. Supplementary Figure 1. Meta-analyses of approximately 2,534,500 SNPs tested for association with (a) FEV 1 /FVC and (b) FEV 1 in all participants from the CHARGE consortium. The quantile-quantile plots compare the observed P values (black dots) to expected P values (red identity line) on the logarithmic scale. 12

13 a. b. 13

14 c. d. Supplementary Figure 2. Meta-analyses of approximately 2,534,500 SNPs for association with FEV 1 /FVC in the CHARGE consortium. The quantile-quantile plots (a and c) compare the observed P values (black dots) to expected P values (red identity line) on the logarithmic scale for meta-analysis in (a) never smokers only and (c) ever smokers only. The Manhattan plots (b and d) show the chromosomal position of SNPs exceeding the genome-wide significance threshold (P<5x10-8 as indicated by the solid black line) in (b) never smokers only and (d) ever smokers only. 14

15 a. b. 15

16 c. d. Supplementary Figure 3. Meta-analyses of approximately 2,534,500 SNPs for association with FEV 1 in the CHARGE consortium. The quantile-quantile plots (a and c) compare the observed P values (black dots) to expected P values (red identity line) on the logarithmic scale for meta-analysis in (a) never smokers only and (c) ever smokers only. The Manhattan plots (b and d) show the chromosomal position of SNPs exceeding the genome-wide significance threshold (P<5x10-8 as indicated by the solid black line) in (b) never smokers only and (d) ever smokers only. 16

17 a. b. Supplementary Figure 4. Quantile-quantile plots comparing the observed P values (black dots) to expected P values (red identity line) on the logarithmic scale for (a) the FEV 1 /FVC meta-analysis in all participants with 1,862 genome-wide significant SNPs and nearby SNPs correlated at r 2 >0.2 with the top SNP for each locus removed and (b) the FEV 1 meta-analysis in all participants with 284 genome-wide significant SNPs and nearby SNPs correlated at r 2 >0.2 with the top SNP for the locus removed. 17