Genome-wide association study identifies multiple susceptibility loci for pulmonary fibrosis

Transcription

1 correction notice Nat. Genet. 45, (2013); published online 14 April 2013; corrected online 1 October 2013 Genome-wide association study identifies multiple susceptibility loci for pulmonary fibrosis Tasha E Fingerlin, Elissa Murphy, Weiming Zhang, Anna L Peljto, Kevin K Brown, Mark P Steele, James E Loyd, Gregory P Cosgrove, David Lynch, Steve Groshong, Harold R Collard, Paul J Wolters, Williamson Z Bradford, Karl Kossen, Scott D Seiwert, Roland M du Bois, Christine Kim Garcia, Megan S Devine, Gunnar Gudmundsson, Helgi J Isaksson, Naftali Kaminski, Yingze Zhang, Kevin F Gibson, Lisa H Lancaster, Joy D Cogan, Wendi R Mason, Toby M Maher, Philip L Molyneaux, Athol U Wells, Miriam F Moffatt, Moises Selman, Annie Pardo, Dong Soon Kim, James D Crapo, Barry J Make, Elizabeth A Regan, Dinesha S Walek, Jerry J Daniel, Yoichiro Kamatani, Diana Zelenika, Keith Smith, David McKean, Brent S Pedersen, Janet Talbert, Raven N Kidd, Cheryl R Markin, Kenneth B Beckman, Mark Lathrop, Marvin I Schwarz & David A Schwartz In the version of this supplementary file initially posted online, there was an error in footnote b of Supplementary Tables 5 and 6. In both tables, this footnote should have read: Minor allele in combined case and control group listed first. This error has been corrected in this file as of 1 October nature genetics

2 Supplementary Information Genome-wide association study identifies multiple susceptibility loci for pulmonary fibrosis Tasha E. Fingerlin, Elissa Murphy, Weiming Zhang, Anna L. Peljto, Kevin K. Brown, Mark P. Steele, James E. Loyd, Gregory P. Cosgrove, David Lynch, Steve Groshong, Harold R. Collard, Paul J. Wolters, Williamson Z. Bradford, Karl Kossen, Scott D. Seiwert, Roland M. du Bois, Christine Kim Garcia, Megan S. Devine, Gunnar Gudmundsson, Helgi J. Isaksson, Naftali Kaminski, Yingze Zhang, Kevin F. Gibson, Lisa H. Lancaster, Joy D. Cogan, Wendi R. Mason, Toby M. Maher, Philip L. Molyneaux, Athol U. Wells, Miriam F. Moffatt, Moises Selman, Annie Pardo, Dong Soon Kim, James D. Crapo, Barry J. Make, Elizabeth A. Regan, Dinesha S. Walek, Jerry J. Daniel, Yoichiro Kamatani, Diana Zelenika, Keith Smith, David McKean, Brent S. Pedersen, Janet Talbert, Ravin N. Kidd, Cheryl R. Markin, Kenneth B. Beckman, Mark Lathrop, Marvin I. Schwarz, David A. Schwartz 1

3 Table of Contents Supplementary Table 1: Characteristics of GWAS and Replication Samples...3 Supplementary Table 2: Specific IIP diagnosis information for GWAS discovery samples...4 Supplementary Table 3: Sample origin for GWAS and replication IIP cases genotyped....5 Supplementary Table 4: Association information for all 198 SNPs chosen for replication....6 Supplementary Table 5: Genotype counts and Hardy-Weinberg Equilibrium (HWE) P-values among cases and controls in the discovery set for all 198 SNPs taken into replication set...15 Supplementary Table 6: Genotype counts and Hardy-Weinberg Equilibrium (HWE) P-values among cases and controls in the replication set for all SNPs successfully genotyped in replication Supplementary Table 7: Specific IIP diagnosis information for replication samples Supplementary Table 8: Association information for SNPs chosen for replication among the GWAS cases (n=1127) and controls (n=2832) homozygous for the H1 haplotype (non-h2 carriers) on chromosome 17q Supplementary Table 9: Association information for SNPs chosen for replication among the replication cases (n=617) and controls (n=1138) homozygous for the H1 haplotype on chromosome 17q Supplementary Table 10: Association information for imputed SNPs across genome-wide significant loci Supplementary Table 11: Adjusted association information for all genome-wide significant SNPs in meta-analysis using joint genotypes from subset of GWAS cases, all replication cases and all replication controls...41 Supplementary Figure 1: Quantile-Quantile (Q-Q) plot of observed vs. expected p-value distribution for GWAS across 439,828 high quality SNPs...44 Supplementary Figure 2: Locus-specific plots with genotyped (circles) and imputed (squares) SNP results (based on GWAS discovery cases and controls only) for 6 loci reaching genomewide significance in the GWAS discovery analysis and meta-analysis of the discovery and replication results Supplementary Figure 3: Locus-specific plots with genotyped (circles) and imputed (squares) SNP results (based on GWAS discovery cases and controls only) for 4 loci reaching genomewide significance in the meta-analysis of the discovery and replication results Supplementary Figure 4: Linkage disequilibrium among the genome-wide significant SNPs at 11p15 and rs

4 Supplementary Table 1: Characteristics of GWAS and Replication Samples Discovery GWAS Replication Cases (n=1616) Controls a (n=4683) P-value b Cases (n=876) Controls (n=1890) P-value b Male e e-24 Age in years (SD) 65.5 (9.5) NA NA 63.4 (9.7) 58.4 (9.7) 1.02e-35 a Age information not available on out-of-study controls b Cases and controls compared via chi-squared test of association (Male) or two-sample t-test (Age) 3

5 Supplementary Table 2: Specific IIP diagnosis information for GWAS discovery samples. Genotyped (N=1914) Included after QC (N=1616) Sporadic a Familial b Sporadic a Familial b IPF 1055 (55%) 445 (24%) 948 (58%) 303 (19%) NSIP 51 (3%) 60 (3%) 44 (3%) 47 (3%) COP 3 (<1%) 3 (<1%) 3 (<1%) 3 (<1%) RB-ILD 8 (<1%) 3 (<1%) 8 (<1%) 3 (<1%) DIP 5 (<1%) 0 5 (<1%) 0 Unclassified 226 (12%) 55 (3%) 218 (13%) 34 (2%) a No known family history b At least 2 affected relatives (3 rd degree or closer) QC: Quality control; IPF: Idiopathic pulmonary fibrosis; NSIP: Non-specific interstitial pneumonia; COP: Cryptogenic organizing pneumonia; RB-ILD: Respiratory bronchiolitis-associated interstitial lung disease; DIP: Desquamative interstitial pneumonia 4

6 Supplementary Table 3: Sample origin for GWAS and replication IIP cases genotyped. GWAS Cases (n=1914) Replication Cases (n=1027) Familial Pulmonary Fibrosis 566 United Kingdom* 222 National Jewish Health 238 Duke 238 InterMune IPF Trials 720 U. Texas Southwestern 192 University of California San Francisco 66 Pittsburgh 232 NHLBI LTRC/LGRC 219 Vanderbilt 143 Vanderbilt 105 5

7 Supplementary Table 4: Association information for all 198 SNPs chosen for replication. Blank Replication and Joint columns correspond to SNPs not successfully genotyped in replication. Chr. SNP a Chr. 1 MAF b Case MAF b Control Discovery GWAS rs (1.12,1.41) rs (1.1,1.35) rs (1.13,1.39) rs (0.62,0.85) rs (0.33,0.64) Chr. 2 rs (1.14,1.48) rs (0.73,0.90) rs (1.17,1.54) rs (0.77,0.92) rs (0.72,0.89) rs (0.72,0.89) rs (1.21,1.66) rs (1.34,2.26) rs (1.34,2.04) rs (1.34,2.03) rs (1.33,2.01) rs (1.30,1.94) rs (1.32,1.98) rs (1.15,1.53) rs (1.09,1.34) OR c MAF b (95% CI) P-value d Case MAF b Control Replication 8.81e (0.74,1.03) 4.05e (0.91,1.21) 6.45e (0.92,1.22) 6.21e (0.80,1.20) 3.75e e (0.79,1.17) 4.30e (1.09,1.45) 4.54e (0.83,1.22) 9.17e (0.93,1.18) 1.31e (0.91,1.21) 1.33e (0.91,1.21) 2.74e (0.89,1.40) 5.06e (0.64,1.45) 7.16e (0.73,1.39) 7.42e e (0.77,1.42) 3.61e (0.80,1.47) 1.75e (0.78,1.43) 3.65e (0.94,1.42) 9.83e (0.97,1.31) Meta Analysis OR c (95% CI) P-value d P-value d e e e-05 6

8 Chr. 3 rs (1.17,1.53) rs (1.15,1.44) rs (1.10,1.31) rs (0.70,0.88) rs (0.80,0.94) rs (1.16,1.37) rs (1.19,1.43) rs (1.19,1.42) rs (1.19,1.42) rs (0.74,0.90) Chr. 4 rs (0.23,0.66) rs (0.23,0.61) rs (0.69,0.87) rs (0.69,0.87) rs (0.71,0.9) rs (0.73,0.87) rs (1.18,1.42) rs (0.7,0.85) rs (0.73,0.86) rs (0.73,0.85) rs (0.75,0.89) rs (0.74,0.89) rs (0.74,0.89) rs (0.75,0.88) rs (1.15,1.36) 3.15e (0.73,1.06) 3.53e (0.90,1.25) 7.37e (0.99,1.30) 9.67e (0.86,1.17) 6.14e (0.88,1.11) 3.60e (1.06,1.36) 3.90e (1.17,1.52) 3.71e (1.21,1.55) 3.20e (1.23,1.58) 4.99e (0.80,1.04) 7.79e (0.88,2.7) 2.34e (0.61,1.58) 3.52e (0.76,1.06) 3.35e e (0.82,1.13) 6.66e (0.80,1.03) 5.27e (1.25,1.64) 3.73e (0.82,1.09) 7.54e (0.85,1.08) 7.59e (0.79,1.00) 8.49e (0.79,1.01) 4.72e (0.79,1.02) 5.42e (0.79,1.01) 2.93e (0.83,1.06) 5.35e (0.93,1.18) e e e e e e e e e e e e e e e e e e e e e-05 7

9 rs (0.77,0.91) rs (0.74,0.88) rs (1.12,1.37) rs (0.67,0.86) Chr. 5 rs (0.67,0.79) rs (0.70,0.84) rs (0.79,0.93) rs (1.14,1.44) rs (1.10,1.33) rs (0.70,0.89) rs (0.70,0.88) rs (0.66,0.84) rs (0.67,0.87) rs (0.62,0.85) Chr. 6 rs (1.15,1.56) rs (1.15,1.42) rs (0.70,0.85) rs (1.32,1.55) rs (1.20,1.43) rs (0.71,0.87) rs (1.21,1.57) rs (1.20,1.56) rs (1.21,1.57) rs (1.20,1.55) rs (1.23,1.54) 4.19e (0.86,1.09) 5.73e (0.83,1.07) 6.16e (0.74,1.00) 9.30e e (0.65,0.83) 8.93e (0.73,0.96) 3.80e (0.94,1.19) 2.68e (0.85,1.18) 7.65e (0.85,1.14) 6.49e (0.74,1.04) 7.08e (0.68,0.94) 2.96e (0.74,1.04) 8.39e (0.81,1.17) 5.04e (0.77,1.20) 4.64e (1.00,1.52) 2.92e (1.13,1.54) 3.41e (0.71,0.94) 1.14e (1.13,1.42) 6.41e (0.95,1.22) 1.54e (0.72,0.95) 4.73e (0.86,1.26) 2.76e (0.93,1.35) 2.58e (0.98,1.44) 3.38e (0.96,1.40) 2.26e e e e e e e e e e e e e e e e e-05 8

10 rs (1.21,1.51) rs (0.75,0.89) rs (1.09,1.28) rs (1.12,1.33) rs (1.14,1.51) Chr. 7 rs (1.13,1.33) rs (1.23,1.67) rs (1.18,1.60) rs (1.13,1.45) rs (1.16,1.36) rs (1.20,1.41) rs (1.10,1.31) rs (1.15,1.38) rs (1.14,1.44) Chr. 8 rs (1.45,2.19) rs (1.11,1.36) rs (1.17,1.72) rs (1.41,2.73) rs (0.68,0.86) rs (1.11,1.36) rs (1.18,1.55) rs (0.77,0.91) rs (0.77,0.91) rs (0.77,0.91) rs (0.73,0.87) Chr e e (0.86,1.10) 8.43e e (0.95,1.23) 6.11e (0.84,1.26) 3.96e (0.92,1.16) 8.71e (0.90,1.41) 7.92e (0.80,1.24) 8.90e (0.81,1.16) 5.87e (1.00,1.26) 6.72e (0.98,1.24) 5.10e (0.86,1.10) 1.02e (0.90,1.17) 6.39e (0.85,1.19) 5.74e (0.86,1.59) 7.76e (0.81,1.10) 5.97e (0.9,1.59) 8.65e (0.45,1.60) 6.35e (0.89,1.25) 6.92e (0.87,1.16) 1.18e (0.93,1.39) 1.90e (0.78,0.99) 1.83e e (0.81,1.03) 2.92e (0.76,0.97) e e e e e e e e e e e e-07 9

11 rs (0.30,0.69) rs (0.25,0.68) rs (1.29,1.95) rs (1.10,1.29) Chr. 10 rs (1.15,1.60) rs (1.16,1.46) rs (1.15,1.46) rs (0.75,0.9) rs (0.75,0.9) rs (0.68,0.87) rs (1.13,1.36) rs (0.74,0.88) rs (0.74,0.87) rs (0.74,0.87) rs (0.74,0.87) rs (0.66,0.85) rs (0.66,0.85) rs (1.12,1.33) rs (1.12,1.33) Chr. 11 rs (1.15,1.35) rs (1.15,1.35) rs (1.27,1.50) rs (0.72,0.86) rs (0.66,0.82) rs (0.61,0.83) 3.54e (0.59,1.58) 9.57e (0.56,1.64) 4.12e (0.74,1.35) 1.99e (0.84,1.06) 7.33e (1.1,1.66) 7.92e (0.79,1.10) 8.57e (0.78,1.09) 3.40e (0.88,1.12) 3.23e (0.88,1.12) 6.25e (0.82,1.16) 2.50e (0.90,1.17) 1.24e (0.72,0.91) 4.73e (0.77,0.97) 4.65e (0.77,0.98) 2.82e (0.77,0.97) 8.46e e (0.80,1.13) 6.47e (0.89,1.15) 4.01e (0.93,1.19) 1.86e (1.00,1.26) 1.90e (1.03,1.3) 9.29e (0.98,1.25) 3.10e (0.90,1.16) 5.90e (0.86,1.15) 1.69e (0.68,1.05) e e e e e e e e e e e-05 10

12 rs (1.40,1.65) rs (1.39,1.64) rs (0.64,0.75) rs (0.67,0.8) rs (0.71,0.89) rs (0.59,0.70) rs (0.73,0.86) rs (0.71,0.84) rs (0.71,0.84) rs (0.72,0.84) rs (0.71,0.84) rs (0.63,0.80) rs (0.69,0.82) rs (0.74,0.88) rs (1.18,1.57) rs (1.1,1.30) rs (1.18,1.60) rs (1.18,1.60) Chr. 12 rs (1.14,1.46) rs (0.65,0.86) Chr. 13 rs (0.58,0.83) rs (0.72,0.88) Chr. 14 rs (1.11,1.38) rs (0.45,0.75) rs (0.76,0.91) 5.46e (1.39,1.76) 1.62e (1.39,1.77) 4.17e (0.78,0.98) 8.47e (0.81,1.03) 4.73e (0.84,1.14) 1.26e (0.69,0.87) 8.58e e (0.76,0.96) 1.48e (0.76,0.96) 7.52e (0.72,0.91) 7.77e e (0.59,0.84) 3.69e (0.69,0.88) 3.98e (0.75,0.95) 4.42e (1.01,1.52) 2.85e (0.96,1.21) 4.66e (0.81,1.25) 4.21e (0.83,1.30) 8.70e (0.94,1.35) 5.05e (0.94,1.38) 4.79e e (0.70,0.92) 6.84e (0.98,1.34) 7.43e (0.59,1.14) 2.91e (0.83,1.08) 1.49e e e e e e e e e e e e e e e e e e e e e e

13 rs (1.09,1.28) Chr. 15 rs (0.71,0.85) rs (0.71,0.85) rs (0.77,0.91) rs (0.76,0.90) rs (1.14,1.33) rs (0.71,0.84) rs (0.77,0.91) rs (1.29,2.17) rs (0.60,0.85) rs (0.72,0.89) rs (1.15,1.36) rs (1.15,1.36) rs (1.15,1.36) rs (1.14,1.36) rs (1.15,1.36) rs (1.14,1.35) rs (1.17,1.63) rs (1.17,1.63) Chr. 16 rs (1.12,1.38) rs (1.13,1.54) rs (0.63,0.87) Chr. 17 rs (0.65,0.8) rs (0.7,0.85) rs (0.68,0.83) 9.45e e (0.73,0.94) 3.49e (0.75,0.96) 2.14e (0.78,0.99) 6.53e e (1.07,1.36) 1.86e (0.74,0.93) 8.14e e (0.56,1.25) 3.91e (0.88,1.39) 3.65e (0.90,1.21) 1.11e (0.89,1.13) 1.12e (0.87,1.11) 9.74e (0.89,1.13) 3.36e (0.92,1.19) 1.03e (1.00,1.27) 3.05e (0.93,1.18) 9.68e (0.84,1.39) 8.39e (0.79,1.31) 3.45e (0.88,1.20) 9.21e (0.89,1.38) 8.65e (0.76,1.18) 9.26e (0.71,0.95) 1.57e (0.79,1.04) 1.49e e e e e e e e e e e-05 12

14 rs (0.68,0.82) rs (0.64,0.79) rs (0.71,0.86) rs (0.64,0.78) rs (0.64,0.78) rs (0.64,0.79) rs (0.72,0.86) rs (0.65,0.80) rs (0.64,0.79) rs (0.64,0.79) rs (0.68,0.83) rs (0.64,0.79) rs (0.71,0.86) rs (0.64,0.80) rs (0.65,0.80) Chr. 18 rs (1.11,1.37) Chr. 19 rs (1.18,1.41) rs (1.18,1.40) rs (0.71,0.88) rs (1.10,1.29) Chr. 20 rs (1.18,1.57) rs (0.78,0.92) rs (1.13,1.38) Chr.21 rs (1.35,2.57) 9.18e (0.73,0.97) 7.07e (0.58,0.79) 3.42e (0.65,0.86) 3.39e (0.58,0.79) 2.52e (0.58,0.79) 3.87e (0.61,0.83) 7.60e (0.70,0.89) 1.29e (0.60,0.81) 9.61e (0.57,0.77) 1.04e (0.58,0.78) 6.95e (0.73,0.97) 2.33e (0.60,0.82) 3.48e (0.77,0.99) 5.19e (0.59,0.81) 7.86e (0.62,0.84) 8.30e (0.94,1.27) 9.57e (1.15,1.47) 1.22e (1.10,1.41) 1.92e (0.80,1.09) 5.00e (0.86,1.08) 5.23e (0.94,1.47) 5.27e (0.80,1.01) 9.58e (0.98,1.29) 9.90e (0.68,1.86) e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e

15 rs (1.14,1.46) Chr e (0.89,1.25) rs e (1.21,1.63) (0.83,1.32) rs e-06 (1.23,1.63) rs e (1.07,1.31) (0.94,1.24) a Bolded SNPs were genome-wide significant in meta-analysis e b MAF: Minor allele frequency; minor allele defined as minor allele in combined case and control group; c OR: Odds ratio for the minor allele; CI: Confidence Interval d Adjusted for sex 14

16 Supplementary Table 5: Genotype counts and Hardy-Weinberg Equilibrium (HWE) P-values among cases and controls in the discovery set for all 198 SNPs taken into replication set. Chr. Cases Controls SNP Position a Alleles b Minor c Hets d Major e HWE P f Minor c Hets d Major e HWE P f Chr. 1 rs A/G rs A/G rs C/A rs G/A < rs G/A < Chr. 2 rs A/G rs A/G rs C/T rs G/A rs T/C rs A/G rs C/T < rs A/G rs C/T rs T/C rs T/C rs G/T rs A/G rs A/C < rs C/A Chr. 3 rs C/T < rs T/C rs C/A rs T/C rs G/A rs G/A rs T/C rs T/C rs C/T

17 rs T/C Chr. 4 rs A/G < rs T/C < rs C/A rs G/A rs C/T rs G/A rs G/T rs T/C rs C/T rs T/C rs T/C rs A/G rs T/C rs T/C rs T/C rs T/G rs A/G rs C/T rs C/T Chr. 5 rs C/A < rs T/C rs T/G rs G/A rs G/A rs A/G rs C/T rs A/G rs G/A rs T/C Chr. 6 rs G/A rs C/T rs C/T rs G/T rs A/G rs A/G rs A/G

18 rs T/C rs A/G rs G/A rs A/G rs G/A rs T/C rs A/G rs C/T rs A/G Chr. 7 rs C/T rs T/C rs C/T rs C/T rs G/A rs A/C rs G/A rs T/G rs G/A Chr. 8 rs C/T < <0.01 rs A/G rs A/G < rs A/G < rs T/G rs T/C rs C/A <0.01 rs G/A rs G/T rs A/G rs A/G Chr. 9 rs A/G rs A/G < rs T/C < <0.01 rs G/A Chr. 10 rs G/A rs C/A rs C/T

19 rs T/C rs T/C rs T/C rs C/T rs G/T rs G/A rs A/G rs G/A rs T/C rs C/A rs G/T rs C/T Chr. 11 rs G/A rs C/T rs C/T rs C/T rs A/G rs G/A rs T/C rs T/C rs C/T rs C/T rs G/T rs T/C rs A/G rs C/T rs G/A rs C/T rs T/C rs A/G rs C/A rs C/T rs G/A rs T/G rs T/C rs A/G Chr. 12 rs A/G

20 rs G/A Chr. 13 rs T/C rs A/G Chr. 14 rs T/C rs C/T rs C/T rs C/T Chr. 15 rs A/G rs T/C rs G/A rs G/A rs T/C rs G/A rs A/C rs G/A rs C/T rs A/C rs C/A rs C/T rs T/C rs G/A rs G/A rs A/G rs C/T rs C/T Chr. 16 rs G/T rs A/C rs G/A Chr. 17 rs G/A rs G/A rs G/A rs C/T rs A/G rs T/C <0.01 rs G/A

21 rs A/G rs G/A rs G/A rs G/A rs C/T rs A/G rs A/G rs G/A rs G/A rs A/G rs C/T Chr. 18 rs T/C Chr. 19 rs G/A rs A/G rs C/T rs T/C Chr. 20 rs T/C rs T/C rs T/G Chr.21 rs C/T < rs G/T Chr.23 rs A/G rs A/G rs G/A a Genomic position based on NCBI Build 36 b Minor allele in combined case and control group listed first. c Minor: Count of minor allele homozygous subjects d Het: Count of heterozygous subjects e Major: Count of major allele (more frequent allele) homozygous subjects f P-value for HWE goodness-of-fit test 20

22 Supplementary Table 6: Genotype counts and Hardy-Weinberg Equilibrium (HWE) P-values among Chr. Cases Controls SNP Position a Alleles b Minor c Hets d Major e HWE P f Minor c Hets d Major e HWE P f Chr. 1 rs A/G rs T/C g rs C/A rs G/A Rs G/A Chr. 2 rs T/C g rs A/G rs C/T rs C/T g rs T/C rs T/C g rs C/T rs A/G rs C/T rs A/G g rs G/T rs T/C g rs A/C rs C/A Chr. 3 rs C/T rs T/C rs C/A rs T/C rs T/C g rs C/T g rs T/C < rs A/G g rs C/T rs T/C Chr. 4 cases and controls in the replication set for all SNPs successfully genotyped in replication. rs A/G

23 rs T/C rs C/A rs C/T rs G/A rs G/T rs T/C rs C/T rs T/C rs T/C rs A/G rs T/C rs T/C rs T/C rs T/G rs T/C g rs C/T Chr. 5 rs G/T g rs A/G g rs A/C g rs G/A rs C/T g rs T/C g rs C/T rs T/C g rs C/T g rs A/G g Chr. 6 rs G/A rs C/T <0.01 rs C/T rs G/T rs A/G rs A/G rs T/C g rs A/G g rs A/G rs G/A rs T/C rs G/A g

24 rs T/C g Chr. 7 rs C/T rs T/C rs C/T rs G/A g rs G/A rs A/C rs G/A rs A/C g rs G/A Chr. 8 rs G/A g rs A/G rs A/G rs A/G rs T/G rs A/G g rs C/A rs G/A rs A/G < <0.01 rs A/G Chr. 9 rs A/G rs T/C g rs T/C rs C/T g Chr. 10 rs G/A rs C/A rs C/T rs T/C rs A/G g rs A/G g rs C/T rs G/T rs C/T g rs T/C g rs G/A rs C/A

25 rs G/T rs C/T Chr. 11 rs G/A rs C/T rs G/A g rs C/T rs T/C g rs C/T g rs A/G g rs A/G g rs G/A g rs C/T rs C/A g rs T/C rs C/T rs G/A rs C/T rs T/C g rs C/A rs C/T rs G/A rs T/G rs A/G g rs A/G Chr. 12 rs A/G rs G/A Chr. 13 rs A/G Chr. 14 rs T/C rs C/T rs C/T Chr. 15 rs T/C g rs A/G g rs C/T g rs T/C rs C/T g <

26 rs C/T g rs C/T rs A/C rs C/A rs C/T rs T/C rs G/A rs G/A rs A/G rs C/T rs C/T Chr. 16 rs G/T rs A/C < rs G/A Chr. 17 rs G/A rs C/T g rs C/T rs A/G rs T/C rs G/A rs A/G rs G/A rs G/A rs C/T g rs G/A g rs T/C g rs A/G rs G/A rs G/A rs T/C g rs G/A g Chr. 18 rs T/C Chr. 19 rs G/A rs A/G rs C/T rs A/G g

27 Chr. 20 rs T/C rs T/C rs T/G Chr.21 rs C/T rs G/T Chr.23 rs A/G rs G/A a Genomic position based on NCBI Build 36 b Minor allele in combined case and control group listed first. c Minor: Count of minor allele homozygous subjects d Het: Count of heterozygous subjects e Major: Count of major allele (more frequent allele) homozygous subjects f P-value for HWE goodness-of-fit test\ g Alleles listed are on opposite strand as those from the GWAS panel listed in Supplementary Table 3 26

28 Supplementary Table 7: Specific IIP diagnosis information for replication samples. Genotyped (N=1027) Included after QC (N=876) Sporadic a Familial b Sporadic a Familial b IPF 881 (86%) 32 (3%) 749 (86%) 25 (3%) NSIP 66 (6%) 1 (<1%) 58 (7%) 1 (<1%) COP 6 (1%) 0 5 (1%) 0 RB-ILD 3 (<1%) 0 2 (<1%) 0 DIP 6 (1%) 0 5 (1%) 0 Unclassified 31 (3%) 1 (<1%) 30 (3%) 1 (<1%) a No known family history b At least 2 affected relatives (3 rd degree or closer) QC: Quality control; IPF: Idiopathic pulmonary fibrosis; NSIP: Non-specific interstitial pneumonia; COP: Cryptogenic organizing pneumonia; RB-ILD: Respiratory bronchiolitis-associated interstitial lung disease; DIP: Desquamative interstitial pneumonia 27

29 Supplementary Table 8: Association information for SNPs chosen for replication among the GWAS cases (n=1127) and controls (n=2832) homozygous for the H1 haplotype (non-h2 carriers) on chromosome 17q21. Chr. SNP a Position b OR c 95% CI d P-value e Chr. 1 rs (1.09,1.39) 4.10e-04 rs (1.07,1.38) 1.44e-03 Chr. 2 rs (0.72,0.93) 2.53e-03 rs (1.18,1.65) 7.33e-04 rs (0.75,0.93) 5.88e-04 rs (0.68,0.88) 3.47e-04 rs (0.68,0.88) 3.27e-04 rs (1.07,1.38) 4.68e-04 Chr. 3 rs (1.05,1.39) 7.25e-03 rs (1.06,1.32) 3.06e-03 rs (0.72,0.96) 2.60e-02 rs (1.08,1.31) 1.56e-04 rs (1.2,1.47) 1.41e-06 rs (1.17,1.46) 3.27e-05 rs (1.18,1.47) 1.47e-05 rs (1.18,1.46) 2.12e-05 rs (0.77,0.97) 2.07e-02 Chr. 4 rs (0.69,0.91) 1.00e-03 rs (0.7,0.87) 2.67e-04 rs (1.17,1.47) 3.56e-05 rs (0.65,0.83) 2.01e-05 rs (0.68,0.84) 7.15e-06 rs (0.68,0.83) 3.57e-07 rs (0.69,0.86) 1.60e-05 rs (0.69,0.86) 1.35e-05 rs (0.69,0.86) 1.71e-05 rs (0.71,0.86) 2.39e-05 rs (1.17,1.44) 2.45e-06 rs (0.74,0.9) 1.21e-04 rs (0.68,0.84) 1.25e-05 rs (1.09,1.38) 1.64e-03 Chr. 5 rs (0.68,0.82) 3.13e-09 rs (0.69,0.87) 3.52e-05 rs (0.78,0.95) 9.33e-04 rs (1.09,1.38) 5.08e-04 rs (0.58,0.85) 1.99e-04 28

30 Chr. 6 rs (1.05,1.52) 1.15e-02 rs (1.09,1.41) 3.27e-03 rs (0.72,0.92) 8.17e-04 rs (1.29,1.58) 4.28e-11 rs (1.18,1.46) 2.04e-06 rs (0.69,0.88) 2.66e-04 rs (1.11,1.47) 2.24e-03 rs (1.1,1.46) 3.58e-03 rs (0.79,0.98) 9.43e-03 rs (1.02,1.25) 1.73e-02 rs (1.06,1.31) 1.64e-03 Chr. 7 rs (1.09,1.33) 4.74e-04 rs (1.12,1.36) 1.99e-04 rs (1.17,1.43) 6.20e-06 rs (1.08,1.33) 1.48e-03 rs (1.15,1.43) 3.12e-05 Chr. 8 rs (1.08,1.39) 2.63e-03 rs (1.06,1.36) 5.61e-03 rs (0.79,0.96) 1.26e-02 rs (0.79,0.96) 1.13e-02 rs (0.78,0.95) 9.25e-03 rs (0.74,0.92) 1.46e-03 Chr. 9 rs (1.05,1.29) 3.68e-03 Chr. 10 rs (0.7,0.86) 1.92e-05 rs (0.7,0.86) 1.87e-05 rs (1.12,1.4) 2.07e-04 rs (0.72,0.88) 1.57e-04 rs (0.72,0.88) 1.03e-05 rs (0.72,0.88) 1.19e-05 rs (0.71,0.87) 5.84e-06 rs (0.63,0.86) 1.20e-04 rs (0.63,0.86) 1.54e-04 rs (1.11,1.38) 5.49e-04 rs (1.1,1.36) 8.66e-04 Chr. 11 rs (1.1,1.34) 2.95e-04 rs (1.1,1.34) 2.78e-04 rs (1.24,1.51) 8.36e-09 rs (0.69,0.86) 1.05e-05 rs (0.64,0.83) 1.24e-05 rs (1.41,1.73) 1.21e-16 rs (1.4,1.72) 2.97e-16 rs (0.63,0.77) 2.37e-12 29

31 rs (0.64,0.8) 1.98e-10 rs (0.68,0.9) 1.55e-03 rs (0.58,0.71) 3.89e-17 rs (0.7,0.86) 5.02e-05 rs (0.68,0.84) 5.88e-06 rs (0.68,0.83) 4.78e-06 rs (0.69,0.84) 4.43e-06 rs (0.68,0.84) 8.05e-06 rs (0.59,0.79) 3.07e-08 rs (0.67,0.82) 7.44e-07 rs (0.71,0.87) 9.81e-05 rs (1.14,1.62) 1.14e-03 rs (1.11,1.36) 3.39e-04 rs (1.16,1.69) 1.38e-03 rs (1.16,1.69) 1.36e-03 Chr. 13 rs (0.68,0.87) 2.26e-05 Chr. 14 rs (1.08,1.4) 3.33e-03 rs (0.76,0.95) 1.52e-03 rs (1.1,1.34) 1.25e-04 Chr. 15 rs (0.72,0.88) 6.29e-05 rs (0.71,0.88) 5.27e-05 rs (0.77,0.94) 1.84e-03 rs (0.76,0.92) 4.47e-04 rs (1.13,1.38) 5.36e-05 rs (0.7,0.86) 3.22e-06 rs (0.77,0.94) 4.79e-03 rs (0.68,0.88) 2.21e-04 rs (1.11,1.36) 3.86e-04 rs (1.11,1.36) 3.40e-04 rs (1.12,1.37) 2.46e-04 rs (1.1,1.37) 1.32e-03 rs (1.11,1.37) 3.28e-04 rs (1.09,1.35) 8.27e-04 Chr. 16 rs (1.07,1.39) 6.65e-04 rs (1.1,1.63) 2.51e-04 Chr. 17 rs (0.82,1.04) 2.75e-01 rs (0.89,1.29) 5.54e-01 Chr. 18 rs (1.08,1.4) 2.42e-03 Chr. 19 rs (1.17,1.44) 3.09e-06 rs (1.14,1.41) 1.23e-05 rs (0.69,0.9) 2.20e-04 30

32 rs (1.08,1.32) 4.15e-04 Chr. 20 rs (0.76,0.93) 7.97e-04 rs (1.1,1.4) 2.64e-03 Chr. 23 rs (1.29,1.85) 2.00e-05 rs (1.3,1.83) 3.79e-06 rs (1.03,1.31) 3.44e-03 a SNPs with <5 homozygotes for the rare allele in either cases or controls excluded. b Based on NCBI Build 36 c OR: Odds ratio for the minor allele d CI: Confidence Interval e Adjusted for sex 31

33 Supplementary Table 9: Association information for SNPs chosen for replication among the replication cases (n=617) and controls (n=1138) homozygous for the H1 haplotype on chromosome 17q21. Chr. SNP a Position b OR c 95% CI d P-value e Chr. 1 rs (0.67,1.01) 0.06 rs (0.9,1.27) 0.46 rs (0.94,1.34) 0.20 rs (0.73,1.21) 0.63 Chr. 2 rs (0.75,1.22) 0.72 rs (1.07,1.53) rs (0.77,1.24) 0.86 rs (0.89,1.2) 0.64 rs (0.85,1.21) 0.91 rs (0.84,1.2) 0.94 rs (0.81,1.42) 0.61 rs (0.44,1.31) 0.32 rs (0.62,1.4) 0.74 rs (0.71,1.53) 0.84 rs (0.73,1.56) 0.74 rs (0.71,1.52) 0.85 rs (0.78,1.31) 0.92 rs (0.86,1.24) 0.74 Chr. 3 rs (0.7,1.11) 0.28 rs (0.76,1.13) 0.46 rs (0.87,1.22) 0.72 rs (0.8,1.16) 0.69 rs (0.86,1.15) 0.97 rs (1.03,1.41) rs (1.16,1.6) rs (1.21,1.65) 1.65e-05 rs (1.22,1.67) 7.24e-06 rs (0.83,1.15) 0.77 Chr. 4 rs (0.98,3.75) rs (0.79,2.53) 0.24 rs (0.77,1.16) 0.58 rs (0.84,1.24) 0.83 rs (0.8,1.09) 0.38 rs (1.21,1.69) 3.52e-05 rs (0.79,1.11) 0.44 rs (0.85,1.15) 0.9 rs (0.79,1.05) 0.21 rs (0.74,1.01)

34 rs (0.75,1.02) rs (0.75,1.02) rs (0.84,1.13) 0.76 rs (0.88,1.18) 0.83 rs (0.84,1.12) 0.69 rs (0.84,1.14) 0.78 rs (0.7,1.01) Chr. 5 rs (0.63,0.84) 1.69e-05 rs (0.69,0.95) rs (0.9,1.21) 0.58 rs (0.73,1.1) 0.3 rs (0.76,1.09) 0.31 rs (0.8,1.21) 0.86 rs (0.64,0.96) 0.02 rs (0.66,1.0) rs (0.78,1.22) 0.82 Chr. 6 rs (0.96,1.4) 0.14 rs (0.74,1.02) rs (1.05,1.39) rs (0.92,1.25) 0.38 rs (0.71,1.0) rs (0.77,1.24) 0.86 rs (0.81,1.29) 0.88 rs (0.87,1.39) 0.43 rs (0.81,1.29) 0.85 rs (0.84,1.14) 0.78 rs (0.89,1.22) 0.63 rs (0.71,1.18) 0.51 Chr. 7 rs (0.86,1.14) 0.9 rs (0.92,1.57) 0.19 rs (0.78,1.33) 0.9 rs (0.82,1.27) 0.88 rs (1.06,1.42) rs (1.03,1.38) rs (0.84,1.16) 0.89 rs (0.88,1.22) 0.71 rs (0.79,1.18) 0.73 Chr. 8 rs (0.77,1.59) 0.59 rs (0.78,1.12) 0.44 rs (0.72,1.49) 0.84 rs (0.4,1.88) 0.71 rs (0.83,1.24) 0.9 rs (0.76,1.09) 0.31 rs (0.87,1.44)

35 rs (0.81,1.08) 0.35 rs (0.84,1.11) 0.62 rs (0.77,1.03) 0.12 Chr. 9 rs (0.51,1.77) 0.88 rs (0.57,2.14) 0.76 rs (0.62,1.31) 0.59 rs (0.82,1.1) 0.52 Chr. 10 rs (1.1,1.79) rs (0.8,1.21) 0.87 rs (0.8,1.21) 0.86 rs (0.87,1.17) 0.93 rs (0.87,1.17) 0.92 rs (0.76,1.16) 0.55 rs (0.82,1.14) 0.68 rs (0.69,0.93) rs (0.78,1.05) 0.18 rs (0.79,1.06) 0.23 rs (0.79,1.05) 0.21 rs (0.87,1.31) 0.52 rs (0.87,1.19) 0.83 rs (0.91,1.23) 0.47 Chr. 11 rs (1.02,1.36) rs (1.06,1.42) rs (0.97,1.3) 0.14 rs (0.92,1.25) 0.37 rs (0.83,1.18) 0.88 rs (0.65,1.09) 0.19 rs (1.33,1.78) 5.33e-09 rs (1.34,1.79) 3.19e-09 rs (0.74,0.98) rs (0.79,1.06) 0.25 rs (0.83,1.2) 1 rs (0.61,0.82) 3.65e-06 rs (0.78,1.04) 0.15 rs (0.78,1.04) 0.14 rs (0.72,0.96) rs (0.66,0.9) rs (0.71,0.95) rs (0.97,1.61) rs (0.9,1.19) 0.61 Chr. 12 rs (0.83,1.29) 0.76 rs (0.71,1.14) 0.38 Chr. 13 rs (0.66,0.93)

36 Chr. 14 rs (0.92,1.36) 0.25 rs (0.65,1.36) 0.73 rs (0.82,1.14) 0.71 Chr. 15 rs (0.67,0.91) rs (0.68,0.93) rs (0.71,0.96) rs (1.07,1.43) rs (0.7,0.92) rs (0.57,1.49) 0.74 rs (1.01,1.76) rs (0.89,1.28) 0.49 rs (0.9,1.2) 0.57 rs (0.88,1.17) 0.83 rs (0.89,1.18) 0.76 rs (0.88,1.21) 0.73 rs (0.98,1.32) rs (0.88,1.19) 0.75 rs (0.78,1.43) 0.73 rs (0.73,1.35) 0.97 Chr. 16 rs (0.79,1.16) 0.64 rs (0.85,1.47) 0.42 rs (0.82,1.39) 0.63 Chr. 17 rs (0.79,1.12) 0.49 rs (1.09,1.93) rs (1.08,1.66) Chr. 18 rs (0.89,1.29) 0.49 Chr. 19 rs (1.02,1.38) rs (0.98,1.32) rs (0.77,1.14) 0.52 rs (0.76,1.02) Chr. 20 rs (0.92,1.59) 0.17 rs (0.83,1.09) 0.48 rs (1.08,1.51) Chr. 21 rs (0.48,1.74) 0.78 rs (0.89,1.35) 0.39 Chr. 23 rs (0.9,1.56) 0.24 rs (0.88,1.24) 0.64 a SNPs with <5 homozygotes for the rare allele in either cases or controls excluded. b Based on NCBI Build 36 35

37 c OR: Odds ratio for the minor allele d CI: Confidence Interval e Adjusted for sex 36

38 Supplementary Table 10: Association information for imputed SNPs across genome-wide significant loci. Cases Controls Chr SNP a Position b Allele A AA c AB c BB c AA c AB c BB c P-value d Chr. 3 rs A e-09 rs A e-09 rs C e-09 rs A e-09 rs A e-09 rs * C e-08 rs A e-08 rs C e-09 rs C e-09 rs C e-09 rs A e-09 rs * C e-09 rs * C e-09 rs C e-09 rs G e-09 Chr. 4 rs C e-08 rs * C e-08 rs C e-08 rs * C e-09 rs C e-09 rs C e-08 37

39 Chr. 5 rs C e-11 rs * A e-14 rs * C e-08 rs A e-09 Chr. 6 rs * G e-18 rs C e-10 rs * A e-09 rs A e-08 rs A e-08 Chr. 7 rs C e-08 rs C e-10 rs * A e-10 rs A e-13 Chr. 11 rs A e-14 rs G e-14 rs C e-14 rs C e-14 rs A e-14 rs * C e-14 rs * A e-08 rs C e-09 rs * T e-24 rs * T e-23 rs * C e-18 rs * C e-12 rs C e-11 38

40 rs868903* C e-25 rs A e-10 rs C e-12 rs * A e-08 rs A e-09 rs C e-09 rs C e-09 rs * C e-09 rs * A e-10 rs A e-19 rs A e-12 rs * C e-09 rs * T e-09 rs C e-10 rs G e-08 rs C e-08 rs * A e-08 rs * A e-10 rs C e-10 rs A e-10 rs G e-14 Chr. 15 rs * A e-08 rs * C e-08 rs A e-10 rs C e-10 rs A e-10 rs A e-10 rs A e-10 rs A e-10 39

41 rs * A e-10 rs C e-10 rs A e-10 rs A e-09 rs C e-08 rs A e-09 rs A e-08 Chr. 19 rs * A e-09 rs * A e-08 a SNPs that were genotyped as part of GWAS marked with * ; imputed results presented for all SNPs to make p-values comparable between the imputed and genotyped SNPs. b Based on NCBI Build 36 c Genotypic counts based on imputed genotypes d P-value based on Snptest v2 40

42 Supplementary Table 11: Adjusted association information for all genome-wide significant SNPs in meta-analysis using joint genotypes from subset of GWAS cases, all replication cases and all replication controls. Joint Analysis a Joint Analysis Adjusted for top SNP b OR OR Gene (95% CI) P-value (95% CI) P-value GWAS P-value and Meta-analysis P-value < 5x10-8 Chr. 5p15 rs TERT 0.75 (0.677,0.822) 3.39e-09 N/A N/A Chr. 6p24 rs DSP 1.30 (1.184,1.431) 5.33e-08 N/A N/A Chr. 7q22 rs (1.082,1.315) 4.06e-04 N/A N/A Chr. 11p15 rs e-10 (0.666,0.810) (0.934,1.162) 0.46 rs MUC e-21 (1.459,1.778) (0.944,1.182) 0.34 rs MUC e-21 (1.464,1.784) (0.944,1.183) 0.34 rs MUC e-05 (0.747,0.906) (0.988,1.225) 0.08 rs e-03 (1.042,1.271) (0.846,1.054) 0.31 rs e-03 (0.782,0.957) (1.015,1.268) 0.03 rs e-06 (0.626,0.828) (0.766,1.034) 0.13 rs e-06 (0.716,0.877) (0.905,1.130) 0.85 Chr. 15q14-15 rs e-04 N/A N/A rs Chr. 17q21 rs rs rs Chr. 19p13 rs rs DISP2 MAPT MAPT MAPT DPP9 DPP9 (0.765,0.924) 0.85 (0.763,0.940) 0.69 (0.604,0.776) 0.69 (0.605,0.776) 0.70 (0.617,0.791) 1.35 (1.214,1.495) 1.31 (1.179,1.446) 1.83e (0.804,1.080) e-09 N/A N/A 2.72e e (0.171,2.704) 1.69 (0.720,3.939) e-08 N/A N/A 3.01e (0.641,1.208) 0.43 Joint Analysis Adjusted for age c OR (95% CI) P-value 0.76 (0.685,0.839) 1.29 (1.170,1.425) 1.18 (1.068,1.308) 0.75 (0.681,0.834) 1.57 (1.413,1.735) 1.57 (1.415,1.737) 0.85 (0.772,0.942) 1.10 (0.995,1.224) 0.90 (0.809,0.998) 0.75 (0.649,0.869) 0.80 (0.719,0.888) 0.84 (0.756,0.921) 0.84 (0.754,0.938) 0.71 (0.621,0.805) 0.71 (0.621,0.804) 0.72 (0.636,0.822) 1.32 (1.185,1.471) 1.28 (1.154,1.427) 7.49e e e e e e e e e e e e e e e e-06 41

43 GWAS (5x10-8 < P-value <.0001) and Meta-analysis (P-value < 5x10-8 ) Chr. 3q26 rs e-04 (1.089,1.335) (0.794,1.081) 0.33 rs MYNN e-08 (1.212,1.507) (0.708,1.250) 0.67 rs e-09 (1.231,1.524) (0.139,1.966) 0.34 rs LRRC (1.242,1.535) 2.32e-09 N/A N/A Chr. 4q22 rs FAM13A 1.32 (1.179,1.481) 1.66e-06 N/A N/A Chr. 5p15 rs TERT e-03 (0.742,0.928) (0.83,1.06) 0.32 Chr. 6p24 rs Chr. 10q24 rs rs rs Chr. 11p15 rs rs rs Chr. 13q34 rs Chr. 15q14-15 rs rs Chr. 17q21 rs rs rs rs rs rs DSP OBFC1 OBFC1 OBFC1 TOLLIP MUC5B ATP11A DISP2 IVD CRHR1, C17orf69 IMP5 KIAA1267 KIAA1267 KIAA (0.699,0.880) 0.84 (0.761,0.929) 0.86 (0.781,0.947) 0.86 (0.780,0.945) 1.17 (1.062,1.288) 0.78 (0.706,0.858) 0.82 (0.747,0.907) 0.80 (0.708,0.893) 0.84 (0.753,0.929) 1.14 (1.037,1.262) 0.77 (0.683,0.872) 0.69 (0.604,0.776) 0.76 (0.676,0.853) 0.69 (0.613,0.784) 0.67 (0.590,0.758) 0.68 (0.599,0.769) 3.60e e e (0.76,1.03) 0.88 (0.751,1.040) 1.25 (0.533,2.915) e-03 N/A N/A 1.49e e e (0.920,1.136) 1.03 (0.927,1.150) 1.10 (0.990,1.228) e-04 N/A N/A 8.26e e e e e e e e (0.80,1.07) 1.00 (0.87,1.17) 4.29 (2.315,7.940) 0.71 (0.173,2.882) 1.18 (0.920,1.506) 0.90 (0.553,1.462) 0.42 (0.190,0.938) 0.37 (0.127,1.104) e (1.052,1.300) 1.34 (1.197,1.502) 1.37 (1.228,1.532) 1.38 (1.238,1.543) 1.29 (1.144,1.451) 0.85 (0.753,0.950) 0.79 (0.703,0.892) 0.84 (0.758,0.933) 0.88 (0.799,0.976) 0.88 (0.798,0.974) 1.13 (1.025,1.254) 0.79 (0.713,0.872) 0.84 (0.759,0.928) 0.78 (0.695,0.885) 0.84 (0.749,0.930) 1.15 (1.041,1.276) 0.82 (0.721,0.930) 0.71 (0.622,0.806) 0.77 (0.682,0.869) 0.72 (0.635,0.820) 0.69 (0.607,0.786) 0.70 (0.616,0.798) 3.65e e e e e e e e e e e e e e e e e e e-08 42

44 rs NSF e (0.622,0.804) (0.778,1.507) (0.639,0.834) 3.48e-06 rs NSF e (0.625,0.809) (0.792,1.499) (0.647,0.846) 1.00e-05 rs WNT e (0.633,0.817) (0.800,1.381) (0.659,0.858) 2.20e-05 a Based on joint analysis of a subset of the GWAS cases (n=859) and all replication cases (876) compared to replication controls (n=1890) to allow for adjustment for rs , which is not on GWAS panel, and age; GWAS cases were re-genotyped for Supplemental Table 2 SNPs and rs using same platform and at same time as replication cases and controls. b Each SNP was tested for association in a logistic regression model that also included the most highly associated SNP from the meta-analysis at that locus in addition to sex. The exception is chromosome 11p15, where each SNP was tested for association in a logistic regression model that also included rs c each SNP was tested for association in a logistic regression model that also included age in addition to sex. 43

45 Supplementary Figure 1: Quantile-Quantile (Q-Q) plot of observed vs. expected p-value distribution for GWAS across 439,828 high quality SNPs. 44

46 Supplementary Figure 2: Locus-specific plots with genotyped (circles) and imputed (squares) SNP results (based on GWAS discovery cases and controls only) for 6 loci reaching genome-wide significance in the GWAS discovery analysis and meta-analysis of the discovery and replication results. All P values based on imputation analysis for comparability of levels of statistical significance (see Online Methods). For each plot, the log 10 P values (y axis) of the SNPs are shown according to their chromosomal positions (x axis). The significant loci are on chromosomes 5p15 (a), 6p24 (b), 7q22 (c), 11p15 (d), 15q14-15 (e), and 19p13 (f). The estimated recombination rates (cm/mb) from the HapMap Project (NCBI Build 36) are shown as light blue lines, and the genomic locations of genes within the regions of interest in the NCBI Build 36 human assembly are shown as arrows. SNPs shown in red, orange, green, light blue and blue have r 2 0.8, r 2 0.6, r 2 0.4, r and r 2 < 0.2 with the most highly-associated SNP, respectively. 45

47 46

48 Supplementary Figure 3: Locus-specific plots with genotyped (circles) and imputed (squares) SNP results (based on GWAS discovery cases and controls only) for 4 loci reaching genome-wide significance in the meta-analysis of the discovery and replication results. All P values based on imputation analysis for comparability of levels of statistical significance (see Online Methods). For each plot, the log 10 P values (y axis) of the SNPs are shown according to their chromosomal positions (x axis). The significant loci are on chromosomes 3q26 (a), 4q22 (b), 10q24 (c), and 13q34 (d). The estimated recombination rates (cm/mb) from the HapMap Project (NCBI Build 36) are shown as light blue lines, and the genomic locations of genes within the regions of interest in the NCBI Build 36 human assembly are shown as arrows. SNPs shown in red, orange, green, light blue and blue have r 2 0.8, r 2 0.6, r 2 0.4, r and r 2 < 0.2 with the most highly-associated SNP, respectively. 47

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50 Supplementary Figure 4: Linkage disequilibrium among the genome-wide significant SNPs at 11p15 and rs Color is D : red indicates D estimate = 1, white a D estimate =0. Numbers in squares correspond to r 2 *100. Estimates based on joint case and control genotypes as used in analyses for Table 3 and Supplementary Table 8. 49