Genome-Wide Joint Meta-Analysis of SNP and SNP-by-Smoking Interaction Identifies Novel Loci for Pulmonary Function

DB Hancock; MS Artigas; SA Gharib; A Henry; A Manichaikul; A Ramasamy; Daan Loth; M Imboden; B Koch; WL McArdle; AV Smith; J Smolonska; A Sood; WB Tang; JB Wilk; GJ Zhai; JH Zhao; H Aschard; KM Burkart; I Curjuric; Mark Eijgelsheim; P Elliott; XJ Gu; TB Harris; C Janson; G Homuth; PG Hysi; JZ Liu; LR Loehr; K Lohman; RJF Loos; AK Manning; KD Marciante; M Obeidat; DS Postma; MC Aldrich; Guy Brusselle; TH Chen; G Eiriksdottir; N Franceschini; J (Joachim) Heinrich; JI Rotter; C Wijmenga; OD Williams; AR Bentley; Bert Hofman; CC Laurie; T Lumley; AC Morrison; BR Joubert; Fernando Rivadeneira; DJ Couper; SB Kritchevsky; YM Liu; M Wjst; LV Wain; JM Vonk; André Uitterlinden; T Rochat; SS Rich; BM Psaty; GT O'Connor; KE North; DB Mirel; B Meibohm; LJ (Lenore) Launer; KT Khaw; AL Hartikainen; CJ Hammond; S Glaser; J Marchini; P Kraft; NJ Wareham; H Volzke; Bruno Stricker; TD Spector; NM Probst-Hensch; D Jarvis; MR Jarvelin; SR Heckbert; V Gudnason; M Boezen; RG Barr; PA Cassano; DP Strachan; M Fornage; IP Hall; J Dupuis; MD Tobin; SJ London

doi:10.1371/journal.pgen.1003098

Genome-Wide Joint Meta-Analysis of SNP and SNP-by-Smoking Interaction Identifies Novel Loci for Pulmonary Function

DB Hancock, MS Artigas, SA Gharib, A Henry, A Manichaikul, A Ramasamy, Daan Loth, M Imboden, B Koch, WL McArdle, AV Smith, J Smolonska, A Sood, WB Tang, JB Wilk, GJ Zhai, JH Zhao, H Aschard, KM Burkart, I CurjuricMark Eijgelsheim, P Elliott, XJ Gu, TB Harris, C Janson, G Homuth, PG Hysi, JZ Liu, LR Loehr, K Lohman, RJF Loos, AK Manning, KD Marciante, M Obeidat, DS Postma, MC Aldrich, Guy Brusselle, TH Chen, G Eiriksdottir, N Franceschini, J (Joachim) Heinrich, JI Rotter, C Wijmenga, OD Williams, AR Bentley, Bert Hofman, CC Laurie, T Lumley, AC Morrison, BR Joubert, Fernando Rivadeneira, DJ Couper, SB Kritchevsky, YM Liu, M Wjst, LV Wain, JM Vonk, André Uitterlinden, T Rochat, SS Rich, BM Psaty, GT O'Connor, KE North, DB Mirel, B Meibohm, LJ (Lenore) Launer, KT Khaw, AL Hartikainen, CJ Hammond, S Glaser, J Marchini, P Kraft, NJ Wareham, H Volzke, Bruno Stricker, TD Spector, NM Probst-Hensch, D Jarvis, MR Jarvelin, SR Heckbert, V Gudnason, M Boezen, RG Barr, PA Cassano, DP Strachan, M Fornage, IP Hall, J Dupuis, MD Tobin, SJ London

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Abstract

Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV1), and its ratio to forced vital capacity (FEV1/FVC). Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on FEV1 and FEV1/FVC across 19 studies (total N = 50,047). We identified three novel loci not previously associated with pulmonary function. SNPs in or near DNER (smallest P-JMA = 5.00 x 10(-11)), HLA-DQB1 and HLA-DQA2 (smallest P-JMA = 4.35 x 10(-9)), and KCNJ2 and SOX9 (smallest P-JMA = 1.28 x 10(-8)) were associated with FEV1/FVC or FEV1 in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years) interaction. The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated. We evaluated DNER, KCNJ2, and SOX9 and found them to be expressed in human lung tissue. DNER and SOX9 further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers. Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects.

Original language	Undefined/Unknown
Journal	PLoS Genetics (print)
Volume	8
Issue number	12
DOIs	https://doi.org/10.1371/journal.pgen.1003098
Publication status	Published - 2012

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EMC NIHES-03-77-02

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Cite this

Hancock, DB., Artigas, MS., Gharib, SA., Henry, A., Manichaikul, A., Ramasamy, A., Loth, D., Imboden, M., Koch, B., McArdle, WL., Smith, AV., Smolonska, J., Sood, A., Tang, WB., Wilk, JB., Zhai, GJ., Zhao, JH., Aschard, H., Burkart, KM., ... London, SJ. (2012). Genome-Wide Joint Meta-Analysis of SNP and SNP-by-Smoking Interaction Identifies Novel Loci for Pulmonary Function. PLoS Genetics (print), 8(12). https://doi.org/10.1371/journal.pgen.1003098

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title = "Genome-Wide Joint Meta-Analysis of SNP and SNP-by-Smoking Interaction Identifies Novel Loci for Pulmonary Function",

abstract = "Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV1), and its ratio to forced vital capacity (FEV1/FVC). Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on FEV1 and FEV1/FVC across 19 studies (total N = 50,047). We identified three novel loci not previously associated with pulmonary function. SNPs in or near DNER (smallest P-JMA = 5.00 x 10(-11)), HLA-DQB1 and HLA-DQA2 (smallest P-JMA = 4.35 x 10(-9)), and KCNJ2 and SOX9 (smallest P-JMA = 1.28 x 10(-8)) were associated with FEV1/FVC or FEV1 in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years) interaction. The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated. We evaluated DNER, KCNJ2, and SOX9 and found them to be expressed in human lung tissue. DNER and SOX9 further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers. Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects.",

author = "DB Hancock and MS Artigas and SA Gharib and A Henry and A Manichaikul and A Ramasamy and Daan Loth and M Imboden and B Koch and WL McArdle and AV Smith and J Smolonska and A Sood and WB Tang and JB Wilk and GJ Zhai and JH Zhao and H Aschard and KM Burkart and I Curjuric and Mark Eijgelsheim and P Elliott and XJ Gu and TB Harris and C Janson and G Homuth and PG Hysi and JZ Liu and LR Loehr and K Lohman and RJF Loos and AK Manning and KD Marciante and M Obeidat and DS Postma and MC Aldrich and Guy Brusselle and TH Chen and G Eiriksdottir and N Franceschini and Heinrich, {J (Joachim)} and JI Rotter and C Wijmenga and OD Williams and AR Bentley and Bert Hofman and CC Laurie and T Lumley and AC Morrison and BR Joubert and Fernando Rivadeneira and DJ Couper and SB Kritchevsky and YM Liu and M Wjst and LV Wain and JM Vonk and Andr{\'e} Uitterlinden and T Rochat and SS Rich and BM Psaty and GT O'Connor and KE North and DB Mirel and B Meibohm and Launer, {LJ (Lenore)} and KT Khaw and AL Hartikainen and CJ Hammond and S Glaser and J Marchini and P Kraft and NJ Wareham and H Volzke and Bruno Stricker and TD Spector and NM Probst-Hensch and D Jarvis and MR Jarvelin and SR Heckbert and V Gudnason and M Boezen and RG Barr and PA Cassano and DP Strachan and M Fornage and IP Hall and J Dupuis and MD Tobin and SJ London",

year = "2012",

doi = "10.1371/journal.pgen.1003098",

language = "Undefined/Unknown",

volume = "8",

journal = "PLoS Genetics (print)",

issn = "1553-7390",

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Hancock, DB, Artigas, MS, Gharib, SA, Henry, A, Manichaikul, A, Ramasamy, A, Loth, D, Imboden, M, Koch, B, McArdle, WL, Smith, AV, Smolonska, J, Sood, A, Tang, WB, Wilk, JB, Zhai, GJ, Zhao, JH, Aschard, H, Burkart, KM, Curjuric, I, Eijgelsheim, M, Elliott, P, Gu, XJ, Harris, TB, Janson, C, Homuth, G, Hysi, PG, Liu, JZ, Loehr, LR, Lohman, K, Loos, RJF, Manning, AK, Marciante, KD, Obeidat, M, Postma, DS, Aldrich, MC, Brusselle, G, Chen, TH, Eiriksdottir, G, Franceschini, N, Heinrich, J, Rotter, JI, Wijmenga, C, Williams, OD, Bentley, AR, Hofman, B, Laurie, CC, Lumley, T, Morrison, AC, Joubert, BR, Rivadeneira, F, Couper, DJ, Kritchevsky, SB, Liu, YM, Wjst, M, Wain, LV, Vonk, JM, Uitterlinden, A, Rochat, T, Rich, SS, Psaty, BM, O'Connor, GT, North, KE, Mirel, DB, Meibohm, B, Launer, LJ, Khaw, KT, Hartikainen, AL, Hammond, CJ, Glaser, S, Marchini, J, Kraft, P, Wareham, NJ, Volzke, H, Stricker, B, Spector, TD, Probst-Hensch, NM, Jarvis, D, Jarvelin, MR, Heckbert, SR, Gudnason, V, Boezen, M, Barr, RG, Cassano, PA, Strachan, DP, Fornage, M, Hall, IP, Dupuis, J, Tobin, MD & London, SJ 2012, 'Genome-Wide Joint Meta-Analysis of SNP and SNP-by-Smoking Interaction Identifies Novel Loci for Pulmonary Function', PLoS Genetics (print), vol. 8, no. 12. https://doi.org/10.1371/journal.pgen.1003098

TY - JOUR

T1 - Genome-Wide Joint Meta-Analysis of SNP and SNP-by-Smoking Interaction Identifies Novel Loci for Pulmonary Function

AU - Hancock, DB

AU - Artigas, MS

AU - Gharib, SA

AU - Henry, A

AU - Manichaikul, A

AU - Ramasamy, A

AU - Loth, Daan

AU - Imboden, M

AU - Koch, B

AU - McArdle, WL

AU - Smith, AV

AU - Smolonska, J

AU - Sood, A

AU - Tang, WB

AU - Wilk, JB

AU - Zhai, GJ

AU - Zhao, JH

AU - Aschard, H

AU - Burkart, KM

AU - Curjuric, I

AU - Eijgelsheim, Mark

AU - Elliott, P

AU - Gu, XJ

AU - Harris, TB

AU - Janson, C

AU - Homuth, G

AU - Hysi, PG

AU - Liu, JZ

AU - Loehr, LR

AU - Lohman, K

AU - Loos, RJF

AU - Manning, AK

AU - Marciante, KD

AU - Obeidat, M

AU - Postma, DS

AU - Aldrich, MC

AU - Brusselle, Guy

AU - Chen, TH

AU - Eiriksdottir, G

AU - Franceschini, N

AU - Heinrich, J (Joachim)

AU - Rotter, JI

AU - Wijmenga, C

AU - Williams, OD

AU - Bentley, AR

AU - Hofman, Bert

AU - Laurie, CC

AU - Lumley, T

AU - Morrison, AC

AU - Joubert, BR

AU - Rivadeneira, Fernando

AU - Couper, DJ

AU - Kritchevsky, SB

AU - Liu, YM

AU - Wjst, M

AU - Wain, LV

AU - Vonk, JM

AU - Uitterlinden, André

AU - Rochat, T

AU - Rich, SS

AU - Psaty, BM

AU - O'Connor, GT

AU - North, KE

AU - Mirel, DB

AU - Meibohm, B

AU - Launer, LJ (Lenore)

AU - Khaw, KT

AU - Hartikainen, AL

AU - Hammond, CJ

AU - Glaser, S

AU - Marchini, J

AU - Kraft, P

AU - Wareham, NJ

AU - Volzke, H

AU - Stricker, Bruno

AU - Spector, TD

AU - Probst-Hensch, NM

AU - Jarvis, D

AU - Jarvelin, MR

AU - Heckbert, SR

AU - Gudnason, V

AU - Boezen, M

AU - Barr, RG

AU - Cassano, PA

AU - Strachan, DP

AU - Fornage, M

AU - Hall, IP

AU - Dupuis, J

AU - Tobin, MD

AU - London, SJ

PY - 2012

Y1 - 2012

N2 - Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV1), and its ratio to forced vital capacity (FEV1/FVC). Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on FEV1 and FEV1/FVC across 19 studies (total N = 50,047). We identified three novel loci not previously associated with pulmonary function. SNPs in or near DNER (smallest P-JMA = 5.00 x 10(-11)), HLA-DQB1 and HLA-DQA2 (smallest P-JMA = 4.35 x 10(-9)), and KCNJ2 and SOX9 (smallest P-JMA = 1.28 x 10(-8)) were associated with FEV1/FVC or FEV1 in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years) interaction. The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated. We evaluated DNER, KCNJ2, and SOX9 and found them to be expressed in human lung tissue. DNER and SOX9 further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers. Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects.

AB - Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV1), and its ratio to forced vital capacity (FEV1/FVC). Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on FEV1 and FEV1/FVC across 19 studies (total N = 50,047). We identified three novel loci not previously associated with pulmonary function. SNPs in or near DNER (smallest P-JMA = 5.00 x 10(-11)), HLA-DQB1 and HLA-DQA2 (smallest P-JMA = 4.35 x 10(-9)), and KCNJ2 and SOX9 (smallest P-JMA = 1.28 x 10(-8)) were associated with FEV1/FVC or FEV1 in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years) interaction. The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated. We evaluated DNER, KCNJ2, and SOX9 and found them to be expressed in human lung tissue. DNER and SOX9 further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers. Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects.

U2 - 10.1371/journal.pgen.1003098

DO - 10.1371/journal.pgen.1003098

M3 - Article

C2 - 23284291

SN - 1553-7390

VL - 8

JO - PLoS Genetics (print)

JF - PLoS Genetics (print)

IS - 12

ER -