Multiple Independent Loci at Chromosome 15q25.1 Affect Smoking Quantity: a Meta-Analysis and Comparison with Lung Cancer and COPD

English version České info

Recently, genetic association findings for nicotine dependence, smoking behavior, and smoking-related diseases converged to implicate the chromosome 15q25.1 region, which includes the CHRNA5-CHRNA3-CHRNB4 cholinergic nicotinic receptor subunit genes. In particular, association with the nonsynonymous CHRNA5 SNP rs16969968 and correlates has been replicated in several independent studies. Extensive genotyping of this region has suggested additional statistically distinct signals for nicotine dependence, tagged by rs578776 and rs588765. One goal of the Consortium for the Genetic Analysis of Smoking Phenotypes (CGASP) is to elucidate the associations among these markers and dichotomous smoking quantity (heavy versus light smoking), lung cancer, and chronic obstructive pulmonary disease (COPD). We performed a meta-analysis across 34 datasets of European-ancestry subjects, including 38,617 smokers who were assessed for cigarettes-per-day, 7,700 lung cancer cases and 5,914 lung-cancer-free controls (all smokers), and 2,614 COPD cases and 3,568 COPD-free controls (all smokers). We demonstrate statistically independent associations of rs16969968 and rs588765 with smoking (mutually adjusted p-values<10⁻³⁵ and <10⁻⁸ respectively). Because the risk alleles at these loci are negatively correlated, their association with smoking is stronger in the joint model than when each SNP is analyzed alone. Rs578776 also demonstrates association with smoking after adjustment for rs16969968 (p<10⁻⁶). In models adjusting for cigarettes-per-day, we confirm the association between rs16969968 and lung cancer (p<10⁻²⁰) and observe a nominally significant association with COPD (p = 0.01); the other loci are not significantly associated with either lung cancer or COPD after adjusting for rs16969968. This study provides strong evidence that multiple statistically distinct loci in this region affect smoking behavior. This study is also the first report of association between rs588765 (and correlates) and smoking that achieves genome-wide significance; these SNPs have previously been associated with mRNA levels of CHRNA5 in brain and lung tissue.

Vyšlo v časopise: Multiple Independent Loci at Chromosome 15q25.1 Affect Smoking Quantity: a Meta-Analysis and Comparison with Lung Cancer and COPD. PLoS Genet 6(8): e32767. doi:10.1371/journal.pgen.1001053
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1001053

Souhrn

Zdroje

1. MackayJ

EriksenM

ShafeyO

2006 The Tobacco Atlas. 2 ed Atlanta, GA American Cancer Society

2. American Cancer Society 2009 Cancer Facts and Figures Atlanta American Cancer Society

3. SacconeSF

HinrichsAL

SacconeNL

ChaseGA

KonvickaK

2007 Cholinergic nicotinic receptor genes implicated in a nicotine dependence association study targeting 348 candidate genes with 3713 SNPs. Human Molecular Genetics 16 36 49

4. SacconeNL

WangJC

BreslauN

JohnsonEO

HatsukamiD

2009 The CHRNA5-CHRNA3-CHRNB4 nicotinic receptor subunit gene cluster affects risk for nicotine dependence in African-Americans and in European-Americans. Cancer Res 69 6848 6856

5. BerrettiniW

YuanX

TozziF

SongK

FrancksC

2008 alpha-5/alpha-3 nicotinic receptor subunit alleles increase risk for heavy smoking. Molecular Psychiatry 13 368 373

6. ThorgeirssonTE

GellerF

SulemP

RafnarT

WisteA

2008 A variant associated with nicotine dependence, lung cancer and peripheral arterial disease. Nature 452 638 642

7. WeissRB

BakerTB

CannonDS

von NierderhausernA

DunnDM

2008 A candidate gene approach identifies the CHRNA5-A3-B4 region as a risk factor for age-dependent nicotine addiction. PLoS Genet 4 e1000125 doi:10.1371/journal.pgen.1000125

8. StevensVL

BierutLJ

TalbotJT

WangJC

SunJ

2008 Nicotinic receptor gene variants influence susceptibility to heavy smoking. Cancer Epidemiol Biomarkers Prev 17 3517 3525

9. ShervaR

WilhelmsenK

PomerleauCS

ChasseSA

RiceJP

2008 Association of a SNP in neuronal acetylcholine receptor subunit alpha 5 (CHRNA5) with smoking status and with “pleasurable buzz” during early experimentation with smoking. Addiction 103 1544 1552

10. BakerTB

WeissRB

BoltD

von NiederhausernA

FioreMC

2009 Human neuronal acetylcholine receptor A5-A3-B4 haplotypes are associated with multiple nicotine dependence phenotypes. Nicotine Tob Res 11 785 796

11. KeskitaloK

BromsU

HeliovaaraM

RipattiS

SurakkaI

2009 Association of serum cotinine level with a cluster of three nicotinic acetylcholine receptor genes (CHRNA3/CHRNA5/CHRNB4) on chromosome 15. Hum Mol Genet 18 4007 4012

12. ThorgeirssonTE

GudbjartssonDF

SurakkaI

VinkJM

AminN

2010 Sequence variants at CHRNB3-CHRNA6 and CYP2A6 affect smoking behavior. Nat Genet 42 448 453

13. LiuJZ

TozziF

WaterworthDM

PillaiSG

MugliaP

2010 Meta-analysis and imputation refines the association of 15q25 with smoking quantity. Nat Genet 42 436 440

14. The Tobacco and Genetics Consortium 2010 Genome-wide meta-analyses identify multiple loci associated with smoking behavior. Nat Genet 42 441 447

15. AmosCI

WuX

BroderickP

GorlovIP

GuJ

2008 Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1. Nat Genet 40 616 622

16. HungRJ

McKayJD

GaborieauV

BoffettaP

HashibeM

2008 A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25. Nature 452 633 637

17. LiuP

VikisHG

WangD

LuY

WangY

2008 Familial aggregation of common sequence variants on 15q24-25.1 in lung cancer. J Natl Cancer Inst 100 1326 1330

18. PillaiSG

GeD

ZhuG

KongX

ShiannaKV

2009 A genome-wide association study in chronic obstructive pulmonary disease (COPD): identification of two major susceptibility loci. PLoS Genet 5 e1000421 doi:10.1371/journal.pgen.1000421

19. BierutLJ

StitzelJA

WangJC

HinrichsAL

GruczaRA

2008 Variants in nicotinic receptors and risk for nicotine dependence. Am J Psychiatry 165 1163 1171

20. SacconeNL

SacconeSF

HinrichsAL

StitzelJA

DuanW

2009 Multiple distinct risk loci for nicotine dependence identified by dense coverage of the complete family of nicotinic receptor subunit (CHRN) genes. Am J Med Genet B Neuropsychiatr Genet 150B 453 466

21. WangJC

GruczaR

CruchagaC

HinrichsAL

BertelsenS

2009 Genetic variation in the CHRNA5 gene affects mRNA levels and is associated with risk for alcohol dependence. Mol Psychiatry 14 501 510

22. WangJC

CruchagaC

SacconeNL

BertelsenS

LiuP

2009 Risk for nicotine dependence and lung cancer is conferred by mRNA expression levels and amino acid change in CHRNA5. Hum Mol Genet 18 3125 3135

23. WangJC

BierutLJ

GoateAM

2009 Variants weakly correlated with CHRNA5 D398N polymorphism should be considered in transcriptional deregulation at the 15q25 locus associated with lung cancer risk. Clin Cancer Res 15 5599; author reply 5599

24. FalvellaFS

GalvanA

FrullantiE

DraganiTA

2009 Reply to the Letter to the Editor from Wang. Clin Cancer Res 15 5599

25. FalvellaFS

GalvanA

FrullantiE

SpinolaM

CalabroE

2009 Transcription deregulation at the 15q25 locus in association with lung adenocarcinoma risk. Clin Cancer Res 15 1837 1842

26. BarrettJC

FryB

MallerJ

DalyMJ

2005 Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21 263 265

27. The International HapMap Consortium 2005 A haplotype map of the human genome. Nature 437 1299 1320

28. R Development Core Team 2008 R: A language and environment for statistical computing Vienna, Austria R Foundation for Statistical Computing

29. PurcellS

NealeB

Todd-BrownK

ThomasL

FerreiraMA

2007 PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81 559 575

30. LumleyT

rmeta: Meta-analysis, R package version 2.15

31. CongerAJ

1974 A revised definition for suppressor variables: A guide to their identification and interpretation. Educational and Psychological Measurement 34 35 46

32. MacKinnonDP

KrullJL

LockwoodCM

2000 Equivalence of the mediation, confounding, and suppression effect. Prevention Science 1 173 181

33. DicksonSP

WangK

KrantzI

HakonarsonH

GoldsteinDB

2010 Rare variants create synthetic genome-wide associations. PLoS Biol 8 e1000294 doi:10.1371/journal.pbio.1000294

34. Le MarchandL

DerbyKS

MurphySE

HechtSS

HatsukamiD

2008 Smokers with the CHRNA lung cancer-associated variants are exposed to higher levels of nicotine equivalents and a carcinogenic tobacco-specific nitrosamine. Cancer Res 68 9137 9140

35. WangY

BroderickP

MatakidouA

EisenT

HoulstonRS

2010 Role of 5p15.33 (TERT-CLPTM1L), 6p21.33 and 15q25.1 (CHRNA5-CHRNA3) variation and lung cancer risk in never-smokers. Carcinogenesis 31 234 238

36. SpitzMR

AmosCI

DongQ

LinJ

WuX

2008 The CHRNA5-A3 region on chromosome 15q24-25.1 is a risk factor both for nicotine dependence and for lung cancer. J Natl Cancer Inst 100 1552 1556

37. LandiMT

ChatterjeeN

YuK

GoldinLR

GoldsteinAM

2009 A genome-wide association study of lung cancer identifies a region of chromosome 5p15 associated with risk for adenocarcinoma. Am J Hum Genet 85 679 691

38. BierutLJ

MaddenPA

BreslauN

JohnsonEO

HatsukamiD

2007 Novel genes identified in a high-density genome wide association study for nicotine dependence. Hum Mol Genet 16 24 35

39. HarrisKM

HalpernCT

SmolenA

HaberstickBC

2006 The National Longitudinal Study of Adolescent Health (Add Health) twin data. Twin Res Hum Genet 9 988 997

40. StallingsMC

CorleyRP

HewittJK

KrauterKS

LessemJM

2003 A genome-wide search for quantitative trait loci influencing substance dependence vulnerability in adolescence. Drug Alcohol Depend 70 295 307

41. StallingsMC

CorleyRP

DenneheyB

HewittJK

KrauterKS

2005 A genome-wide search for quantitative trait Loci that influence antisocial drug dependence in adolescence. Arch Gen Psychiatry 62 1042 1051

42. CalleEE

RodriguezC

JacobsEJ

AlmonML

ChaoA

2002 The American Cancer Society Cancer Prevention Study II Nutrition Cohort: rationale, study design, and baseline characteristics. Cancer 94 2490 2501

43. VestboJ

AndersonW

CoxsonHO

CrimC

DawberF

2008 Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE). Eur Respir J 31 869 873

44. RimmEB

GiovannucciEL

WillettWC

ColditzGA

AscherioA

1991 Prospective study of alcohol consumption and risk of coronary disease in men. Lancet 338 464 468

45. PaiJK

MukamalKJ

RexrodeKM

RimmEB

2008 C-reactive protein (CRP) gene polymorphisms, CRP levels, and risk of incident coronary heart disease in two nested case-control studies. PLoS One 3 e1395 doi:10.1371/journal.pone.0001395

46. CurhanGC

TaylorEN

2008 24-h uric acid excretion and the risk of kidney stones. Kidney Int 73 489 496

47. QiL

CornelisMC

KraftP

StanyaKJ

KaoWH

2010 Genetic variants at 2q24 are associated with susceptibility to type 2 diabetes. Hum Mol Genet 19 2706 2715

48. AnthonisenNR

ConnettJE

KileyJP

AltoseMD

BaileyWC

1994 Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1. The Lung Health Study. JAMA 272 1497 1505

49. SpitzMR

WeiQ

DongQ

AmosCI

WuX

2003 Genetic susceptibility to lung cancer: the role of DNA damage and repair. Cancer Epidemiol Biomarkers Prev 12 689 698

50. Van den OordEJ

RujescuD

RoblesJR

GieglingI

BirrellC

2006 Factor structure and external validity of the PANSS revisited. Schizophr Res 82 213 223

51. SacconeSF

PergadiaML

LoukolaA

BromsU

MontgomeryGW

2007 Genetic linkage to chromosome 22q12 for a heavy-smoking quantitative trait in two independent samples. Am J Hum Genet 80 856 866

52. LoukolaA

BromsU

MaunuH

WidenE

HeikkilaK

2008 Linkage of nicotine dependence and smoking behavior on 10q, 7q and 11p in twins with homogeneous genetic background. Pharmacogenomics J 8 209 219

53. LandiMT

ConsonniD

RotunnoM

BergenAW

GoldsteinAM

2008 Environment And Genetics in Lung cancer Etiology (EAGLE) study: an integrative population-based case-control study of lung cancer. BMC Public Health 8 203

54. HayesRB

RedingD

KoppW

SubarAF

BhatN

2000 Etiologic and early marker studies in the prostate, lung, colorectal and ovarian (PLCO) cancer screening trial. Control Clin Trials 21 349S 355S

55. CaporasoN

GuF

ChatterjeeN

Sheng-ChihJ

YuK

2009 Genome-wide and candidate gene association study of cigarette smoking behaviors. PLoS ONE 4 e4653 doi:10.1371/journal.pone.0004653

56. HunterDJ

KraftP

JacobsKB

CoxDG

YeagerM

2007 A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat Genet 39 870 874

57. ColditzGA

RimmEB

GiovannucciE

StampferMJ

RosnerB

1991 A prospective study of parental history of myocardial infarction and coronary artery disease in men. Am J Cardiol 67 933 938

58. ElliottDS

HuizingaD

AgetonSS

1985 Explaining delinquency and drug use Beverly Hills, CA Sage Publications

59. ElliottDS

HuizingaD

MenardS

1989 Multiple Problem Youth: Delinquency, Drugs and Mental Health Problems New York, NY Springer

60. HoftNR

CorleyRP

McQueenMB

SchlaepferIR

HuizingaD

2009 Genetic association of the CHRNA6 and CHRNB3 genes with tobacco dependence in a nationally representative sample. Neuropsychopharmacology 34 698 706

61. BroderickP

WangY

VijayakrishnanJ

MatakidouA

SpitzMR

2009 Deciphering the impact of common genetic variation on lung cancer risk: A genome-wide association study. Cancer Res 69 6633 6641

62. LiMD

XuQ

LouXY

PayneTJ

NiuT

2010 Association and interaction analysis of variants in CHRNA5/CHRNA3/CHRNB4 gene cluster with nicotine dependence in African and European Americans. Am J Med Genet B Neuropsychiatr Genet 153B 745 756

63. ChenX

ChenJ

WilliamsonVS

AnSS

HettemaJM

2009 Variants in nicotinic acetylcholine receptors alpha5 and alpha3 increase risks to nicotine dependence. Am J Med Genet B Neuropsychiatr Genet

64. SchwartzAG

CoteML

WenzlaffAS

LandS

AmosCI

2009 Racial differences in the association between SNPs on 15q25.1, smoking behavior, and risk of non-small cell lung cancer. J Thorac Oncol 4 1195 1201

65. FarrerLA

KranzlerHR

YuY

WeissRD

BradyKT

2009 Association of variants in MANEA with cocaine-related behaviors. Arch Gen Psychiatry 66 267 274

66. ZhangH

KranzlerHR

WeissRD

LuoX

BradyKT

2009 Pro-opiomelanocortin gene variation related to alcohol or drug dependence: evidence and replications across family- and population-based studies. Biol Psychiatry 66 128 136

67. GelernterJ

YuY

WeissR

BradyK

PanhuysenC

2006 Haplotype spanning TTC12 and ANKK1, flanked by the DRD2 and NCAM1 loci, is strongly associated to nicotine dependence in two distinct American populations. Hum Mol Genet 15 3498 3507