Multiple independent loci at chromosome 15q25.1 affect smoking quantity: a meta-analysis and comparison with lung cancer and COPD.
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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2010-08-01
|
| Series: | PLoS Genetics |
| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20700436/?tool=EBI |
| _version_ | 1811306405846581248 |
|---|---|
| author | Nancy L Saccone Robert C Culverhouse Tae-Hwi Schwantes-An Dale S Cannon Xiangning Chen Sven Cichon Ina Giegling Shizhong Han Younghun Han Kaisu Keskitalo-Vuokko Xiangyang Kong Maria Teresa Landi Jennie Z Ma Susan E Short Sarah H Stephens Victoria L Stevens Lingwei Sun Yufei Wang Angela S Wenzlaff Steven H Aggen Naomi Breslau Peter Broderick Nilanjan Chatterjee Jingchun Chen Andrew C Heath Markku Heliövaara Nicole R Hoft David J Hunter Majken K Jensen Nicholas G Martin Grant W Montgomery Tianhua Niu Thomas J Payne Leena Peltonen Michele L Pergadia John P Rice Richard Sherva Margaret R Spitz Juzhong Sun Jen C Wang Robert B Weiss William Wheeler Stephanie H Witt Bao-Zhu Yang Neil E Caporaso Marissa A Ehringer Tim Eisen Susan M Gapstur Joel Gelernter Richard Houlston Jaakko Kaprio Kenneth S Kendler Peter Kraft Mark F Leppert Ming D Li Pamela A F Madden Markus M Nöthen Sreekumar Pillai Marcella Rietschel Dan Rujescu Ann Schwartz Christopher I Amos Laura J Bierut |
| author_facet | Nancy L Saccone Robert C Culverhouse Tae-Hwi Schwantes-An Dale S Cannon Xiangning Chen Sven Cichon Ina Giegling Shizhong Han Younghun Han Kaisu Keskitalo-Vuokko Xiangyang Kong Maria Teresa Landi Jennie Z Ma Susan E Short Sarah H Stephens Victoria L Stevens Lingwei Sun Yufei Wang Angela S Wenzlaff Steven H Aggen Naomi Breslau Peter Broderick Nilanjan Chatterjee Jingchun Chen Andrew C Heath Markku Heliövaara Nicole R Hoft David J Hunter Majken K Jensen Nicholas G Martin Grant W Montgomery Tianhua Niu Thomas J Payne Leena Peltonen Michele L Pergadia John P Rice Richard Sherva Margaret R Spitz Juzhong Sun Jen C Wang Robert B Weiss William Wheeler Stephanie H Witt Bao-Zhu Yang Neil E Caporaso Marissa A Ehringer Tim Eisen Susan M Gapstur Joel Gelernter Richard Houlston Jaakko Kaprio Kenneth S Kendler Peter Kraft Mark F Leppert Ming D Li Pamela A F Madden Markus M Nöthen Sreekumar Pillai Marcella Rietschel Dan Rujescu Ann Schwartz Christopher I Amos Laura J Bierut |
| author_sort | Nancy L Saccone |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-13T08:43:52Z |
| format | Article |
| id | doaj.art-ec22c1d8d2fc40a4a6583be408b4a69a |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-04-13T08:43:52Z |
| publishDate | 2010-08-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-ec22c1d8d2fc40a4a6583be408b4a69a2022-12-22T02:53:48ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042010-08-0168e100105310.1371/journal.pgen.1001053Multiple independent loci at chromosome 15q25.1 affect smoking quantity: a meta-analysis and comparison with lung cancer and COPD. Nancy L SacconeRobert C CulverhouseTae-Hwi Schwantes-AnDale S CannonXiangning ChenSven CichonIna GieglingShizhong HanYounghun HanKaisu Keskitalo-VuokkoXiangyang KongMaria Teresa LandiJennie Z MaSusan E ShortSarah H StephensVictoria L StevensLingwei SunYufei WangAngela S WenzlaffSteven H AggenNaomi BreslauPeter BroderickNilanjan ChatterjeeJingchun ChenAndrew C HeathMarkku HeliövaaraNicole R HoftDavid J HunterMajken K JensenNicholas G MartinGrant W MontgomeryTianhua NiuThomas J PayneLeena PeltonenMichele L PergadiaJohn P RiceRichard ShervaMargaret R SpitzJuzhong SunJen C WangRobert B WeissWilliam WheelerStephanie H WittBao-Zhu YangNeil E CaporasoMarissa A EhringerTim EisenSusan M GapsturJoel GelernterRichard HoulstonJaakko KaprioKenneth S KendlerPeter KraftMark F LeppertMing D LiPamela A F MaddenMarkus M NöthenSreekumar PillaiMarcella RietschelDan RujescuAnn SchwartzChristopher I AmosLaura J BierutRecently, 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.https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20700436/?tool=EBI |
| spellingShingle | Nancy L Saccone Robert C Culverhouse Tae-Hwi Schwantes-An Dale S Cannon Xiangning Chen Sven Cichon Ina Giegling Shizhong Han Younghun Han Kaisu Keskitalo-Vuokko Xiangyang Kong Maria Teresa Landi Jennie Z Ma Susan E Short Sarah H Stephens Victoria L Stevens Lingwei Sun Yufei Wang Angela S Wenzlaff Steven H Aggen Naomi Breslau Peter Broderick Nilanjan Chatterjee Jingchun Chen Andrew C Heath Markku Heliövaara Nicole R Hoft David J Hunter Majken K Jensen Nicholas G Martin Grant W Montgomery Tianhua Niu Thomas J Payne Leena Peltonen Michele L Pergadia John P Rice Richard Sherva Margaret R Spitz Juzhong Sun Jen C Wang Robert B Weiss William Wheeler Stephanie H Witt Bao-Zhu Yang Neil E Caporaso Marissa A Ehringer Tim Eisen Susan M Gapstur Joel Gelernter Richard Houlston Jaakko Kaprio Kenneth S Kendler Peter Kraft Mark F Leppert Ming D Li Pamela A F Madden Markus M Nöthen Sreekumar Pillai Marcella Rietschel Dan Rujescu Ann Schwartz Christopher I Amos Laura J Bierut Multiple independent loci at chromosome 15q25.1 affect smoking quantity: a meta-analysis and comparison with lung cancer and COPD. PLoS Genetics |
| title | Multiple independent loci at chromosome 15q25.1 affect smoking quantity: a meta-analysis and comparison with lung cancer and COPD. |
| title_full | Multiple independent loci at chromosome 15q25.1 affect smoking quantity: a meta-analysis and comparison with lung cancer and COPD. |
| title_fullStr | Multiple independent loci at chromosome 15q25.1 affect smoking quantity: a meta-analysis and comparison with lung cancer and COPD. |
| title_full_unstemmed | Multiple independent loci at chromosome 15q25.1 affect smoking quantity: a meta-analysis and comparison with lung cancer and COPD. |
| title_short | Multiple independent loci at chromosome 15q25.1 affect smoking quantity: a meta-analysis and comparison with lung cancer and COPD. |
| title_sort | multiple independent loci at chromosome 15q25 1 affect smoking quantity a meta analysis and comparison with lung cancer and copd |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20700436/?tool=EBI |
| work_keys_str_mv | AT nancylsaccone multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT robertcculverhouse multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT taehwischwantesan multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT dalescannon multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT xiangningchen multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT svencichon multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT inagiegling multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT shizhonghan multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT younghunhan multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT kaisukeskitalovuokko multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT xiangyangkong multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT mariateresalandi multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT jenniezma multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT susaneshort multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT sarahhstephens multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT victorialstevens multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT lingweisun multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT yufeiwang multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT angelaswenzlaff multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT stevenhaggen multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT naomibreslau multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT peterbroderick multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT nilanjanchatterjee multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT jingchunchen multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT andrewcheath multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT markkuheliovaara multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT nicolerhoft multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT davidjhunter multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT majkenkjensen multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT nicholasgmartin multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT grantwmontgomery multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT tianhuaniu multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT thomasjpayne multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT leenapeltonen multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT michelelpergadia multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT johnprice multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT richardsherva multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT margaretrspitz multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT juzhongsun multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT jencwang multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT robertbweiss multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT williamwheeler multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT stephaniehwitt multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT baozhuyang multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT neilecaporaso multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT marissaaehringer multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT timeisen multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT susanmgapstur multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT joelgelernter multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT richardhoulston multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT jaakkokaprio multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT kennethskendler multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT peterkraft multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT markfleppert multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT mingdli multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT pamelaafmadden multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT markusmnothen multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT sreekumarpillai multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT marcellarietschel multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT danrujescu multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT annschwartz multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT christopheriamos multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd AT laurajbierut multipleindependentlociatchromosome15q251affectsmokingquantityametaanalysisandcomparisonwithlungcancerandcopd |