THE GENETICS OF VULNERABILITY TO NICOTINE ADDICTIONS

尼古丁成瘾易感性的遗传学

• 批准号: 8661422
• 负责人: Pamela Ann Madden
• 金额: $ 0.74万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-25 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8661422
• 关键词: 22q12; ADRBK2 gene; Accounting; Alcohol or Other Drugs use; Australia; Behavior; Beta Carotene; Beta-Adrenergic Receptor Kinase 2; Biological; Cancer Etiology; Candidate Disease Gene; Cessation of life; Chemoprevention; Chromosomes; Chromosomes, Human, Pair 22; Cigarette; Collaborations; Communities; Consumption; DNA; DNA Sequence; Data; Data Set; Ensure; Epidemiology; Family; Female; Finland; Funding; Genes; Genetic; Genetic Predisposition to Disease; Genome Scan; Genotype; Goals; Haplotypes; Hour; Individual; Lead; Malignant neoplasm of lung; Measures; Mental disorders; Microsatellite Repeats; Nicotine Dependence; Parents; Participant; Phase; Phenotype; Population; Population Control; Premature Mortality; Psychopathology; Quantitative Trait Loci; Recruitment Activity; Risk; SNP genotyping; Sampling; Series; Severities; Siblings; Signal Transduction; Smoke; Smoker; Smoking; Smoking History; Source; Specificity; Staging; Symptoms; Tobacco; Twin Multiple Birth; Update; Variant; alpha Tocopherol; base; cancer chemoprevention; cigarette smoking; cohort; density; family genetics; follow-up; genetic association; genetic epidemiology; genetic linkage; genetic linkage analysis; genetic variant; genome-wide; high risk; improved; indexing; male; novel; response; smoking cessation; trend

DESCRIPTION (provided by applicant): Long-term smoking is the leading preventable cause of cancers and of premature mortality, with approximately one billion smoking-related deaths projected globally, based on present trends, in the current century. This is the re-revised (A2) competing continuation of a genetic epidemiologic collaboration to identify genes that influence risks for heavy smoking and nicotine dependence. During the first five-year funding period, QTL linkage analyses using 10cM microsatellite marker genome scan data have identified a strong linkage signal in both Australian and Finnish sibships, for our primary heaviness-of-smoking (HoS) phenotype, on Chr 22q12 (in updated analyses, multi-point LODs of 3.05 and 3.21 respectively). Genotyping of two additional microsatellite markers flanking the linkage peaks, in both Finnish and Australian genome-scan samples, yielded a combined multipoint LOD of 5.21 (genome-wide significance p=.006) at 25cM. This competing continuation seeks to identify the gene or genes at 22q12 which are contributing to HoS using the efficiency of existing data and DNAs and large informative samples, with complementary strengths, that were drawn from the same populations in which the original linkage signal was obtained. This goal will be achieved by (i) conducting a genetic association study, with high-throughput genotyping of 1436 SNPs across a 1-LOD support interval within our primary linkage region in 1000 unrelated Finnish male heavy smokers (ATBC chemoprevention trial participants who smoked 40+ cigarettes per day) and 1000 Finnish male population controls (Health2000 participants) (Aim 1: 'Finnish series I'; 'stage 1 genotyping'); (ii) conducting follow-up genotyping of SNPs found nominally significant at stage 1 in two separate series: (a) an additional 2000 unrelated heavy smokers (who smoked 30+ cigarettes per day) and 2000 population controls ('Finnish series II'); and (b) a family-based series of 4429 siblings who are smokers (55 percent female) from a community-based series of Australian large sibships ('BIGSIB' sample) ascertained solely on the basis of large sibship size from the Australian twin panel, from the same cohorts as the Australian linkage families (Aim 2: 'stage 2 genotyping'). Combining Finnish series I and II will ensure adequate power to detect quite modest QTL effect sizes; confirmation of nominal stage 1 associations in the Australian series will ensure that we are able to detect genetic effects that may be only modest in male long-term smokers, but more potent in female smokers. For genes with SNPs confirmed to be associated with HoS, we will conduct DNA sequencing in individuals with high-risk and low-risk haplotypes, selected from the original Finnish and Australian linkage families, to attempt to identify variants that might be functional (Aim 3), and will characterize using family-based association approaches the effects of genetic variants (or haplotypes) thus identified on cigarette-smoking and related behaviors (including correlated substance use and other psychiatric disorders), using the original Finnish NAG families and the Australian BIGSIB sample (Aim 4). The importance of genetic influences on risk of becoming a long-term heavy smoker has been known for many years. Understanding the genetic mechanisms by which some individuals are at increased risk should ultimately lead to improved therapies to assist smoking cessation.

描述(申请人提供)：长期吸烟是癌症和过早死亡的主要可预防原因，根据目前的趋势，预计本世纪全球与吸烟有关的死亡约为10亿人。这是一项基因流行病学合作的重新修订(A2)竞争性延续，以确定影响重度吸烟和尼古丁依赖风险的基因。在第一个五年资助期间，使用10 cM微卫星标记基因组扫描数据进行的QTL连锁分析发现，在澳大利亚和芬兰的兄弟姐妹中，我们的主要吸烟量(Hos)表型在Chr 22q12上存在强烈的连锁信号(在最新分析中，多点LOD分别为3.05和3.21)。在芬兰和澳大利亚的基因组扫描样本中，对连接峰两侧的另外两个微卫星标记进行基因分型，在25 cM处产生了5.21的多点LOD(全基因组意义p=0.006)。这种竞争的延续试图利用现有数据和DNA的效率，以及从获得原始连锁信号的相同群体中提取的具有互补优势的大信息样本，来识别22q12上对HOS有贡献的一个或多个基因。这一目标将通过以下方式实现：(I)开展一项遗传关联研究，在1000名无关的芬兰男性重度吸烟者(每天吸烟40支以上的ATBC化学预防试验参与者)和1000名芬兰男性对照组(Health2000参与者)中，对我们主要连锁区内1-LOD支持区间内的1436个SNPs进行高通量基因分型(目标1：‘芬兰系列I’；‘阶段1基因分型’)；(Ii)对第一阶段发现的两个独立系列中名义上有意义的SNPs进行后续基因分型：(A)另外2000名无关的重度吸烟者(每天吸烟30多支)和2000名人口控制组(“芬兰系列II”)；以及(B)一个以家庭为基础的系列系列，其中4429名兄弟姐妹(55%为女性)是吸烟者，他们来自以社区为基础的澳大利亚大兄弟姐妹系列(“BIGSIB”样本)，完全基于澳大利亚双胞胎小组的大兄弟姐妹规模，来自与澳大利亚连锁家庭相同的队列(目标2：“第二阶段基因分型”)。结合芬兰系列I和II将确保有足够的能力检测相当温和的QTL效应大小；澳大利亚系列中名义阶段1关联的确认将确保我们能够检测到可能仅在男性长期吸烟者中轻微、但在女性吸烟者中更有效的遗传影响。对于被证实与HOS相关的SNPs基因，我们将在具有高风险和低风险单倍型的个体中进行DNA测序，这些单倍型来自最初的芬兰和澳大利亚连锁家系，试图确定可能具有功能的变异(目标3)，并将使用基于家庭的关联方法，使用原始芬兰NAG家系和澳大利亚BIGSIB样本(目标4)，表征如此确定的遗传变异(或单倍型)对吸烟和相关行为(包括相关物质使用和其他精神障碍)的影响。多年来，基因影响对成为长期重度吸烟者的风险的重要性已经为人所知。了解一些个体风险增加的遗传机制最终应该会导致改进的治疗方法，以帮助戒烟。

项目成果

Genome-wide association for major depressive disorder: a possible role for the presynaptic protein piccolo.

• DOI: 10.1038/mp.2008.125
• 发表时间: 2009-04
• 期刊: Molecular psychiatry
• 影响因子: 11

Genetics and smoking.

• DOI: 10.1007/s40429-013-0006-3
• 发表时间: 2014-03-01
• 期刊: Current addiction reports
• 影响因子: 4.3

Multiple distinct risk loci for nicotine dependence identified by dense coverage of the complete family of nicotinic receptor subunit (CHRN) genes.

• DOI: 10.1002/ajmg.b.30828
• 发表时间: 2009-06-05
• 期刊: American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics
• 作者: Saccone NL;Saccone SF;Hinrichs AL;Stitzel JA;Duan W;Pergadia ML;Agrawal A;Breslau N;Grucza RA;Hatsukami D;Johnson EO;Madden PA;Swan GE;Wang JC;Goate AM;Rice JP;Bierut LJ
• 通讯作者: Bierut LJ

Longevity candidate genes and their association with personality traits in the elderly.

• DOI: 10.1002/ajmg.b.32013
• 发表时间: 2012-03
• 期刊: AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS
• 影响因子: 2.8
• 作者: Luciano, Michelle;Lopez, Lorna M.;de Moor, Marleen H. M.;Harris, Sarah E.;Davies, Gail;Nutile, Teresa;Krueger, Robert F.;Esko, Tonu;Schlessinger, David;Toshiko, Tanaka;Derringer, Jaime L.;Realo, Anu;Hansell, Narelle K.;Pergadia, Michele L.;Pesonen, Anu-Katriina;Sanna, Serena;Terracciano, Antonio;Madden, Pamela A. F.;Penninx, Brenda;Spinhoven, Philip;Hartman, Catherina A.;Oostra, Ben A.;Janssens, A. Cecile J. W.;Eriksson, Johan G.;Starr, John M.;Cannas, Alessandra;Ferrucci, Luigi;Metspalu, Andres;Wright, Margeret J.;Heath, Andrew C.;van Duijn, Cornelia M.;Bierut, Laura J.;Raikkonen, Katri;Martin, Nicholas G.;Ciullo, Marina;Rujescu, Dan;Boomsma, Dorret I.;Deary, Ian J.
• 通讯作者: Deary, Ian J.

Associations of nicotine intake measures with CHRN genes in Finnish smokers.

芬兰吸烟者尼古丁摄入量与 CHRN 基因的关联。

• DOI: 10.1093/ntr/ntr059
• 发表时间: 2011
• 期刊: Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco
• 作者: Keskitalo-Vuokko,Kaisu;Pitkäniemi,Janne;Broms,Ulla;Heliövaara,Markku;Aromaa,Arpo;Perola,Markus;Ripatti,Samuli;Salminen,Outi;Salomaa,Veikko;Loukola,Anu;Kaprio,Jaakko
• 通讯作者: Kaprio,Jaakko