Developmental Genetic Epidemiology of Smoking

描述（由申请人提供）：本项目旨在通过检查个体和环境影响来增加我们对吸烟的病因、发展、异质性和共病的理解。它的重点是青少年，他们开始吸烟的风险最大，预防和控制持续吸烟对公共卫生有最大的潜在好处。在过去的十年中，复杂性状的定量统计方法和大量遗传信息流行病学样本取得了巨大的发展，这些样本现在使我们能够测试关键的复杂问题。我们有三个关于青春期双胞胎及其父母的纵向遗传信息数据集，六个关于已发表的青少年吸烟数据集和三个扩展双胞胎（ET）亲属关系研究的数据集。一名成人和三名青少年/青年双胞胎样本的吸烟行为的详细数据可用。数据来自美国、比利时、荷兰、芬兰、澳大利亚和瑞典。我们将检验以下关于SI的假设：1)青春期早期的SI主要受共同环境因素的影响；遗传因素逐渐增加青少年后期和青年期的自杀倾向，2)自杀率因文化而异（美国、欧洲和澳大利亚），但方差成分没有变化，3)父母和父母吸烟的影响减少，兄弟姐妹和同伴的影响增加，4)测量的环境因素的影响逐渐减少，测量的基因（在GWAS中确定）的影响在青春期增加。5)被测基因对SI的影响随环境因子（GxE）的变化而变化；6)基因和环境的作用在男性和女性中是相同的。第二组假设涉及SI与SP/尼古丁依赖（ND）之间的关系。我们将测试7)是否有重要但不是完整的遗传和环境之间的重叠SI和SP和ND的措施在青春期/青年,8)有显著的测量方差以年龄和性别为SP / ND, 9)相同的基因和环境影响SI和SP在青春期,10)基因重叠SI,如果发病的年龄,发病的年龄与SP / ND, 11)环境风险因素的贡献更大比SP / ND SI,12)测量基因（在GWAS中鉴定）对SP/ND的贡献大于SI。我们拥有丰富的发展（前瞻性和回顾性）数据集，以及我们在遗传信息样本统计建模方面的专业知识，这使我们在解决这些具体目标方面处于独特而理想的地位。这样做将大大提高对先天和后天如何相互作用产生吸烟倾向的理解。

DESCRIPTION (provided by applicant): This project aims to increase our understanding of the etiology, development, heterogeneity and comorbidity of smoking by examining both individual and contextual influences. It focuses on adolescents, who are at greatest risk for smoking initiation (SI) and in whom prevention and control of smoking persistence (SP) would have the greatest potential benefit to public health. The last decade has seen tremendous growth in quantitative statistical methods for complex traits, and in large genetically informative epidemiological samples, which now allow us to test critical complex questions. We have access to three longitudinal genetically informative data sets of adolescent twins and their parents, six data sets with published adolescent smoking data and three extended twin (ET) kinship studies. Detailed data on smoking behavior are available in one adult and in three adolescent/young adult twin samples. Data are from the United States, Belgium, the Netherlands, Finland, Australia and Sweden. We will test the following hypotheses about SI: 1) SI in early adolescence is primarily influenced by shared environmental factors; genetic factors gradually contribute more to liability to SI in later adolescence and young adulthood, 2) the rates of SI vary by culture (US, Europe, Australia), but variance components do not, 3) the influence of parents and parental smoking decreases and that of siblings and peers increases from adolescence to young adulthood, 4) the influence of measured environmental factors gradually decreases and that of measured genes (identified in GWAS) increases over adolescence, 5) the effect of measured genes on SI varies as a function of environmental factors (GxE), 6) the role of genes and environment is the same for males and females. The second set of hypotheses concerns the relationship between SI and SP/ nicotine dependence (ND). We will test whether 7) there is significant but not complete genetic and environmental overlap between SI and measures of SP & ND in adolescence/ young adulthood, 8) there is significant measurement variance by age and sex for SP/ND, 9) the same genes and environments influence SI and SP throughout adolescence, 10) there is genetic overlap between SI, age of onset of SI and between age of onset and SP/ND, 11) the contribution of environmental risk factors is greater to SI than to SP/ND, and 12) the contribution of measured genes (identified in GWAS) is greater for SP/ND than for SI. Our access to rich developmental (prospective and retrospective) data sets and our expertise in statistical modeling of genetically informative samples, puts us in a unique and ideal position to address these specific aims. Doing so will substantially improve understanding of how nature and nurture interact to generate liability to smoking. PUBLIC HEALTH RELEVANCE: This project aims to increase our understanding of the etiology, development, heterogeneity and comorbidity of smoking, which remains the leading preventable cause of death in the US, accounting for approximately 1 or ever 5 deaths. We will focus on both individual and contextual influences in order to make progress in prevention and control of smoking behavior, and thus influence public health.