Developmental Genetic Epidemiology of Smoking

描述（由申请人提供）：该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，异质性和共病性的理解。它重点关注青少年，他们开始吸烟（SI）的风险最大，预防和控制持续吸烟（SP）将对公共卫生产生最大的潜在益处。在过去的十年里，复杂性状的定量统计方法和大量遗传信息流行病学样本有了巨大的发展，现在我们可以测试关键的复杂问题。我们有机会获得三个纵向的遗传信息数据集的青少年双胞胎和他们的父母，六个数据集的青少年吸烟数据和三个扩展双胞胎（ET）亲属关系的研究。关于吸烟行为的详细数据可在一个成年人和三个青少年/年轻成人双胞胎样本中获得。数据来自美国、比利时、荷兰、芬兰、澳大利亚和瑞典。本研究将检验以下关于同感的假设：1）青少年早期的同感主要受共同环境因素的影响;在青春期后期和青年期，遗传因素逐渐增加对SI的易感性，2）SI的发生率因文化而异（美国，欧洲，澳大利亚），但方差分量不，（3）从青少年到青年，父母和父母吸烟的影响逐渐减弱，兄弟姐妹和同伴吸烟的影响逐渐增强，4）环境因子的影响逐渐减弱，基因的影响逐渐减弱（在GWAS中鉴定）在青春期增加，5）测量的基因对SI的影响随环境因素（GxE）而变化，6）基因和环境的作用对男性和女性是一样的。第二组假设涉及SI和SP/尼古丁依赖（ND）之间的关系。我们将测试7）在青春期/年轻成年期SI和SP & ND的测量之间是否存在显著但不完全的遗传和环境重叠，8）SP/ND的年龄和性别的测量差异是否显著，9）相同的基因和环境在整个青春期影响SI和SP，10）SI和SP之间是否存在遗传重叠，11）环境危险因素对SI的贡献大于对SP/ND的贡献，和12）测量基因（在GWAS中鉴定的）对SP/ND的贡献大于对SI的贡献。我们对丰富的发展（前瞻性和回顾性）数据集的访问以及我们在遗传信息样本统计建模方面的专业知识，使我们处于一个独特而理想的位置，以实现这些特定的目标。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。 公共卫生相关性：该项目旨在增加我们对吸烟的病因、发展、异质性和共病性的理解，吸烟仍然是美国主要的可预防死亡原因，约占1例或5例死亡。我们将关注个人和环境的影响，以便在预防和控制吸烟行为方面取得进展，从而影响公众健康。

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.