Tobacco smoking is the leading cause of preventable death globally. Smoking quantity, measured in cigarettes per day (CPD), is influenced both by the age of onset of regular smoking (AOS) and by genetic factors, including a strong effect of the non-synonymous single nucleotide polymorphism rs16969968. A previous study by Hartz et al. reported an interaction between these two factors, whereby rs16969968 risk allele carriers who started smoking earlier showed increased risk for heavy smoking compared to those who started later. This finding has yet to be replicated in a large, independent sample. We performed a preregistered, direct replication attempt of the rs16969968xAOS interaction on smoking quantity in 128,383 unrelated individuals from the UK Biobank, meta-analyzed across ancestry groups. We fit statistical association models mirroring the original publication as well as formal interaction tests on multiple phenotypic and analytical scales. We replicated the main effects of rs16969968 and AOS on CPD but failed to replicate the interaction using previous methods. Nominal significance of the rs16969968xAOS interaction term depended strongly on the scale of analysis and the particular phenotype, as did associations stratified by early/late AOS. No interaction tests passed genome-wide correction (α=5e-8), and all estimated interaction effect sizes were much smaller in magnitude than previous estimates. We failed to replicate the strong rs16969968xAOS interaction effect previously reported. If such gene-moderator interactions influence complex traits, they likely depend on scale of measurement, and current biobanks lack the power to detect significant genome-wide associations given the minute effect sizes expected.

中文翻译：

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基于吸烟年龄，rs16969968对重度吸烟的改良遗传效应的证据很少

吸烟是全球可预防的死亡的主要原因。每天吸烟量（CPD）中的吸烟量受规律吸烟（AOS）发病年龄和遗传因素的影响，包括非同义单核苷酸多态性rs16969968的强烈影响。Hartz等人先前的研究。报道了这两个因素之间的相互作用，据此rs16969968风险较高的等位基因携带者与较早开始吸烟的人相比，较早开始吸烟的人患重烟的风险增加。这一发现尚未在大型的独立样本中得到重复。我们对来自英国生物银行的128,383名无关亲戚进行了针对吸烟量的rs16969968xAOS交互作用的预先注册的直接复制尝试，并对所有祖先组进行了荟萃分析。我们拟合了反映原始出版物以及多种表型和分析量表的正式相互作用测试的统计关联模型。我们复制了rs16969968和AOS对CPD的主要影响，但未能使用以前的方法复制交互作用。rs16969968xAOS交互作用术语的名义重要性在很大程度上取决于分析的规模和特定的表型，与早期/晚期AOS分层的关联也是如此。没有相互作用测试通过全基因组校正（α= 5e-8），并且所有估计的相互作用效应大小在大小上都比以前的估计小得多。我们未能复制先前报道的强大的rs16969968xAOS交互作用。如果此类基因-调节剂相互作用影响复杂性状，则可能取决于测量范围，