Institute for Behavioral Genetics, University of Colorado-Boulder, Boulder, CO.
Department of Applied Mathematics, University of Colorado-Boulder, Boulder, CO.
Nicotine Tob Res. 2021 May 24;23(6):1055-1063. doi: 10.1093/ntr/ntaa229.
Tobacco smoking is the leading cause of preventable death globally. Smoking quantity, measured in cigarettes per day, is influenced both by the age of onset of regular smoking (AOS) and by genetic factors, including a strong effect of the nonsynonymous 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 with 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 rs16969968 × AOS 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 cigarettes per day but failed to replicate the interaction using previous methods. Nominal significance of the rs16969968 × AOS 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 rs16969968 × AOS 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.
We failed to replicate the strong rs16969968 × AOS interaction effect on smoking quantity previously reported. If such gene-moderator interactions influence complex traits, current biobanks lack the power to detect significant genome-wide associations given the minute effect sizes expected. Furthermore, many potential interaction effects are likely to depend on the scale of measurement employed.
吸烟是全球可预防死亡的主要原因。吸烟量（以每天吸烟的支数来衡量）既受开始规律吸烟的年龄（AOS）的影响，也受遗传因素的影响，包括非同义单核苷酸多态性 rs16969968 的强烈影响。Hartz 等人的先前研究报告称，这两个因素之间存在相互作用，即与开始吸烟较晚的携带者相比，携带 rs16969968 风险等位基因且较早开始吸烟的人患重度吸烟的风险增加。这一发现尚未在一个大型的、独立的样本中得到复制。
我们在英国生物银行的 128383 名无亲缘关系的个体中，对 rs16969968 与 AOS 对吸烟量的相互作用进行了预先注册的直接重复尝试，按祖先群体进行了荟萃分析。我们拟合了与原始出版物相匹配的统计关联模型，以及在多个表型和分析尺度上的正式相互作用检验。
我们复制了 rs16969968 和 AOS 对每天吸烟量的主要影响，但未能使用以前的方法复制相互作用。rs16969968 与 AOS 相互作用项的名义显著性强烈依赖于分析的尺度和特定的表型，按早期/晚期 AOS 分层的关联也是如此。没有相互作用检验通过全基因组校正（α=5e-8），并且所有估计的相互作用效应大小都比以前的估计值小得多。
我们未能复制先前报道的 rs16969968 与 AOS 之间的强烈相互作用效应。如果这种基因-调节剂相互作用影响复杂性状，它们可能取决于测量的尺度，并且鉴于预期的微小效应大小，当前的生物库缺乏检测全基因组显著关联的能力。
我们未能复制先前报道的 rs16969968 与 AOS 对吸烟量的强烈相互作用效应。如果这种基因-调节剂相互作用影响复杂性状，鉴于预期的微小效应大小，当前的生物库缺乏检测全基因组显著关联的能力。此外，许多潜在的相互作用效应可能取决于所使用的测量尺度。
