Background

The incidence of type 1 diabetes (T1D) is increasing globally. One hypothesis is that increasing childhood obesity rates may explain part of this increase, but, as T1D is rare, intervention studies are challenging to perform. The aim of this study was to assess this hypothesis with a Mendelian randomization approach that uses genetic variants as instrumental variables to test for causal associations.

Methods and findings

We created a genetic instrument of 23 single nucleotide polymorphisms (SNPs) associated with childhood adiposity in children aged 2–10 years. Summary-level association results for these 23 SNPs with childhood-onset (<17 years) T1D were extracted from a meta-analysis of genome-wide association study with 5,913 T1D cases and 8,828 reference samples. Using inverse-variance weighted Mendelian randomization analysis, we found support for an effect of childhood adiposity on T1D risk (odds ratio 1.32, 95% CI 1.06–1.64 per standard deviation score in body mass index [SDS-BMI]). A sensitivity analysis provided evidence of horizontal pleiotropy bias (p = 0.04) diluting the estimates towards the null. We therefore applied Egger regression and multivariable Mendelian randomization methods to control for this type of bias and found evidence in support of a role of childhood adiposity in T1D (odds ratio in Egger regression, 2.76, 95% CI 1.40–5.44). Limitations of our study include that underlying genes and their mechanisms for most of the genetic variants included in the score are not known. Mendelian randomization requires large sample sizes, and power was limited to provide precise estimates. This research has been conducted using data from the Early Growth Genetics (EGG) Consortium, the Genetic Investigation of Anthropometric Traits (GIANT) Consortium, the Tobacco and Genetics (TAG) Consortium, and the Social Science Genetic Association Consortium (SSGAC), as well as meta-analysis results from a T1D genome-wide association study.

Conclusions

This study provides genetic support for a link between childhood adiposity and T1D risk. Together with evidence from observational studies, our findings further emphasize the importance of measures to reduce the global epidemic of childhood obesity and encourage mechanistic studies.

中文翻译：

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儿童肥胖与1型糖尿病的风险：孟德尔随机研究

背景

全球1型糖尿病（T1D）的发病率正在增加。一种假设是，儿童肥胖率的上升可能可以解释这种上升的部分原因，但是由于T1D很少见，因此干预研究难以进行。这项研究的目的是使用孟德尔随机化方法评估该假设，该方法使用遗传变异作为工具变量来检验因果关系。

方法和发现

我们创建了23种单核苷酸多态性（SNP）与2-10岁儿童肥胖相关的遗传工具。这是从儿童年龄（<17岁）T1D的这23个SNP的汇总水平关联结果中提取的，涉及对5,913个T1D病例和8,828个参考样本进行的全基因组关联研究的荟萃分析。使用逆方差加权孟德尔随机分析，我们发现支持儿童肥胖对T1D风险的影响（赔率比1.32，体重指数[SDS-BMI]每标准偏差得分的95％CI 1.06-1.64）。敏感性分析为水平多向性偏倚提供了证据（p= 0.04）将估算值稀释为零。因此，我们应用了Egger回归和多变量孟德尔随机化方法来控制这种类型的偏倚，并发现了证据支持儿童肥胖在T1D中的作用（Egger回归的比值比为2.76，95％CI为1.40-5.44）。我们研究的局限性在于，分数中包含的大多数遗传变异的潜在基因及其机制尚不清楚。孟德尔随机化需要大样本量，并且功效有限，无法提供精确的估计值。这项研究是使用早期生长遗传学（EGG）联盟，人体测量学特征（GIANT）联盟，烟草和遗传学（TAG）联盟以及社会科学遗传协会联盟（SSGAC）的数据进行的，

结论

这项研究为儿童肥胖与T1D风险之间的联系提供了遗传支持。结合观察研究的证据，我们的发现进一步强调了采取措施减少全球儿童肥胖症流行并鼓励进行机理研究的重要性。