Constructing a polygenic risk score for childhood obesity using functional data analysis.
Constructing a polygenic risk score for childhood obesity using functional data analysis.
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DOI：
10.1016/j.ecosta.2021.10.014
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发表时间：
2023-01
影响因子：
1.9
通讯作者：
Makova KD
中科院分区：
文献类型：
--
作者：
Craig SJC;Kenney AM;Lin J;Paul IM;Birch LL;Savage JS;Marini ME;Chiaromonte F;Reimherr ML;Makova KD
肥胖是一种高度遗传性的疾病，影响着越来越多的成年人，令人担忧的是，也影响着越来越多的儿童。然而，只有一小部分的遗传能力归因于特定的遗传变异。这些变异传统上是通过全基因组关联研究（GWAS）来确定的，GWAS利用的是收集了单个汇总测量（例如BMI）的数万或数十万个体的样本。另一种方法是将重点放在更小、更深入的特征样本上，并结合利用纵向表型的高级统计模型。新颖的功能数据分析（FDA）技术用于利用纵向增长信息从出生和三岁之间的儿童队列。在超高维环境中，筛选了数十万个单核苷酸多态性（SNP），并使用加权方法构建了儿童肥胖的两个多基因风险评分（PRS），该方法结合了SNP效应的动态和联合性质。这些分数在婴儿体重快速增加（与没有）的儿童中明显更高——这是以后生活中肥胖的预测指标。通过两个独立的队列，研究表明，在幼儿中发现的遗传变异也适用于年龄较大的儿童和成人，这与儿童早期肥胖可以预测以后的肥胖一致。相比之下，基于成人肥胖GWAS鉴定的snp的prs不能预测幼儿队列的体重增加。这是FDA成功应用于GWAS的一个例子。该应用程序与模拟相辅相成，模拟表明，深度表征样本可以与具有横截面响应的可比研究一样有效，如果不是更有效的话。总体而言，研究表明，纵向表型的深入、统计复杂的特征可以为样本量相对较小的研究提供更高的统计能力；并展示了FDA的方法如何被用作传统GWAS的替代方法。
Obesity is a highly heritable condition that affects increasing numbers of adults and, concerningly, of children. However, only a small fraction of its heritability has been attributed to specific genetic variants. These variants are traditionally ascertained from genome-wide association studies (GWAS), which utilize samples with tens or hundreds of thousands of individuals for whom a single summary measurement (e.g., BMI) is collected. An alternative approach is to focus on a smaller, more deeply characterized sample in conjunction with advanced statistical models that leverage longitudinal phenotypes. Novel functional data analysis (FDA) techniques are used to capitalize on longitudinal growth information from a cohort of children between birth and three years of age. In an ultra-high dimensional setting, hundreds of thousands of single nucleotide polymorphisms (SNPs) are screened, and selected SNPs are used to construct two polygenic risk scores (PRS) for childhood obesity using a weighting approach that incorporates the dynamic and joint nature of SNP effects. These scores are significantly higher in children with (vs. without) rapid infant weight gain—a predictor of obesity later in life. Using two independent cohorts, it is shown that the genetic variants identified in very young children are also informative in older children and in adults, consistent with early childhood obesity being predictive of obesity later in life. In contrast, PRSs based on SNPs identified by adult obesity GWAS are not predictive of weight gain in the cohort of young children. This provides an example of a successful application of FDA to GWAS. This application is complemented with simulations establishing that a deeply characterized sample can be just as, if not more, effective than a comparable study with a cross-sectional response. Overall, it is demonstrated that a deep, statistically sophisticated characterization of a longitudinal phenotype can provide increased statistical power to studies with relatively small sample sizes; and shows how FDA approaches can be used as an alternative to the traditional GWAS.
影响因子：
3.7
作者：
Andersson EA;Pilgaard K;Pisinger C;Harder MN;Grarup N;Færch K;Sandholt C;Poulsen P;Witte DR;Jørgensen T;Vaag A;Pedersen O;Hansen T
通讯作者：
Hansen T
影响因子：
6.9
作者：
Llewellyn, C. H.;Trzaskowski, M.;Plomin, R.;Wardle, J.
通讯作者：
Wardle, J.