Abstract

Contemporary genome-wide association study (GWAS) methods typically do not account for variability in genetic effects throughout development. We applied genomic structural equation modeling to combine developmentally-informative phenotype data and GWAS to create polygenic scores (PGS) for alcohol use frequency that are specific to developmental stage. Longitudinal cohort studies targeted for gene-identification analyses include the Collaborative Study on the Genetics of Alcoholism (adolescence n = 1,118, early adulthood n = 2,762, adulthood n = 5,255), the National Longitudinal Study of Adolescent to Adult Health (adolescence n = 3,089, early adulthood n = 3,993, adulthood n = 5,149), and the Avon Longitudinal Study of Parents and Children (ALSPAC; adolescence n = 5,382, early adulthood n = 3,613). PGS validation analyses were conducted in the COGA sample using an alternate version of the discovery analysis with COGA removed. Results suggest that genetic liability for alcohol use frequency in adolescence may be distinct from genetic liability for alcohol use frequency later in developmental periods. The age-specific PGS predicts an increase of 4 drinking days per year per PGS standard deviation when modeled separately from the common factor PGS in adulthood. The current work was underpowered at all steps of the analysis plan. Though small sample sizes and low statistical power limit the substantive conclusions that can be drawn regarding these research questions, this work provides a foundation for future genetic studies of developmental variability in the genetic underpinnings of alcohol use behaviors and genetically-informed, age-matched phenotype prediction.

中文翻译：

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酒精使用频率的发育信息全基因组关联研究

摘要

当代全基因组关联研究（GWAS）方法通常不考虑整个发育过程中遗传效应的变异性。我们应用基因组结构方程模型将发育信息表型数据和 GWAS 结合起来，创建特定于发育阶段的饮酒频率的多基因评分 (PGS)。针对基因识别分析的纵向队列研究包括酒精中毒遗传学合作研究（青春期 n = 1,118、成年早期 n = 2,762、成年期 n = 5,255）、国家青少年到成人健康纵向研究（青春期 n = 3,089） ，成年早期 n = 3,993，成年期 n = 5,149)，以及雅芳父母和儿童纵向研究 (ALSPAC；青春期 n = 5,382，成年早期 n = 3,613)。使用去除 COGA 的替代版本的发现分析在 COGA 样品中进行 PGS 验证分析。结果表明，青春期饮酒频率的遗传倾向可能与发育后期饮酒频率的遗传倾向不同。当与成年期的公因子 PGS 分开建模时，特定年龄的 PGS 预测每个 PGS 标准差每年饮酒天数会增加 4 个。目前的工作在分析计划的所有步骤上都动力不足。尽管样本量小和统计功效低限制了就这些研究问题得出的实质性结论，但这项工作为未来酒精使用行为遗传基础的发育变异性和遗传信息、年龄匹配表型的遗传研究奠定了基础预言。