Identifying Genetic Variants for Addiction via Propensity Score Adjusted Generalized Kendall's Tau

• 成果类型: Article
• 署名作者: Jiang, Yuan; Li, Ni; Zhang, Heping
• 署名单位: Oregon State University; Hainan Normal University; Yale University; Yale University; Sun Yat Sen University
• 刊物名称: JOURNAL OF THE AMERICAN STATISTICAL ASSOCIATION
• ISSN/ISSBN: 0162-1459
• DOI: 10.1080/01621459.2014.901223
• 发表日期: 2014
• 页码: 905-930
• 关键词: genome-wide association; nicotine dependence; alcohol dependence; molecular-genetics; unified approach; smoking-cessation; ordinal traits; tests; RISK; metaanalysis

摘要

Identifying replicable genetic variants for addiction has been extremely challenging. Besides the common difficulties with genome-wide association studies (GWAS), environmental factors are known to be critical to addiction, and comorbidity is widely observed. Despite the importance of environmental factors and comorbidity for addiction study, few GWAS analyses adequately considered them due to the limitations of the existing statistical methods. Although parametric methods have been developed to adjust for covariates in association analysis, difficulties arise when the traits are multivariate because there is no ready-to-use model for them. Recent nonparametric development includes U-statistics to measure the phenotype-genotype association weighted by a similarity score of covariates. However, it is not clear how to optimize the similarity score. Therefore, we propose a semiparametric method to measure the association adjusted by covariates. In our approach, the nonparametric U-statistic is adjusted by parametric estimates of propensity scores using the idea of inverse probability weighting. The new measurement is shown to be asymptotically unbiased under our null hypothesis while the previous nonweighted and weighted ones are not. Simulation results show that our test improves power as opposed to the nonweighted and two other weighted U-statistic methods, and it is particularly powerful for detecting gene-environment interactions. Finally, we apply our proposed test to the Study of Addiction: Genetics and Environment (SAGE) to identify genetic variants for addiction. Novel genetic variants are found from our analysis, which warrant further investigation in the future.