Gene-Based Association Testing of Dichotomous Traits With Generalized Functional Linear Mixed Models Using Extended Pedigrees: Applications to Age-Related Macular Degeneration

• 成果类型: Article
• 署名作者: Jiang, Yingda; Chiu, Chi-Yang; Yan, Qi; Chen, Wei; Gorin, Michael B.; Conley, Yvette P.; Lakhal-Chaieb, M'hamed Lajmi; Cook, Richard J.; Amos, Christopher, I; Wilson, Alexander F.; Bailey-Wilson, Joan E.; McMahon, Francis J.; Vazquez, Ana, I; Yuan, Ao; Zhong, Xiaogang; Xiong, Momiao; Weeks, Daniel E.; Fan, Ruzong
• 署名单位: Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; University of Tennessee System; University of Tennessee Health Science Center; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Laval University; Baylor College of Medicine; National Institutes of Health (NIH) - USA; NIH National Human Genome Research Institute (NHGRI); NIH National Institute on Aging (NIA); National Institutes of Health (NIH) - USA; NIH National Institute of Mental Health (NIMH); National Institutes of Health (NIH) - USA; NIH National Institute of Mental Health (NIMH); Michigan State University; Georgetown University; University of Texas System; University of Texas Health Science Center Houston; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; National Institutes of Health (NIH) - USA; NIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD); Cornell University; Weill Cornell Medicine; NewYork-Presbyterian Hospital; Columbia University
• 刊物名称: JOURNAL OF THE AMERICAN STATISTICAL ASSOCIATION
• ISSN/ISSBN: 0162-1459
• DOI: 10.1080/01621459.2020.1799809
• 发表日期: 2021
• 页码: 531-545
• 关键词: genome-wide association; population-structure; quantitative traits; rare; LEVEL; metaanalysis; regression; loci; susceptibility; scan

摘要

Genetics plays a role in age-related macular degeneration (AMD), a common cause of blindness in the elderly. There is a need for powerful methods for carrying out region-based association tests between a dichotomous trait like AMD and genetic variants on family data. Here, we apply our new generalized functional linear mixed models (GFLMM) developed to test for gene-based association in a set of AMD families. Using common and rare variants, we observe significant association with two known AMD genes:CFH and ARMS2. Using rare variants, we find suggestive signals in four genes:ASAH1,CLEC6A,TMEM63C, and SGSM1. Intriguingly, ASAH1 is down-regulated in AMD aqueous humor, andASAH1deficiency leads to retinal inflammation and increased vulnerability to oxidative stress. These findings were made possible by our GFLMM which model the effect of a major gene as a fixed mean, the polygenic contributions as a random variation, and the correlation of pedigree members by kinship coefficients. Simulations indicate that the GFLMM likelihood ratio tests (LRTs) accurately control the Type I error rates. The LRTs have similar or higher power than existing retrospective kernel and burden statistics. Our GFLMM-based statistics provide a new tool for conducting family-based genetic studies of complex diseases.for this article, including a standardized description of the materials available for reproducing the work, are available as an online supplement.