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

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.