Comparison of methods for multivariate gene-based association tests for complex diseases using common variants

Complex diseases are usually associated with multiple correlated phenotypes, and the analysis of composite scores or disease status may not fully capture the complexity (or multidimensionality). Joint analysis of multiple disease-related phenotypes in genetic tests could potentially increase power to detect association of a disease with common SNPs (or genes). Gene-based tests are designed to identify genes containing multiple risk variants that individually are weakly associated with a univariate trait. We combined three multivariate association tests (O’Brien method, TATES, and MultiPhen) with two gene-based association tests (GATES and VEGAS) and compared performance (type I error and power) of six multivariate gene-based methods using simulated data. Data (n = 2000) for genetic sequence and correlated phenotypes were simulated by varying causal variant proportions and phenotype correlations for various scenarios. These simulations showed that two multivariate association tests (TATES and MultiPhen, but not O’Brien) paired with VEGAS have inflated type I error in all scenarios, while the three multivariate association tests paired with GATES have correct type I error. MultiPhen paired with GATES has higher power than competing methods if the correlations among phenotypes are low (r < 0.57). We applied these gene-based association methods to a GWAS dataset from the Alzheimer’s Disease Genetics Consortium containing three neuropathological traits related to Alzheimer disease (neuritic plaque, neurofibrillary tangles, and cerebral amyloid angiopathy) measured in 3500 autopsied brains. Gene-level significant evidence (P < 2.7 × 10(−6)) was identified in a region containing three contiguous genes (TRAPPC12, TRAPPC12-AS1, ADI1) using O’Brien and VEGAS. Gene-wide significant associations were not observed in univariate gene-based tests.