A Constrained Generalized Functional Linear Model for Multi-Loci Genetic Mapping

In genome-wide association studies (GWAS), efficient incorporation of linkage disequilibria (LD) among densely typed genetic variants into association analysis is a critical yet challenging problem. Functional linear models (FLM), which impose a smoothing structure on the coefficients of correlated covariates, are advantageous in genetic mapping of multiple variants with high LD. Here we propose a novel constrained generalized FLM (cGFLM) framework to perform simultaneous association tests on a block of linked SNPs with various trait types, including continuous, binary and zero-inflated count phenotypes. The new cGFLM applies a set of inequality constraints on the FLM to ensure model identifiability under different genetic codings. The method is implemented via B-splines, and an augmented Lagrangian algorithm is employed for parameter estimation. For hypotheses testing, a test statistic that accounts for the model constraints was derived, following a mixture of chi-square distributions. Simulation results show that cGFLM is effective in identifying causal loci and gene clusters compared to several competing methods based on single markers and SKAT-C. We applied the proposed method to analyze a candidate gene-based COGEND study and a large-scale GWAS data on dental caries risk.