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

Jiayu Huang, Jie Yang, Zhangrong Gu, Wei Zhu and Song Wu
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Jiayu Huang: Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, NY 11790, USA
Jie Yang: Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, NY 11790, USA
Zhangrong Gu: Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, NY 11790, USA
Wei Zhu: Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, NY 11790, USA
Song Wu: Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, NY 11790, USA

Stats, 2021, vol. 4, issue 3, 1-28

Abstract: 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.

Keywords: GWAS; LD mapping; multi-loci genetic mapping; functional linear model; cGFLM (search for similar items in EconPapers)
JEL-codes: C1 C10 C11 C14 C15 C16 (search for similar items in EconPapers)
Date: 2021
References: View references in EconPapers View complete reference list from CitEc
Citations: View citations in EconPapers (1)

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