Bayesian multiple logistic regression for case-control GWAS

PLoS Genet. 2018 Dec 31;14(12):e1007856. doi: 10.1371/journal.pgen.1007856. eCollection 2018 Dec.

Abstract

Genetic variants in genome-wide association studies (GWAS) are tested for disease association mostly using simple regression, one variant at a time. Standard approaches to improve power in detecting disease-associated SNPs use multiple regression with Bayesian variable selection in which a sparsity-enforcing prior on effect sizes is used to avoid overtraining and all effect sizes are integrated out for posterior inference. For binary traits, the logistic model has not yielded clear improvements over the linear model. For multi-SNP analysis, the logistic model required costly and technically challenging MCMC sampling to perform the integration. Here, we introduce the quasi-Laplace approximation to solve the integral and avoid MCMC sampling. We expect the logistic model to perform much better than multiple linear regression except when predicted disease risks are spread closely around 0.5, because only close to its inflection point can the logistic function be well approximated by a linear function. Indeed, in extensive benchmarks with simulated phenotypes and real genotypes, our Bayesian multiple LOgistic REgression method (B-LORE) showed considerable improvements (1) when regressing on many variants in multiple loci at heritabilities ≥ 0.4 and (2) for unbalanced case-control ratios. B-LORE also enables meta-analysis by approximating the likelihood functions of individual studies by multivariate normal distributions, using their means and covariance matrices as summary statistics. Our work should make sparse multiple logistic regression attractive also for other applications with binary target variables. B-LORE is freely available from: https://github.com/soedinglab/b-lore.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bayes Theorem*
  • Case-Control Studies
  • Computer Simulation
  • Coronary Artery Disease / genetics
  • Genetic Variation
  • Genome-Wide Association Study / statistics & numerical data*
  • Humans
  • Likelihood Functions
  • Logistic Models*
  • Models, Genetic*
  • Multifactorial Inheritance
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Software

Grants and funding

This work was supported by the German Federal Ministry of Education and Research (BMBF) within the framework of the e:Med research and funding concept (grant e:AtheroSysMed 01ZX1313A-2014). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.