MCPerm: a Monte Carlo permutation method for accurately correcting the multiple testing in a meta-analysis of genetic association studies

PLoS One. 2014 Feb 21;9(2):e89212. doi: 10.1371/journal.pone.0089212. eCollection 2014.

Abstract

Traditional permutation (TradPerm) tests are usually considered the gold standard for multiple testing corrections. However, they can be difficult to complete for the meta-analyses of genetic association studies based on multiple single nucleotide polymorphism loci as they depend on individual-level genotype and phenotype data to perform random shuffles, which are not easy to obtain. Most meta-analyses have therefore been performed using summary statistics from previously published studies. To carry out a permutation using only genotype counts without changing the size of the TradPerm P-value, we developed a Monte Carlo permutation (MCPerm) method. First, for each study included in the meta-analysis, we used a two-step hypergeometric distribution to generate a random number of genotypes in cases and controls. We then carried out a meta-analysis using these random genotype data. Finally, we obtained the corrected permutation P-value of the meta-analysis by repeating the entire process N times. We used five real datasets and five simulation datasets to evaluate the MCPerm method and our results showed the following: (1) MCPerm requires only the summary statistics of the genotype, without the need for individual-level data; (2) Genotype counts generated by our two-step hypergeometric distributions had the same distributions as genotype counts generated by shuffling; (3) MCPerm had almost exactly the same permutation P-values as TradPerm (r = 0.999; P<2.2e-16); (4) The calculation speed of MCPerm is much faster than that of TradPerm. In summary, MCPerm appears to be a viable alternative to TradPerm, and we have developed it as a freely available R package at CRAN: http://cran.r-project.org/web/packages/MCPerm/index.html.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Databases, Genetic*
  • Genetic Association Studies*
  • Genotype
  • Haplotypes
  • Humans
  • Meta-Analysis as Topic*
  • Monte Carlo Method*
  • Multiple Sclerosis / genetics
  • Neurodegenerative Diseases / genetics
  • Polymorphism, Single Nucleotide
  • Schizophrenia / genetics
  • Software

Grants and funding

This work was supported in part by the National Natural Science Foundation of China (Grant Nos. 81172842, 31200934) and Natural Science Foundation of Heilongjiang Province (Grant No. C201206). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.