APEX (All-in-one Package for Efficient Xqtl analysis) is a toolkit for analysis of molecular quantitative trait loci (xQTLs), such as mRNA expression or methylation levels. It performs cis and trans analysis, single- or multiple-variant analysis, and single-study or meta-analysis.

To install APEX from source or download precompiled binaries, see installation guide below.

Analysis modes and documentation

• xQTL factor analysis. ./apex factor {options}
  • Rapid high-dimensional factor analysis to account for technical and biological variation in molecular trait data.
• xQTL linear mixed model preprocessing. ./apex lmm {options}
  • Precompute null model terms for rapid LMM association analysis.
• cis-xQTL analysis. ./apex cis {options}
  • Analyze xQTL associations within a genomic window of each molecular trait. For example, analyze variant associations within 1 megabase (Mb) of each gene's transcription start site (TSS).
    • trans-xQTL analysis. ./apex trans {options}
  • Analyze xQTL genome-wide associations for each molecular trait, optionally excluding variants within the cis region.
    • xQTL meta-analysis. ./apex meta {options}
  • Meta-analyze xQTL association summary statistics across one or multiple studies.
    • xQTL summary data storage. ./apex store {options}
  • Store genotypic variance-covariance (LD) data matrices for data-sharing or meta-analysis. These files enable accurate multiple-variant analysis from xQTL summary statistics, including joint and conditional regression analysis, Bayesian finemapping, aggregation tests, and penalized regression / variable selection.

Additional documentation pages

See above for documentation pages on each analysis mode (factor, lmm, cis, trans, meta, store). Additional documentation pages are listed below.

• Input file formats for individual-level analysis in modes apex cis, apex trans, and apex store.
• APEX xQTL summary association data file formats generated by apex store and used in apex meta. Documentation coming soon.
• Bayesian finemapping using APEX xQTL summary association data files generated by apex store. Documentation coming soon.

Release notes

• apex-factor
  • Currently, apex-factor assumes sample size is less than the number of molecular traits. In the next release, we will provide optimizations for sample size > number of traits.
  • Currently, apex-factor calculates inferred covariates in a format suitable for OLS or GRM LMMs. To model factor covariates as random effects, inferred covariates must be calculated internally in apex-cis and apex-trans. In the next release, apex-factor will provide inferred factor covariates in a format suitable for low-rank LMMs in apex-cis and apex-trans.
• apex-lmm
  • Currently, apex-lmm supports LMMs with GRMs, but not low-rank LMMs. Low-rank LMMs can be estimated directly in apex-cis and apex-trans. In the next release, apex-lmm will also support low-rank LMMs.
• apex-cis and apex-trans
  • Currently, pre-computed variance component estimates from apex-lmm can be used in apex-cis and apex-trans, but LMM trait residuals and genotypic variance interpolation points are precalculated internally in apex-cis and apex-trans. In the next release, apex-cis and apex-trans will accept precomputed LMM trait residuals and genotypic variance interpolation points from apex-lmm.
• apex-store
  • Currently, apex-store provides adjusted LD for OLS models. In the next release, apex-store will provide options for adjusted LD in LMMs.
• apex-meta
  • Currently, apex-meta supports only cis-xQTL meta-analysis. In the next release, apex-meta will also support trans-xQTL meta-analysis.

Installation

APEX is primarily written in C++. To compile APEX from source, run:

git clone https://github.com/corbinq/apex.git
cd apex 
bash get_dependencies.sh
make

Precompiled binaries are also available for 64-bit Linux systems as follows:

git clone https://github.com/corbinq/apex.git
cd apex/bin
gunzip apex_Linux_x86_64.gz
mv apex_Linux_x86_64 apex && chmod +x apex
./apex --help

Software dependencies

• Eigen C++ matrix library
• HTSlib C library
• github.com/jonathonl/shrinkwrap
• github.com/Taywee/args
• Boost math C++ library

Contact, feedback, bug reports

APEX is a work in progress, and under active development. We appreciate feedback and bug reports, and welcome any questions or feature requests. Contact: qcorbin@hsph.harvard.edu.

Citation

If you use APEX, please cite Quick, C; Guan, L; Z, Li; X, Li; Dey, R; Liu, Y; Scott, L; Lin, X (2020). "A versatile toolkit for molecular QTL mapping and meta-analysis at scale" URL: https://github.com/corbinq/apex (preprint pending). Thanks!

Acknowledgements

APEX is developed by Corbin Quick and Li Guan. Special thanks to

• Yaowu Liu
• Xihao Li
• Zilin Li
• Rounak Dey
• Laura Scott
• Hyun Min Kang
• Xihong Lin