README.md

awesome-multitrait-gwas

List of software packages for multi-trait GWAS. A shameless copy of Sean Davis' awesome-single-cell repo and Mike Love's awesome-multi-omics repo.

Contributions welcome...

For brevity, below lists only the first author of multi-trait GWAS methods.

Software packages and methods

Background

• Multivariate Analysis of Variance (MANOVA)
• Canonical Correlation Analysis (CCA)
• Meta analysis in R
• Combination P-values

General tools

• 2019 - GWAS.utils - Rueger - An R package with basic helper functions for manipulating GWAS data, including two GWAS datasets.
• 2020 - SumTool - Yin - A memory-efficient, parallel-accelerated tool for Summary data based genomic prediction
• 2023 - GWASLab - HE - GWASLab: a Python package for processing and visualizing GWAS summary statistics

Large number of univariate tests

• 2012 - MatrixEQTL - Shabalin - Matrix eQTL: ultra fast eQTL analysis via large matrix operations
• 2015 - PLINK2 - Chang - Second-generation PLINK: rising to the challenge of larger and richer datasets
• 2016 - HASE - Roshchupkin - HASE: Framework for efficient high-dimensional association analyses
• 2017 - BGENIE - Bycroft - The UK Biobank resource with deep phenotyping and genomic data
• 2018 - Ganjgahi - WLS-REML - Fast and powerful genome wide association of dense genetic data with high dimensional imaging phenotypes
• 2019 - fastGWA - Jiang - A resource-efficient tool for mixed model association analysis of large-scale data
• 2021 - REGENIE - Mbatchou - Computationally efficient whole-genome regression for quantitative and binary traits

Direct tests

• 2007 - MV-SNPTEST - Marchini - A new multipoint method for genome-wide association studies by imputation of genotypes
• 2012 - MultiPhen - O'Reilly MultiPhen: Joint Model of Multiple Phenotypes Can Increase Discovery in GWAS
• 2012 - MTMM - Korte - A mixed-model approach for genome-wide association studies of correlated traits in structured populations
• 2013 - BSLMM - Zhou - Polygenic Modeling with Bayesian Sparse Linear Mixed Models
• 2013 - MV-BIMBAM - Stephens - A Unified Framework for Association Analysis with Multiple Related Phenotypes
• 2014 - mvLMM-GEMMA - Zhou - Efficient Algorithms for Multivariate Linear Mixed Models in Genome-wide Association Studies
• 2015 - USAT - Ray - USAT: A Unified Score‐Based Association Test for Multiple Phenotype‐Genotype Analysis
• 2015 - ACL - Wu - Statistical Methods for Association Tests of Multiple Continuous Traits in Genome-Wide Association Studies
• 2018 - SBAT - Elliot - Genome-wide association studies of brain imaging phenotypes in UK Biobank
• 2018 - Q, T, T' - Wu - Fast and Accurate Genome-Wide Association Test of Multiple Quantitative Traits
• 2018 - CLC - Sha - A clustering linear combination approach to jointly analyze multiple phenotypes for GWAS
• 2022 - ceCLC - Wang - A computationally efficient clustering linear combination approach to jointly analyze multiple phenotypes for GWAS
• 2024 - SIR - Sun - Multiple phenotype association tests based on sliced inverse regression

Indirect tests

• 2007 - PCHAT - Klei - Pleiotropy and principal components of heritability combine to increase power for association analysis
• 2009 - MV-PLINK - Ferreira - A multivariate test of association
• 2014 - Combined PC - Aschard - Maximizing the Power of Principal-Component Analysis of Correlated Phenotypes in Genome-wide Association Studies
• 2018 - PCA-based GWAS - Zhang - PCA-Based Multiple-Trait GWAS Analysis: A Powerful Model for Exploring Pleiotropy

Meta-analysis tests

• 2007 - P_ACT (minP) - Coonely - So Many Correlated Tests, So Little Time! Rapid Adjustment of P Values for Multiple Correlated Tests
• 2011 - PRIMe - Huang - PRIMe: a method for characterization and evaluation of pleiotropic regions from multiple genome-wide association studies
• 2012 - Extended O'Briens methods - Yang - Analyze multivariate phenotypes in genetic association studies by combining univariate association tests
• 2010 - METAL - Willer - METAL: fast and efficient meta-analysis of genomewide association scans
• 2012 - ASSET - Bhattacharjee - A subset-based approach improves power and interpretation for the combined analysis of genetic association studies of heterogeneous traits
• 2013 - TATES - van der Sluis - TATES: Efficient Multivariate Genotype-Phenotype Analysis for Genome-Wide Association Studies
• 2014 - Omnibus test / Wald test / Chi-square-based test - Bolormaa - A Multi-Trait, Meta-analysis for Detecting Pleiotropic Polymorphisms for Stature, Fatness and Reproduction in Beef Cattle
• 2015 - S_Hom / S_Het - Zhu - Meta-analysis of Correlated Traits via Summary Statistics from GWASs with an Application in Hypertension
• 2015 - MGAS - van der Sluis - MGAS: a powerful tool for multivariate gene-based genome-wide association analysis
• 2015 - aSPU - Kim - An Adaptive Association Test for Multiple Phenotypes with GWAS Summary Statistics
• 2016 - metaCCA - Cichonska - metaCCA: summary statistics-based multivariate meta-analysis of genome-wide association studies using canonical correlation analysis
• 2016 - Modified Benjamini-Holm - Majumdar - Determining Which Phenotypes Underlie a Pleiotropic Signal
• 2017 - metaUSAT - Ray - Methods for meta-analysis of multiple traits using GWAS summary statistics
• 2017 - MPAT: SUM, VC, mixSD, and MixFisher - Liu - Multiple phenotype association tests using summary statistics in genome-wide association studies
• 2018 - Qi - HIPO - Heritability informed power optimization (HIPO) leads to enhanced detection of genetic associations across multiple traits
• 2018 - Guo - Adaptive PC test - Principal component based adaptive association test of multiple traits using GWAS summary statistics
• 2019 - metaPhat - Lin - MetaPhat: Detecting and decomposing multivariate associations from univariate genomewide association statistics
• 2019 - meta-MultiSKAT - Dutta - Meta‐MultiSKAT: Multiple phenotype meta‐analysis for region‐based association test
• 2019 - MPAT: PCMinP, PCFisher, PCLC, Single PC, WI, PCQ, PCO - Liu - A Geometric Perspective on the Power of Principal Component Association Tests in Multiple Phenotype Studies
• 2018 - Adaptive PC Test & Z-scores test & modified metaUSAT- Guo - Integrate multiple traits to detect novel trait–gene association using GWAS summary data with an adaptive test approach
• 2019 - aMAT - Wu - Multi-trait genome-wide analyses of the brain imaging phenotypes in UK Biobank
• 2019 - Adaptive Pleiotropy Test - Masotti - Pleiotropy informed adaptive association test of multiple traits using genome-wide association study summary data
• 2020 - metapod - Lun - Meta-Analyses on P-Values of Differential Analyses
• 2020 - JASS - Julienne - JASS: command line and web interface for the joint analysis of GWAS results
• 2020 - MOSTest - van der Meer - Understanding the genetic determinants of the brain with MOSTest
• 2021 - OMNI - Liu - An Omnibus Test for Detecting Multiple Phenotype Associations Based on GWAS Summary Level Data
• 2021 - sumZ_r & sumZ_g & sumZ_ica - Julienne - Multitrait GWAS to connect disease variants and biological mechanisms
• 2021 - EBMMT - Liu - The eigen higher criticism and eigen Berk–Jones tests for multiple trait association studies based on GWAS summary statistics
• 2022 fastASSET - Qi - Genome-Wide Large-Scale Multi-Trait Analysis Characterizes Global Patterns of Pleiotropy and Unique Trait-Specific Variants
• 2022 - C-GWAS - Xiong - Combining genome-wide association studies highlight novel loci involved in human facial variation
• 2022 - PolarMorphism - von Berg - PolarMorphism enables discovery of shared genetic variants across multiple traits from GWAS summary statistics
• 2023 - sCLC - Wang - A clustering linear combination method for multiple phenotype association studies based on GWAS summary statistics
• 2023 - TraitScan - Cao - Subset scanning for multi-trait analysis using GWAS summary statistics

Other tests

• 2009 - CMV - Medland - An integrated phenomic approach to multivariate allelic association
• 2012 - PSEA - Ried - PSEA: Phenotype Set Enrichment Analysis—A New Method for Analysis of Multiple Phenotypes
• 2014 - SECA - Nyholt - SECA: SNP effect concordance analysis using genome-wide association summary results
• 2016 - Hierachical error control - Many Phenotypes Without Many False Discoveries: Error Controlling Strategies for Multitrait Association Studies
• 2018 - UNITY - Johnson - A unifying framework for joint trait analysis under a non-infinitesimal model
• 2018 - MTAG - Turley - Multi-trait analysis of genome-wide association summary statistics using MTAG
• 2019 - MSATS - Guo - Powerful and efficient SNP-set association tests across multiple phenotypes using GWAS summary data

Genetic correlation

• 2012 - GEMMA Variance Components - Zhou - Genome-wide efficient mixed-model analysis for association studies
• 2015 - LD score regression - Bulik-Sullivan - An atlas of genetic correlations across human diseases and traits
• 2015 - BOLT-REML - Loh - Contrasting genetic architectures of schizophrenia and other complex diseases using fast variance-components analysis
• 2017 - GNOVA - Lu - A Powerful Approach to Estimating Annotation-Stratified Genetic Covariance via GWAS Summary Statistics
• 2021 - LAVA - Werme - LAVA: An integrated framework for local genetic correlation analysis

Polygenicity and pleiotropy

• 2013 - conditional FDR & conjunction FDR - Andreassen - Improved Detection of Common Variants Associated with Schizophrenia and Bipolar Disorder Using Pleiotropy-Informed Conditional False Discovery Rate
• 2014 - GPA - Chung - GPA: A Statistical Approach to Prioritizing GWAS Results by Integrating Pleiotropy and Annotation
• 2015 - GPS - Li - Meta-analysis of shared genetic architecture across ten pediatric autoimmune diseases
• 2015 - cFDR/uFDR - Liley - A Pleiotropy-Informed Bayesian False Discovery Rate Adapted to a Shared Control Design Finds New Disease Associations From GWAS Summary Statistics
• 2018 - iMAP - Zeng - Pleiotropic mapping and annotation selection in genome-wide association studies with penalized Gaussian mixture models
• 2019 - MiXer - Frei - Bivariate causal mixture model quantifies polygenic overlap between complex traits beyond genetic correlation
• 2020 - PLACO - Ray - A powerful method for pleiotropic analysis under composite null hypothesis identifies novel shared loci between Type 2 Diabetes and Prostate Cancer
• 2021 - cFDR: v-values - Liley - Accurate error control in high-dimensional association testing using conditional false discovery rates
• 2021 - fcfdr - Hutchinson - Leveraging auxiliary data from arbitrary distributions to boost GWAS discovery with Flexible cFDR
• 2021 - MAIUP - Wang - Identifying pleiotropic genes for complex phenotypes with summary statistics from a perspective of composite null hypothesis testing
• 2023 - GPS-GEV - Willis - Accurate detection of shared genetic architecture from GWAS summary statistics in the small-sample context

Imputation of phenotypes

• 2016 - PHENIX - Dahl - A multiple-phenotype imputation method for genetic studies
• 2016 - PhenUMP - Hormozdiari - Imputing Phenotypes for Genome-wide Association Studies
• 2023 - MFRF - Gu - Rapid and accurate multi-phenotype imputation for millions of individuals

Imputation of summary statistics

• 2014 - ImpG-Summary - Pasanuic - Fast and accurate imputation of summary statistics enhances evidence of functional enrichment
• 2018 - ARDISS - Togninalli - Accurate and adaptive imputation of summary statistics in mixed-ethnicity cohorts
• 2018 - SSIMP - Rueger - Evaluation and application of summary statistic imputation to discover new height-associated loci
• 2019 - RAISS - Julienne - RAISS: robust and accurate imputation from summary statistics
• 2020 - SSI - Wu - A Unifying Framework for Imputing Summary Statistics in Genome-Wide Association Studies

Cleaning and decorrelation of summary statistics

• 2012 - GWAtoolbox - Fuchsberger - GWAtoolbox: an R package for fast quality control and handling of genome-wide association studies meta-analysis data
• 2012 - Visschers statistic - Yan - FTO genotype is associated with phenotypic variability of body mass index
• 2014 - QCGWAS - van der Most - QCGWAS: A flexible R package for automated quality control of genome-wide association results
• 2014 - SE-N, P-Z and EAF plots - Winkler - Quality control and conduct of genome-wide association meta-analyses
• 2018 - z_de-corr - LeBlanc - A correction for sample overlap in genome-wide association studies in a polygenic pleiotropy-informed framework
• 2021 - DENTIST - Chen - Improved analyses of GWAS summary statistics by reducing data heterogeneity and errors
• 2021 - MungeSumStats - Murphy - MungeSumstats: a Bioconductor package for the standardization and quality control of many GWAS summary statistics
• 2022 - SumStatsRehab - Matushyn - SumStatsRehab: an efficient algorithm for GWAS summary statistics assessment and restoration

Finemapping

• 2017 - fastPAINTOR - Kichaev - Improved methods for multi-trait fine mapping of pleiotropic risk loci
• 2021 - mashr - Urbut - Flexible statistical methods for estimating and testing effects in genomic studies with multiple conditions
• 2021 - flashfm - Hernandez - The flashfm approach for fine-mapping multiple quantitative traits
• 2023 - mvSuSiE - Zou - Fast and flexible joint fine-mapping of multiple traits via the Sum of Single Effects model

Colocalization

• 2014 - coloc - Giambartolomei - Bayesian Test for Colocalisation between Pairs of Genetic Association Studies Using Summary Statistics
• 2016 - eCAVIAR - Hormozdiari - Colocalization of GWAS and eQTL Signals Detects Target Genes
• 2016 - gwas-pw - Pickrell - Detection and interpretation of shared genetic influences on 42 human traits
• 2017 - Plei - Deng - Testing Genetic Pleiotropy with GWAS Summary Statistics for Marginal and Conditional Analyses
• 2018 - moloc - Giambartolomei - A Bayesian framework for multiple trait colocalization from summary association statistics
• 2020 - jointsum - Deng - A powerful and versatile colocalization test
• 2020 - PRIMO - Gleason - Primo: integration of multiple GWAS and omics QTL summary statistics for elucidation of molecular mechanisms of trait-associated SNPs and detection of pleiotropy in complex traits
• 2020 - PWCoCo - Zheng - Phenome-wide Mendelian randomization mapping the influence of the plasma proteome on complex diseases
• 2021 - HyPrColoc - Foley - A fast and efficient colocalization algorithm for identifying shared genetic risk factors across multiple traits
• 2021 - COLOC/SuSiE - Wallace - A more accurate method for colocalisation analysis allowing for multiple causal variants
• 2023 - OPERA - Wu - Joint analysis of GWAS and multi-omics QTL summary statistics reveals a large fraction of GWAS signals shared with molecular phenotypes
• 2024 - SharePro - Zhang - SharePro: an accurate and efficient genetic colocalization method accounting for multiple causal signals

Rare variants

• 2016 - GAMuT - Broadawy - A Statistical Approach for Testing Cross-Phenotype Effects of Rare Variants
• 2017 - DKAT - Zhan - Powerful Genetic Association Analysis for Common or Rare Variants with High-Dimensional Structured Traits
• 2017 - GHC - Barnett - The Generalized Higher Criticism for Testing SNP-Set Effects in Genetic Association Studies
• 2017 - GBJ - Sun - Genetic Variant Set-Based Tests Using the Generalized Berk–Jones Statistic With Application to a Genome-Wide Association Study of Breast Cancer
• 2018 - Multi-SKAT - Dutta - Multi‐SKAT: General framework to test for rare‐variant association with multiple phenotypes
• 2019 - ACAT - Liu - ACAT: A Fast and Powerful p Value Combination Method for Rare-Variant Analysis in Sequencing Studies
• 2020 - MTAR - Luo - Multi-trait analysis of rare-variant association summary statistics using MTAR

Case studies

• 2012 - Inouye - Novel Loci for Metabolic Networks and Multi-Tissue Expression Studies Reveal Genes for Atherosclerosis
• 2016 - Roshchupkin - Heritability of the shape of subcortical brain structures in the general population
• 2018 - Elliot - Genome-wide association studies of brain imaging phenotypes in UK Biobank
• 2018 - Claes - Genome-wide mapping of global-to-local genetic effects on human facial shape
• 2019 - Fatumo - Complimentary Methods for Multivariate Genome-Wide Association Study Identify New Susceptibility Genes for Blood Cell Traits
• 2019 - Watanabe - A global overview of pleiotropy and genetic architecture in complex traits

Benchmarks and reviews

• 2010 - Minica - Genetic Association in Multivariate Phenotypic Data: Power in Five Models
• 2012 - Shriner - Moving toward system genetics through multiple trait analysis in genome-wide association studies
• 2013 - Stephens - A Unified Framework for Association Analysis with Multiple Related Phenotypes
• 2013 - Solovieff - Pleiotropy in complex traits: challenges and strategies
• 2014 - Galesloot - A Comparison of Multivariate Genome-Wide Association Methods
• 2017 - Hackinger - Statistical methods to detect pleiotropy in human complex traits
• 2017 - Porter - Multivariate simulation framework reveals performance of multi-trait GWAS methods
• 2019 - Couvy-Duchesne - A Fast Method for Estimating Statistical Power of Multivariate GWAS in Real Case Scenarios: Examples from the Field of Imaging Genetics
• 2019 - van Rheenen - Genetic correlations of polygenic disease traits: from theory to practice
• 2019 - Ray - Effect of non-normality and low count variants on cross-phenotype association tests in GWAS
• 2019 - Vroom - The more the merrier? Multivariate approaches to genome-wide association analysis
• 2021 - Sitlani - Comparison of adaptive multiple phenotype association tests using summary statistics in genome-wide association studies
• 2024 - Suzuki - Trait selection strategy in multi-trait GWAS: Boosting SNPs discoverability

Unsorted

• winners curse: https://amandaforde.github.io/winnerscurse/index.html

• QC for meta-analysis studies on the same traits: https://www.nature.com/articles/ejhg2016106

• General review with overview of methods: https://biodatamining.biomedcentral.com/articles/10.1186/s13040-024-00385-x

• JASS update: https://www.biorxiv.org/content/10.1101/2023.10.27.564319v1

• FactorGO: https://www.medrxiv.org/content/10.1101/2023.03.27.23287801v1

• HCM: https://pubmed.ncbi.nlm.nih.gov/29682782/

• AFC: https://www.nature.com/articles/srep34323

• https://arxiv.org/pdf/2303.10221.pdf Higgs method

• GWAMA: https://www.nature.com/articles/s41467-022-34216-6#Sec16

Estimate ancestry of GWAS summary stats?: SUMMIX: https://www.biorxiv.org/content/10.1101/2024.01.29.577805v3