{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T05:27:30Z","timestamp":1770701250352,"version":"3.49.0"},"reference-count":93,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2022,3,22]],"date-time":"2022-03-22T00:00:00Z","timestamp":1647907200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"german-israeli project dfg","award":["4193\/1-1"],"award-info":[{"award-number":["4193\/1-1"]}]},{"name":"israel science foundation","award":["2118\/19"],"award-info":[{"award-number":["2118\/19"]}]},{"name":"koret-uc berkeley-tel aviv university initiative in computational biology and bioinformatics","award":["KBT-TAU-2018.1"],"award-info":[{"award-number":["KBT-TAU-2018.1"]}]},{"name":"edmond j. safra center for bioinformatics at tel aviv university"},{"name":"edmond j. safra center for bioinformatics at tel aviv university"},{"name":"edmond j. safra center for bioinformatics at tel aviv university"}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>To date, genome-wide association studies have identified thousands of statistically-significant associations between genetic variants, and phenotypes related to a myriad of traits and diseases. A key goal for human-genetics research is to translate these associations into functional mechanisms. Popular gene-set analysis tools, like MAGMA, map variants to genes they might affect, and then integrate genome-wide association study data (that is, variant-level associations for a phenotype) to score genes for association with a phenotype. Gene scores are subsequently used in competitive gene-set analyses to identify biological processes that are enriched for phenotype association. By default, variants are mapped to genes in their proximity. However, many variants that affect phenotypes are thought to act at regulatory elements, which can be hundreds of kilobases away from their target genes. Thus, we explored the idea of augmenting a proximity-based mapping scheme with publicly-available datasets of regulatory interactions. We used MAGMA to analyze genome-wide association study data for ten different phenotypes, and evaluated the effects of augmentation by comparing numbers, and identities, of genes and gene sets detected as statistically significant between mappings. We detected several pitfalls and confounders of such \u201caugmented analyses\u201d, and introduced ways to control for them. Using these controls, we demonstrated that augmentation with datasets of regulatory interactions only occasionally strengthened the enrichment for phenotype association amongst (biologically-relevant) gene sets for different phenotypes. Still, in such cases, genes and regulatory elements responsible for the improvement could be pinpointed. For instance, using brain regulatory-interactions for augmentation, we were able to implicate two acetylcholine receptor subunits involved in post-synaptic chemical transmission, namely <jats:italic>CHRNB2<\/jats:italic> and <jats:italic>CHRNE<\/jats:italic>, in schizophrenia. Collectively, our study presents a critical approach for integrating regulatory interactions into gene-set analyses for genome-wide association study data, by introducing various controls to distinguish genuine results from spurious discoveries.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1009908","type":"journal-article","created":{"date-parts":[[2022,3,22]],"date-time":"2022-03-22T18:02:08Z","timestamp":1647972128000},"page":"e1009908","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["Incorporating regulatory interactions into gene-set analyses for GWAS data: A controlled analysis with the MAGMA tool"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8584-1471","authenticated-orcid":true,"given":"David","family":"Groenewoud","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8551-4451","authenticated-orcid":true,"given":"Avinoam","family":"Shye","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3440-1286","authenticated-orcid":true,"given":"Ran","family":"Elkon","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2022,3,22]]},"reference":[{"key":"pcbi.1009908.ref001","doi-asserted-by":"crossref","first-page":"D1005","DOI":"10.1093\/nar\/gky1120","article-title":"The NHGRI-EBI GWAS Catalog of published genome-wide association studies, targeted arrays and summary statistics 2019","volume":"47","author":"A Buniello","year":"2019","journal-title":"Nucleic Acids 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data","volume":"122","author":"P Jia","year":"2010","journal-title":"Schizophr Res"},{"key":"pcbi.1009908.ref033","article-title":"Biological interpretation of genome-wide association studies using predicted gene functions","volume":"6","author":"TH Pers","year":"2015","journal-title":"Nat Commun"},{"key":"pcbi.1009908.ref034","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1038\/s41588-018-0081-4","article-title":"Heritability enrichment of specifically expressed genes identifies disease-relevant tissues and cell types","volume":"50","author":"HK Finucane","year":"2018","journal-title":"Nat Genet"},{"key":"pcbi.1009908.ref035","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.2337\/db08-1378","article-title":"Interrogating type 2 diabetes genome-wide association data using a biological pathway-based approach","volume":"58","author":"JRB Perry","year":"2009","journal-title":"Diabetes"},{"key":"pcbi.1009908.ref036","doi-asserted-by":"crossref","first-page":"1278","DOI":"10.1086\/522374","article-title":"Pathway-Based Approaches for Analysis of Genomewide Association Studies","volume":"81","author":"K Wang","year":"2007","journal-title":"Am J Hum Genet"},{"key":"pcbi.1009908.ref037","doi-asserted-by":"crossref","first-page":"1905","DOI":"10.1101\/gr.176586.114","article-title":"Genome-wide map of regulatory interactions in the human genome","volume":"24","author":"N Heidari","year":"2014","journal-title":"Genome Res"},{"key":"pcbi.1009908.ref038","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1038\/ng.3286","article-title":"Mapping long-range promoter contacts in human cells with high-resolution capture Hi-C","volume":"47","author":"B Mifsud","year":"2015","journal-title":"Nat Genet"},{"key":"pcbi.1009908.ref039","first-page":"15","article-title":"A gene co-expression network-based analysis of multiple brain tissues reveals novel genes and molecular pathways underlying major depression","author":"ZF Gerring","year":"2019","journal-title":"PLoS Genet"},{"key":"pcbi.1009908.ref040","first-page":"1","article-title":"E-MAGMA: an eQTL-informed method to identify risk genes using genome-wide association study summary statistics","author":"ZF Gerring","year":"2021","journal-title":"Bioinformatics"},{"key":"pcbi.1009908.ref041","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/s41593-020-0603-0","article-title":"A computational tool (H-MAGMA) for improved prediction of brain-disorder risk genes by incorporating brain chromatin interaction profiles.","volume":"23","author":"NYA Sey","year":"2020","journal-title":"Nat Neurosci"},{"key":"pcbi.1009908.ref042","article-title":"FOCS: A novel method for analyzing enhancer and gene activity patterns infers an extensive enhancer-promoter map","volume":"19","author":"TA Hait","year":"2018","journal-title":"Genome 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in developing human brain","volume":"538","author":"H Won","year":"2016","journal-title":"Nature"},{"key":"pcbi.1009908.ref047","doi-asserted-by":"crossref","first-page":"1442","DOI":"10.1038\/s41588-019-0494-8","article-title":"A compendium of promoter-centered long-range chromatin interactions in the human genome","volume":"51","author":"I Jung","year":"2019","journal-title":"Nat Genet"},{"key":"pcbi.1009908.ref048","doi-asserted-by":"crossref","first-page":"1252","DOI":"10.1038\/s41588-019-0472-1","article-title":"Mapping cis-regulatory chromatin contacts in neural cells links neuropsychiatric disorder risk variants to target genes","volume":"51","author":"M Song","year":"2019","journal-title":"Nat Genet"},{"key":"pcbi.1009908.ref049","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.35788","article-title":"A promoter interaction map for cardiovascular disease genetics","volume":"7","author":"LE Montefiori","year":"2018","journal-title":"Elife"},{"key":"pcbi.1009908.ref050","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.1038\/s41588-019-0457-0","article-title":"Human pancreatic islet three-dimensional chromatin architecture provides insights into the genetics of type 2 diabetes","volume":"51","author":"I Miguel-Escalada","year":"2019","journal-title":"Nat Genet"},{"key":"pcbi.1009908.ref051","article-title":"A high-resolution 3D epigenomic map reveals insights into the creation of the prostate cancer transcriptome","volume":"10","author":"SK Rhie","year":"2019","journal-title":"Nat Commun"},{"key":"pcbi.1009908.ref052","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.1016\/j.cell.2016.09.037","article-title":"Lineage-Specific Genome Architecture Links Enhancers and Non-coding Disease Variants to Target Gene Promoters","volume":"167","author":"BM Javierre","year":"2016","journal-title":"Cell"},{"key":"pcbi.1009908.ref053","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1038\/s41588-018-0311-9","article-title":"Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer\u2019s disease risk","volume":"51","author":"IE Jansen","year":"2019","journal-title":"Nat Genet"},{"key":"pcbi.1009908.ref054","doi-asserted-by":"crossref","first-page":"1234","DOI":"10.1038\/s41588-018-0171-3","article-title":"Biobank-driven genomic discovery yields new insight into atrial fibrillation biology","volume":"50","author":"JB Nielsen","year":"2018","journal-title":"Nat Genet"},{"key":"pcbi.1009908.ref055","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1038\/s41588-018-0302-x","article-title":"An atlas of genetic influences on osteoporosis in humans and mice","volume":"51","author":"JA Morris","year":"2019","journal-title":"Nat Genet"},{"key":"pcbi.1009908.ref056","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1038\/nature24284","article-title":"Association analysis identifies 65 new breast cancer risk loci","volume":"551","author":"K Michailidou","year":"2017","journal-title":"Nature"},{"key":"pcbi.1009908.ref057","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.1038\/ng.3913","article-title":"Association analyses based on false discovery rate implicate new loci for coronary artery disease","volume":"49","author":"CP Nelson","year":"2017","journal-title":"Nat Genet"},{"key":"pcbi.1009908.ref058","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1038\/ng.3760","article-title":"Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease","volume":"49","author":"KM De Lange","year":"2017","journal-title":"Nat Genet"},{"key":"pcbi.1009908.ref059","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1038\/ng.3448","article-title":"A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants","volume":"48","author":"LG Fritsche","year":"2016","journal-title":"Nat Genet"},{"key":"pcbi.1009908.ref060","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1038\/s41588-018-0142-8","article-title":"Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci","volume":"50","author":"FR Schumacher","year":"2018","journal-title":"Nat Genet"},{"key":"pcbi.1009908.ref061","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1038\/s41588-018-0059-2","article-title":"Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection","volume":"50","author":"AF Pardi\u00f1as","year":"2018","journal-title":"Nat Genet"},{"key":"pcbi.1009908.ref062","doi-asserted-by":"crossref","first-page":"1505","DOI":"10.1038\/s41588-018-0241-6","article-title":"Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps","volume":"50","author":"A Mahajan","year":"2018","journal-title":"Nat Genet"},{"key":"pcbi.1009908.ref063","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/75556","article-title":"Gene Ontology: tool for the unification of biology.","volume":"25","author":"M Ashburner","year":"2000","journal-title":"Nat Genet"},{"key":"pcbi.1009908.ref064","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0021800","article-title":"REVIGO Summarizes and Visualizes Long Lists of Gene Ontology Terms.","volume":"6","author":"F Supek","year":"2011","journal-title":"PLoS One"},{"key":"pcbi.1009908.ref065","article-title":"rrvgo: a Bioconductor package to reduce and visualize Gene Ontology terms","author":"S. Sayols","year":"2020"},{"key":"pcbi.1009908.ref066","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1038\/s41380-018-0041-5","article-title":"Synaptic loss in schizophrenia: a meta-analysis and systematic review of synaptic protein and mRNA measures","volume":"24","author":"EF Osimo","year":"2018","journal-title":"Mol Psychiatry"},{"key":"pcbi.1009908.ref067","first-page":"374","article-title":"Synapse Pathology in Schizophrenia: A Meta-analysis of Postsynaptic Elements in Postmortem Brain Studies.","volume":"46","author":"A Berdenis van Berlekom","year":"2020","journal-title":"Schizophr Bull"},{"key":"pcbi.1009908.ref068","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1001\/archpsyc.63.6.630","article-title":"Proof-of-Concept Trial of an \u03b17 Nicotinic Agonist in Schizophrenia.","volume":"63","author":"A Olincy","year":"2006","journal-title":"Arch Gen Psychiatry."},{"key":"pcbi.1009908.ref069","first-page":"225","article-title":"Schizophrenia and the \u03b17 Nicotinic Acetylcholine Receptor. International Review of Neurobiology Academic Press Inc.","author":"LF Martin","year":"2007"},{"key":"pcbi.1009908.ref070","first-page":"1","article-title":"The role of nicotinic cholinergic neurotransmission in delusional thinking","volume":"6","author":"M Caton","year":"2020","journal-title":"Neuropsychopharmacology"},{"key":"pcbi.1009908.ref071","first-page":"580","article-title":"The Genotype-Tissue Expression (GTEx) project.","author":"The GTEx Consortium","year":"2013","journal-title":"Nature Genetics. Nature Portfolio"},{"key":"pcbi.1009908.ref072","doi-asserted-by":"crossref","first-page":"2059","DOI":"10.2337\/db08-0987","article-title":"Islet-1 is Required for the Maturation, Proliferation, and Survival of the Endocrine Pancreas","volume":"58","author":"A Du","year":"2009","journal-title":"Diabetes"},{"key":"pcbi.1009908.ref073","article-title":"ISL1 Promotes Pancreatic Islet Cell Proliferation.","volume":"6","author":"T Guo","year":"2011","journal-title":"PLoS One"},{"key":"pcbi.1009908.ref074","doi-asserted-by":"crossref","first-page":"4206","DOI":"10.2337\/db14-0096","article-title":"Islet-1 Is Essential for Pancreatic \u03b2-Cell Function","volume":"63","author":"BN Ediger","year":"2014","journal-title":"Diabetes"},{"key":"pcbi.1009908.ref075","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1073\/pnas.0911591107","article-title":"Long-range gene regulation links genomic type 2 diabetes and obesity risk regions to HHEX, SOX4, and IRX3","volume":"107","author":"A Ragvin","year":"2010","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pcbi.1009908.ref076","doi-asserted-by":"crossref","first-page":"1952","DOI":"10.2337\/db15-1489","article-title":"Increased Expression of the Diabetes Gene SOX4 Reduces Insulin Secretion by Impaired Fusion Pore Expansion","volume":"65","author":"SC Collins","year":"2016","journal-title":"Diabetes"},{"key":"pcbi.1009908.ref077","doi-asserted-by":"crossref","first-page":"W90","DOI":"10.1093\/nar\/gkq324","article-title":"i-GSEA4GWAS: A web server for identification of pathways\/gene sets associated with traits by applying an improved gene set enrichment analysis to genome-wide association study","volume":"38","author":"K Zhang","year":"2010","journal-title":"Nucleic Acids Res"},{"key":"pcbi.1009908.ref078","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1186\/1479-7364-4-5-284","article-title":"Functional intronic polymorphisms: Buried treasure awaiting discovery within our 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Kennedy","year":"2017","journal-title":"Int J Immunogenet"},{"key":"pcbi.1009908.ref086","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1093\/bioinformatics\/btq033","article-title":"BEDTools: a flexible suite of utilities for comparing genomic features","volume":"26","author":"AR Quinlan","year":"2010","journal-title":"Bioinformatics"},{"key":"pcbi.1009908.ref087","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1534\/g3.112.002618","article-title":"Uncovering Networks from Genome-Wide Association Studies via Circular Genomic Permutation.","volume":"2","author":"CP Cabrera","year":"2012","journal-title":"G3 Genes|Genomes|Genetics"},{"key":"pcbi.1009908.ref088","first-page":"7","article-title":"Network-assisted analysis of GWAS data identifies a functionally-relevant gene module for childhood-onset asthma","author":"Y Liu","year":"2017","journal-title":"Sci 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cancer","volume":"7","author":"YA Fouad","year":"2017","journal-title":"Am J Cancer Res"},{"key":"pcbi.1009908.ref093","doi-asserted-by":"crossref","DOI":"10.3390\/cancers11050630","article-title":"Tumour-derived laminin \u03b15 (LAMA5) promotes colorectal liver metastasis growth, branching angiogenesis and notch pathway inhibition.","volume":"11","author":"A Gordon-Weeks","year":"2019","journal-title":"Cancers (Basel)."}],"container-title":["PLOS Computational 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