{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2024,9,25]],"date-time":"2024-09-25T16:28:07Z","timestamp":1727281687758},"update-to":[{"updated":{"date-parts":[[2022,10,6]],"date-time":"2022-10-06T00:00:00Z","timestamp":1665014400000},"DOI":"10.1371\/journal.pcbi.1010517","type":"new_version","label":"New version"}],"reference-count":81,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2022,9,26]],"date-time":"2022-09-26T00:00:00Z","timestamp":1664150400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001711","name":"Schweizerischer Nationalfonds zur F\u00f6rderung der Wissenschaftlichen Forschung","doi-asserted-by":"publisher","award":["FN310030_152724\/1"],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"Proximal genetic variants are frequently correlated, implying that the corresponding effect sizes detected by genome-wide association studies (GWAS) are also not independent. Methods already exist to account for this when aggregating effects from a single GWAS across genes or pathways. Here we present a rigorous yet fast method for detecting genes with coherent association signals for two traits, facilitating cross-GWAS analyses. To this end, we devised a new significance test for the covariance of datapoints not drawn independently but with a known inter-sample covariance structure. We show that the distribution of its test statistic is a linear combination of \u03c7<\/jats:italic>2<\/jats:sup> distributions with positive and negative coefficients. The corresponding cumulative distribution function can be efficiently calculated with Davies\u2019 algorithm at high precision. We apply this general framework to test for dependence between SNP-wise effect sizes of two GWAS at the gene level. We extend this test to detect also gene-wise causal links. We demonstrate the utility of our method by uncovering potential shared genetic links between the severity of COVID-19 and (1) being prescribed class M05B medication (drugs affecting bone structure and mineralization), (2) rheumatoid arthritis, (3) vitamin D (25OHD), and (4) serum calcium concentrations. Our method detects a potential role played by chemokine receptor genes linked to T<\/jats:italic>H<\/jats:italic><\/jats:sub>1 versus T<\/jats:italic>H<\/jats:italic><\/jats:sub>2 immune response, a gene related to integrin beta-1 cell surface expression, and other genes potentially impacting the severity of COVID-19. Our approach will be useful for similar analyses involving datapoints with known auto-correlation structures.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1010517","type":"journal-article","created":{"date-parts":[[2022,9,26]],"date-time":"2022-09-26T17:50:58Z","timestamp":1664214658000},"page":"e1010517","update-policy":"http:\/\/dx.doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":3,"title":["Cross-GWAS coherence test at the gene and pathway level"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"http:\/\/orcid.org\/0000-0001-8554-2498","authenticated-orcid":true,"given":"Daniel","family":"Krefl","sequence":"first","affiliation":[]},{"ORCID":"http:\/\/orcid.org\/0000-0002-6785-9034","authenticated-orcid":true,"given":"Sven","family":"Bergmann","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2022,9,26]]},"reference":[{"key":"pcbi.1010517.ref001","doi-asserted-by":"crossref","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":"Vol. 47","author":"A Buniello","year":"2019","journal-title":"Nucleic Acids Research"},{"key":"pcbi.1010517.ref002","doi-asserted-by":"crossref","first-page":"e1004714","DOI":"10.1371\/journal.pcbi.1004714","article-title":"Fast and rigorous computation of gene and pathway scores from SNP-based summary statistics","volume":"12","author":"D Lamparter","year":"2016","journal-title":"PLoS Computational Biology"},{"issue":"4","key":"pcbi.1010517.ref003","doi-asserted-by":"crossref","first-page":"e1004219","DOI":"10.1371\/journal.pcbi.1004219","article-title":"MAGMA: Generalized gene-set analysis of GWAS data","volume":"11","author":"C de Leeuw","journal-title":"PLoS Comput Biol"},{"issue":"6","key":"pcbi.1010517.ref004","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1038\/nrg2361","article-title":"Linkage disequilibrium\u2013understanding the evolutionary past and mapping the medical future","volume":"9","author":"M Slatkin","year":"2008","journal-title":"Nat Rev Genet"},{"key":"pcbi.1010517.ref005","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1038\/nrg3461","article-title":"Pleiotropy in complex traits: challenges and strategies","volume":"14","author":"N Solovieff","year":"2013","journal-title":"Nat Rev Genet"},{"issue":"21","key":"pcbi.1010517.ref006","doi-asserted-by":"crossref","first-page":"8685","DOI":"10.1073\/pnas.0701361104","article-title":"The human disease network","volume":"104","author":"KI Goh","year":"2007","journal-title":"Proceedings of the National Academy of Sciences"},{"issue":"5","key":"pcbi.1010517.ref007","doi-asserted-by":"crossref","first-page":"e1004383","DOI":"10.1371\/journal.pgen.1004383","article-title":"Bayesian Test for Colocalisation between Pairs of Genetic Association Studies Using Summary Statistics","volume":"10","author":"C Giambartolomei","journal-title":"PLOS Genetics"},{"issue":"11","key":"pcbi.1010517.ref008","doi-asserted-by":"crossref","first-page":"1236","DOI":"10.1038\/ng.3406","article-title":"An atlas of genetic correlations across human diseases and traits","volume":"47","author":"B Bulik-Sullivan","year":"2015","journal-title":"Nat Genet"},{"issue":"3","key":"pcbi.1010517.ref009","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1038\/ng.3211","article-title":"LD Score regression distinguishes confounding from polygenicity in genome-wide association studies","volume":"47","author":"BK Bulik-Sullivan","year":"2015","journal-title":"Nat Genet"},{"issue":"5","key":"pcbi.1010517.ref010","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1016\/j.ajhg.2017.09.022","article-title":"Local Genetic Correlation Gives Insights into the Shared Genetic Architecture of Complex Traits","volume":"101","author":"H Shi","year":"2017","journal-title":"Am J Hum Genet"},{"issue":"No. 2","key":"pcbi.1010517.ref011","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1093\/biomet\/60.2.415","article-title":"Numerical Inversion of a Characteristic Function","volume":"Vol. 60","author":"RB Davies","journal-title":"Biometrika"},{"issue":"No. 3","key":"pcbi.1010517.ref012","first-page":"323","article-title":"Algorithm AS 155: The Distribution of a Linear Combination of \u03c72 Random Variables","volume":"Vol. 29","author":"RB Davies","year":"1980","journal-title":"Journal of the Royal Statistical Society. 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