{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T16:34:16Z","timestamp":1764002056617},"reference-count":33,"publisher":"Oxford University Press (OUP)","issue":"14","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,7,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Motivation: The functional mechanisms underlying disease association remain unknown for Genome-wide Association Studies (GWAS) susceptibility variants located outside coding regions. Synthesis of effects from multiple surrounding functional variants has been suggested as an explanation of hard-to-interpret findings. We define filter criteria based on linkage disequilibrium measures and allele frequencies which reflect expected properties of synthesizing variant sets. For eligible candidate sets, we search for haplotype markers that are highly correlated with associated variants.<\/jats:p>\n               <jats:p>Results: Via simulations we assess the performance of our approach and suggest parameter settings which guarantee 95% sensitivity at 20-fold reduced computational cost. We apply our method to 1000 Genomes data and confirmed Crohn\u2019s Disease (CD) and Type 2 Diabetes (T2D) variants. A proportion of 36.9% allowed explanation by three-variant-haplotypes carrying at least two functional variants, as compared to 16.4% for random variants (P=1.72\u00d710\u22128). Association could be explained by missense variants for MUC19, PER3 (CD) and HMG20A (T2D). In a CD GWAS\u2014imputed using haplotype reference consortium data (64 976 haplotypes)\u2014we could confirm the syntheses of MUC19 and PER3 and identified synthesis by missense variants for 6 further genes (ZGPAZ, GPR65, CLN3\/NPIPB8, LOC102723878, rs2872507, GCKR). In all instances, the odds ratios of the synthesizing haplotypes were virtually identical to that of the index SNP. In summary, we demonstrate the potential of synthesis analysis to guide functional follow-up of GWAS findings.<\/jats:p>\n               <jats:p>Availability and implementation: All methods are implemented in the C\/C\u2009++\u2009toolkit GetSynth, available at http:\/\/sourceforge.net\/projects\/getsynth\/.<\/jats:p>\n               <jats:p>Contact: \u00a0tim.becker@uni-greifswald.de<\/jats:p>\n               <jats:p>Supplementary information: \u00a0Supplementary data are available at Bioinformatics online.<\/jats:p>","DOI":"10.1093\/bioinformatics\/btw125","type":"journal-article","created":{"date-parts":[[2016,3,22]],"date-time":"2016-03-22T02:05:11Z","timestamp":1458612311000},"page":"2136-2142","source":"Crossref","is-referenced-by-count":2,"title":["Haplotype synthesis analysis reveals functional variants underlying known genome-wide associated susceptibility loci"],"prefix":"10.1093","volume":"32","author":[{"given":"Andr\u00e9","family":"Lacour","sequence":"first","affiliation":[{"name":"1 German Center for Neurodegenerative Diseases (DZNE), Bonn 53127, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Ellinghaus","sequence":"additional","affiliation":[{"name":"2 Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel 24105, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefan","family":"Schreiber","sequence":"additional","affiliation":[{"name":"2 Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel 24105, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andre","family":"Franke","sequence":"additional","affiliation":[{"name":"2 Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel 24105, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tim","family":"Becker","sequence":"additional","affiliation":[{"name":"3 Institute for Community Medicine, Ernst Moritz Arndt University Greifswald, Greifswald 17475, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2016,3,21]]},"reference":[{"key":"2023020112440584000_btw125-B1","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/nature11632","article-title":"An integrated map of genetic variation from 1,092 human genomes","volume":"491","author":"1000 Genomes Project Consortium","year":"2012","journal-title":"Nature"},{"key":"2023020112440584000_btw125-B2","doi-asserted-by":"crossref","first-page":"e1000580","DOI":"10.1371\/journal.pbio.1000580","article-title":"Synthetic associations are unlikely to account for many common disease genome-wide association signals","volume":"9","author":"Anderson","year":"2011","journal-title":"PLoS Biol"},{"key":"2023020112440584000_btw125-B3","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1038\/nature08800","article-title":"Genome-wide association study of 107 phenotypes in Arabidopsis thaliana inbred lines","volume":"465","author":"Atwell","year":"2010","journal-title":"Nature"},{"key":"2023020112440584000_btw125-B4","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1002\/gepi.10323","article-title":"Maximum-likelihood estimation of haplotype frequencies in nuclear families","volume":"27","author":"Becker","year":"2004","journal-title":"Genet. 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