Improved functional mapping with GSA-MiXeR implicates biologically specific gene-sets and estimates enrichment magnitude
Improved functional mapping with GSA-MiXeR implicates biologically specific gene-sets and estimates enrichment magnitude
Abstract While genome-wide association studies (GWAS) are increasingly successful in discovering genomic loci associated with complex human traits and disorders, the biological interpretation of these findings remains challenging. We developed the GSA-MiXeR analytical tool for gene-set analysis (GSA), which fits a model for gene-set heritability enrichments for complex traits, accounting for linkage disequilibrium across variants, and allowing the quantification of partitioned heritability and fold enrichment for small gene-sets. We validate the method using extensive simulations and sensitivity analyses. When applied to height and schizophrenia, GSA-MiXeR implicates gene-sets with greater biological specificity compared to standard GSA approaches, including insulin-like growth factor for height, as well as calcium channel function, GABAergic and dopaminergic signaling for schizophrenia. Such biologically relevant gene-sets, often with less than ten genes, are more likely to provide new insights into the pathobiology of complex diseases and highlight potential drug targets.
de Leeuw Christiaan、Frei Oleksandr、Hindley Guy、Shadrin Alexey A.、O?ˉConnell Kevin S.、Parker Nadine、Smeland Olav B.、Holland Dominic、Schizophrenia Working Group of the Psychiatric Genomics Consortium、Andreassen Ole A.、Dale Anders M.、Posthuma Danielle、Cheng Weiqiu、Bahrami Shahram、van der Meer Dennis、Akdeniz Bayram C.
Department of Complex Trait Genetics, Centre for Neurogenomics and Cognitive Research, VU UniversityNORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo||Centre for Bioinformatics, Department of Informatics, University of OsloNORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of OsloNORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of OsloNORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of OsloNORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of OsloNORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of OsloCenter for Multimodal Imaging and Genetics, University of California San DiegoNORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of OsloCenter for Multimodal Imaging and Genetics, University of California San DiegoDepartment of Complex Trait Genetics, Centre for Neurogenomics and Cognitive Research, VU UniversityNORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of OsloNORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of OsloNORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo||School of Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht UniversityCentre for Bioinformatics, Department of Informatics, University of Oslo
医学研究方法基础医学神经病学、精神病学
de Leeuw Christiaan,Frei Oleksandr,Hindley Guy,Shadrin Alexey A.,O?ˉConnell Kevin S.,Parker Nadine,Smeland Olav B.,Holland Dominic,Schizophrenia Working Group of the Psychiatric Genomics Consortium,Andreassen Ole A.,Dale Anders M.,Posthuma Danielle,Cheng Weiqiu,Bahrami Shahram,van der Meer Dennis,Akdeniz Bayram C..Improved functional mapping with GSA-MiXeR implicates biologically specific gene-sets and estimates enrichment magnitude[EB/OL].(2025-03-28)[2025-04-30].https://www.medrxiv.org/content/10.1101/2022.12.08.22283159.点此复制
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