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Improved functional mapping of complex trait heritability with GSA-MiXeR implicates biologically specific gene sets.
Frei, Oleksandr; Hindley, Guy; Shadrin, Alexey A; van der Meer, Dennis; Akdeniz, Bayram C; Hagen, Espen; Cheng, Weiqiu; O'Connell, Kevin S; Bahrami, Shahram; Parker, Nadine; Smeland, Olav B; Holland, Dominic; de Leeuw, Christiaan; Posthuma, Danielle; Andreassen, Ole A; Dale, Anders M.
Afiliação
  • Frei O; Centre for Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo, Oslo, Norway. oleksandr.frei@medisin.uio.no.
  • Hindley G; Centre for Bioinformatics, Department of Informatics, University of Oslo, Oslo, Norway. oleksandr.frei@medisin.uio.no.
  • Shadrin AA; Centre for Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
  • van der Meer D; Centre for Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
  • Akdeniz BC; Centre for Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
  • Hagen E; School of Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, the Netherlands.
  • Cheng W; Centre for Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
  • O'Connell KS; Centre for Bioinformatics, Department of Informatics, University of Oslo, Oslo, Norway.
  • Bahrami S; Centre for Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
  • Parker N; Centre for Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
  • Smeland OB; Centre for Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
  • Holland D; Centre for Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
  • de Leeuw C; Centre for Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
  • Posthuma D; Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA, USA.
  • Dale AM; Department of Complex Trait Genetics, Centre for Neurogenomics and Cognitive Research, VU University, Amsterdam, the Netherlands.
Nat Genet ; 56(6): 1310-1318, 2024 Jun.
Article em En | MEDLINE | ID: mdl-38831010
ABSTRACT
While genome-wide association studies are increasingly successful in discovering genomic loci associated with complex human traits and disorders, the biological interpretation of these findings remains challenging. Here we developed the GSA-MiXeR analytical tool for gene set analysis (GSA), which fits a model for the heritability of individual genes, accounting for linkage disequilibrium across variants and allowing the quantification of partitioned heritability and fold enrichment for small gene sets. We validated the method using extensive simulations and sensitivity analyses. When applied to a diverse selection of complex traits and disorders, including schizophrenia, GSA-MiXeR prioritizes gene sets with greater biological specificity compared to standard GSA approaches, implicating voltage-gated calcium channel function and dopaminergic signaling for schizophrenia. Such biologically relevant gene sets, often with fewer than ten genes, are more likely to provide insights into the pathobiology of complex diseases and highlight potential drug targets.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Esquizofrenia / Desequilíbrio de Ligação / Estudo de Associação Genômica Ampla Limite: Humans Idioma: En Revista: Nat Genet Assunto da revista: GENETICA MEDICA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Noruega

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Esquizofrenia / Desequilíbrio de Ligação / Estudo de Associação Genômica Ampla Limite: Humans Idioma: En Revista: Nat Genet Assunto da revista: GENETICA MEDICA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Noruega