title: MicroRNAs enrichment in GWAS of complex human phenotypes.
abstract: BACKGROUND
  The genotype information carried by Genome-wide association studies (GWAS) seems to have the potential to explain more of the 'missing heritability' of complex human phenotypes, given improved statistical approaches. Several lines of evidence support the involvement of microRNA (miRNA) and other non-coding RNA in complex human traits and diseases. We employed a novel, genetic annotation-informed enrichment method for GWAS that captures more polygenic effects than standard GWAS analysis, to investigate if miRNA-tagging Single Nucleotide Polymorphisms (SNPs) are enriched of associations with 15 complex human phenotypes. We then leveraged the enrichment using a conditional False Discovery Rate (condFDR) approach to assess any improvement in the detection of individual miRNA SNPs associated with the disorders.
  
  
  RESULTS
  We found SNPs tagging miRNA transcription regions to be significantly enriched of associations with 10 of 15 phenotypes. The enrichment remained significant after controlling for affiliation to other genomic categories, and was confirmed by replication. Albeit only nominally significant, enrichment was found also in miRNA binding sites for 10 phenotypes out of 15. Leveraging the enrichment in the condFDR framework, we observed a 2-4-fold increase in discovery of SNPs tagging miRNA regions.
  
  
  CONCLUSIONS
  Our results suggest that miRNAs play an important role in the polygenic architecture of complex human disorders and traits, and therefore that miRNAs are a genomic category that can and should be used to improve gene discovery.
authors.affiliation: NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. luiz.goulart@medisin.uio.no.|Department of Medical Genetics, Oslo University Hospital, Oslo, Norway. luiz.goulart@medisin.uio.no.
authors.forename: Luiz F
authors.initials: LF
authors.lastname: Goulart
authors.affiliation: NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. checco74@gmail.com.|Division of Mental Health and Addiction, Oslo University Hospital, 0407, Oslo, Norway. checco74@gmail.com.
authors.forename: Francesco
authors.initials: F
authors.lastname: Bettella
authors.affiliation: NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. i.e.sonderby@medisin.uio.no.|Department of Medical Genetics, Oslo University Hospital, Oslo, Norway. i.e.sonderby@medisin.uio.no.
authors.forename: Ida E
authors.initials: IE
authors.lastname: Sønderby
authors.affiliation: Multimodal Imaging Laboratory, University of California at San Diego, La Jolla, CA, 92037, USA. ajschork@cogsci.ucsd.edu.|Cognitive Sciences Graduate Program, University of California at San Diego, La Jolla, CA, 92037, USA. ajschork@cogsci.ucsd.edu.|Center for Human Development, University of California at San Diego, La Jolla, CA, 92037, USA. ajschork@cogsci.ucsd.edu.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Schork
authors.affiliation: Department of Psychiatry, University of California at San Diego, La Jolla, CA, 92037, USA. wes.stat@gmail.com.
authors.forename: Wesley K
authors.initials: WK
authors.lastname: Thompson
authors.affiliation: NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. morten.mattingsdal@gmail.com.|Division of Mental Health and Addiction, Oslo University Hospital, 0407, Oslo, Norway. morten.mattingsdal@gmail.com.
authors.forename: Morten
authors.initials: M
authors.lastname: Mattingsdal
authors.affiliation: NORMENT, KG Jebsen Centre for Psychosis Research, Department of Clinical Science, University of Bergen, Bergen, Norway. vidar.martin.steen@helse-bergen.no.|Dr. Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway. vidar.martin.steen@helse-bergen.no.
authors.forename: Vidar M
authors.initials: VM
authors.lastname: Steen
authors.affiliation: NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. verena.zuber@ncmm.uio.no.|Division of Mental Health and Addiction, Oslo University Hospital, 0407, Oslo, Norway. verena.zuber@ncmm.uio.no.|Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, Oslo, Norway. verena.zuber@ncmm.uio.no.
authors.forename: Verena
authors.initials: V
authors.lastname: Zuber
authors.affiliation: NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. yunpeng.wng@gmail.com.|Division of Mental Health and Addiction, Oslo University Hospital, 0407, Oslo, Norway. yunpeng.wng@gmail.com.
authors.forename: Yunpeng
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Multimodal Imaging Laboratory, University of California at San Diego, La Jolla, CA, 92037, USA. amdale@ucsd.edu.|Department of Psychiatry, University of California at San Diego, La Jolla, CA, 92037, USA. amdale@ucsd.edu.|Department of Neuroscience, University of California at San Diego, La Jolla, CA, 92037, USA. amdale@ucsd.edu.|Department of Radiology, University of California at San Diego, La Jolla, CA, 92037, USA. amdale@ucsd.edu.
authors.forename: Anders M
authors.initials: AM
authors.lastname: Dale
authors.affiliation: NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. o.a.andreassen@medisin.uio.no.|Division of Mental Health and Addiction, Oslo University Hospital, 0407, Oslo, Norway. o.a.andreassen@medisin.uio.no.|Department of Psychiatry, University of California at San Diego, La Jolla, CA, 92037, USA. o.a.andreassen@medisin.uio.no.
authors.forename: Ole A
authors.initials: OA
authors.lastname: Andreassen
authors.affiliation: NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. srdjan.djurovic@medisin.uio.no.|Department of Medical Genetics, Oslo University Hospital, Oslo, Norway. srdjan.djurovic@medisin.uio.no.|Division of Mental Health and Addiction, Oslo University Hospital, 0407, Oslo, Norway. srdjan.djurovic@medisin.uio.no.
authors.forename: Srdjan
authors.initials: S
authors.lastname: Djurovic
mesh_terms: D001665:Binding Sites; D003424:Crohn Disease / Q000235:genetics / Q000473:pathology; D030541:Databases, Genetic; D015894:Genome, Human; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008077:Lipoproteins, LDL / Q000235:genetics; D035683:MicroRNAs / Q000378:metabolism*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012559:Schizophrenia / Q000235:genetics / Q000473:pathology
chemical_list: D008077:Lipoproteins, LDL; D035683:MicroRNAs