title: Genetic Markers of Human Evolution Are Enriched in Schizophrenia.
abstract: Why schizophrenia has accompanied humans throughout our history despite its negative effect on fitness remains an evolutionary enigma. It is proposed that schizophrenia is a by-product of the complex evolution of the human brain and a compromise for humans' language, creative thinking, and cognitive abilities.
  
  
  
  We analyzed recent large genome-wide association studies of schizophrenia and a range of other human phenotypes (anthropometric measures, cardiovascular disease risk factors, immune-mediated diseases) using a statistical framework that draws on polygenic architecture and ancillary information on genetic variants. We used information from the evolutionary proxy measure called the Neanderthal selective sweep (NSS) score.
  
  
  
  Gene loci associated with schizophrenia are significantly (p = 7.30 × 10(-9)) more prevalent in genomic regions that are likely to have undergone recent positive selection in humans (i.e., with a low NSS score). Variants in brain-related genes with a low NSS score confer significantly higher susceptibility than variants in other brain-related genes. The enrichment is strongest for schizophrenia, but we cannot rule out enrichment for other phenotypes. The false discovery rate conditional on the evolutionary proxy points to 27 candidate schizophrenia susceptibility loci, 12 of which are associated with schizophrenia and other psychiatric disorders or linked to brain development.
  
  
  
  Our results suggest that there is a polygenic overlap between schizophrenia and NSS score, a marker of human evolution, which is in line with the hypothesis that the persistence of schizophrenia is related to the evolutionary process of becoming human.
authors.affiliation: NORMENT, University of Oslo, Oslo, Norway; Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Srinivasan
authors.affiliation: NORMENT, University of Oslo, Oslo, Norway; Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
authors.forename: Francesco
authors.initials: F
authors.lastname: Bettella
authors.affiliation: NORMENT, University of Oslo, Oslo, Norway; Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
authors.forename: Morten
authors.initials: M
authors.lastname: Mattingsdal
authors.affiliation: NORMENT, University of Oslo, Oslo, Norway; Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; Multimodal Imaging Laboratory, University of California, San Diego, La Jolla, California.
authors.forename: Yunpeng
authors.initials: Y
authors.lastname: Wang
authors.affiliation: NORMENT, University of Oslo, Oslo, Norway; Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
authors.forename: Aree
authors.initials: A
authors.lastname: Witoelar
authors.affiliation: Multimodal Imaging Laboratory, University of California, San Diego, La Jolla, California; Cognitive Sciences Graduate Program, University of California, San Diego, La Jolla, California; Center for Human Development, University of California, San Diego, La Jolla, California.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Schork
authors.affiliation: Department of Psychiatry, University of California, San Diego, La Jolla, California.
authors.forename: Wesley K
authors.initials: WK
authors.lastname: Thompson
authors.affiliation: NORMENT, University of Oslo, Oslo, Norway; Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; Centre for Molecular Medicine Norway, Nordic European Molecular Biology Laboratory Partnership, University of Oslo and Oslo University Hospital, Oslo, Norway.
authors.forename: Verena
authors.initials: V
authors.lastname: Zuber
authors.affiliation: KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Neurology and Communication and Research Unit at the Division of Neuroscience, Oslo University Hospital, Ullevål, Oslo, Norway.
authors.forename: Bendik S
authors.initials: BS
authors.lastname: Winsvold
authors.affiliation: KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Neurology and Communication and Research Unit at the Division of Neuroscience, Oslo University Hospital, Ullevål, Oslo, Norway.
authors.forename: John-Anker
authors.initials: JA
authors.lastname: Zwart
authors.affiliation: Eli Lilly and Company, Windlesham, Surrey, United Kingdom.
authors.forename: David A
authors.initials: DA
authors.lastname: Collier
authors.affiliation: Multimodal Imaging Laboratory, University of California, San Diego, La Jolla, California; Neuroradiology Section, Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California.
authors.forename: Rahul S
authors.initials: RS
authors.lastname: Desikan
authors.affiliation: NORMENT, University of Oslo, Oslo, Norway; Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Melle
authors.affiliation: Institute of Biological Psychiatry, Mental Health Center St. Hans, Mental Health Services Copenhagen, Roskilde; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Capital Region of Denmark, Denmark.
authors.forename: Thomas
authors.initials: T
authors.lastname: Werge
authors.affiliation: Multimodal Imaging Laboratory, University of California, San Diego, La Jolla, California; Department of Psychiatry, University of California, San Diego, La Jolla, California; Department of Neuroscience, University of California, San Diego, La Jolla, California; Eli Lilly and Company, Windlesham, Surrey, United Kingdom.
authors.forename: Anders M
authors.initials: AM
authors.lastname: Dale
authors.affiliation: NORMENT, University of Oslo, Oslo, Norway; Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
authors.forename: Srdjan
authors.initials: S
authors.lastname: Djurovic
authors.affiliation: NORMENT, University of Oslo, Oslo, Norway; Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; Department of Psychiatry, University of California, San Diego, La Jolla, California. Electronic address: o.a.andreassen@medisin.uio.no.
authors.forename: Ole A
authors.initials: OA
authors.lastname: Andreassen
mesh_terms: D005075:Biological Evolution; D001921:Brain / Q000378:metabolism; D005819:Genetic Markers / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D020412:Multifactorial Inheritance / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics* / Q000473:pathology
chemical_list: D005819:Genetic Markers
keywords: Evolution; GWAS; Human; Neanderthal; Polygenic; Schizophrenia