Genetic Markers of Human Evolution Are Enriched in Schizophrenia

Saurabh Srinivasan; Francesco Bettella; Morten Mattingsdal; Yunpeng Wang; Aree Witoelar; Andrew J Schork; Wesley K Thompson; Verena Zuber; Schizophrenia Working Group of the Psychiatric Genomics Consortium, The International Headache Genetics Consortium; Bendik S Winsvold; John-Anker Zwart; David A Collier; Rahul S Desikan; Ingrid Melle; Thomas Werge; Anders M Dale; Srdjan Djurovic; Ole A Andreassen

doi:10.1016/j.biopsych.2015.10.009

Genetic Markers of Human Evolution Are Enriched in Schizophrenia

Biol Psychiatry. 2016 Aug 15;80(4):284-292. doi: 10.1016/j.biopsych.2015.10.009. Epub 2015 Oct 21.

Authors

Saurabh Srinivasan¹, Francesco Bettella¹, Morten Mattingsdal¹, Yunpeng Wang², Aree Witoelar¹, Andrew J Schork³, Wesley K Thompson⁴, Verena Zuber⁵; Schizophrenia Working Group of the Psychiatric Genomics Consortium, The International Headache Genetics Consortium; Bendik S Winsvold⁶, John-Anker Zwart⁶, David A Collier⁷, Rahul S Desikan⁸, Ingrid Melle¹, Thomas Werge⁹, Anders M Dale¹⁰, Srdjan Djurovic¹¹, Ole A Andreassen¹²

Affiliations

¹ NORMENT, University of Oslo, Oslo, Norway; Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
² 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.
³ 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.
⁴ Department of Psychiatry, University of California, San Diego, La Jolla, California.
⁵ 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.
⁶ 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.
⁷ Eli Lilly and Company, Windlesham, Surrey, United Kingdom.
⁸ 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.
⁹ 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.
¹⁰ 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.
¹¹ 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.
¹² 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.

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: Evolution; GWAS; Human; Neanderthal; Polygenic; Schizophrenia.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Biological Evolution*
Brain / metabolism
Genetic Markers / genetics*
Genetic Predisposition to Disease / genetics*
Genome-Wide Association Study
Humans
Multifactorial Inheritance / genetics
Polymorphism, Single Nucleotide / genetics*
Schizophrenia / genetics*
Schizophrenia / pathology

Substances

Genetic Markers

Abstract

Publication types

MeSH terms

Substances

Grants and funding