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; Bendik S Winsvold; John-Anker Zwart; David A Collier; Rahul S Desikan; Ingrid Melle; Thomas Werge; Anders M Dale; Srdjan Djurovic; Ole A. Andreassen; Schizophrenia Working Group of the Psychiatric Genomics Consortium, The International Headache Genetics Consortium

doi:10.1016/j.biopsych.2015.10.009

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, Bendik S Winsvold, John-Anker Zwart, David A Collier, Rahul S Desikan, Ingrid Melle, Thomas Werge, Anders M Dale, Srdjan Djurovic, Ole A. Andreassen, Schizophrenia Working Group of the Psychiatric Genomics Consortium, The International Headache Genetics Consortium

Department of Clinical Medicine

49 Citations (Scopus)

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.

Original language	English
Journal	Biological Psychiatry
Volume	80
Issue number	4
Pages (from-to)	284-92
Number of pages	9
ISSN	0006-3223
DOIs	https://doi.org/10.1016/j.biopsych.2015.10.009
Publication status	Published - 15 Aug 2016

Keywords

Journal Article

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.biopsych.2015.10.009

http://www.biologicalpsychiatryjournal.com/article/S0006322315008550/pdf

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Srinivasan, S., Bettella, F., Mattingsdal, M., Wang, Y., Witoelar, A., Schork, A. J., Thompson, W. K., Zuber, V., Winsvold, B. S., Zwart, J-A., Collier, D. A., Desikan, R. S., Melle, I., Werge, T., Dale, A. M., Djurovic, S., Andreassen, O. A., & Schizophrenia Working Group of the Psychiatric Genomics Consortium, The International Headache Genetics Consortium (2016). Genetic Markers of Human Evolution Are Enriched in Schizophrenia. Biological Psychiatry, 80(4), 284-92. https://doi.org/10.1016/j.biopsych.2015.10.009

Srinivasan, S, Bettella, F, Mattingsdal, M, Wang, Y, Witoelar, A, Schork, AJ, Thompson, WK, Zuber, V, Winsvold, BS, Zwart, J-A, Collier, DA, Desikan, RS, Melle, I, Werge, T, Dale, AM, Djurovic, S, Andreassen, OA & Schizophrenia Working Group of the Psychiatric Genomics Consortium, The International Headache Genetics Consortium 2016, 'Genetic Markers of Human Evolution Are Enriched in Schizophrenia', Biological Psychiatry, vol. 80, no. 4, pp. 284-92. https://doi.org/10.1016/j.biopsych.2015.10.009

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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.",

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

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AU - Srinivasan, Saurabh

AU - Bettella, Francesco

AU - Mattingsdal, Morten

AU - Wang, Yunpeng

AU - Witoelar, Aree

AU - Schork, Andrew J

AU - Thompson, Wesley K

AU - Zuber, Verena

AU - Winsvold, Bendik S

AU - Zwart, John-Anker

AU - Collier, David A

AU - Desikan, Rahul S

AU - Melle, Ingrid

AU - Werge, Thomas

AU - Dale, Anders M

AU - Djurovic, Srdjan

AU - Andreassen, Ole A.

AU - Schizophrenia Working Group of the Psychiatric Genomics Consortium, The International Headache Genetics Consortium

PY - 2016/8/15

Y1 - 2016/8/15

N2 - 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.

AB - 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.

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DO - 10.1016/j.biopsych.2015.10.009

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SN - 0006-3223

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SP - 284

EP - 292

JO - Biological Psychiatry

JF - Biological Psychiatry

IS - 4

ER -

Genetic Markers of Human Evolution Are Enriched in Schizophrenia

Abstract

Keywords

UN SDGs

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