. 2016 Aug 15;80(4):284-292.

doi: 10.1016/j.biopsych.2015.10.009. Epub 2015 Oct 21.

Genetic Markers of Human Evolution Are Enriched in Schizophrenia

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.

PMID: 26681495
PMCID: PMC5397584
DOI: 10.1016/j.biopsych.2015.10.009

Genetic Markers of Human Evolution Are Enriched in Schizophrenia

Saurabh Srinivasan et al. Biol Psychiatry. 2016.

. 2016 Aug 15;80(4):284-292.

doi: 10.1016/j.biopsych.2015.10.009. Epub 2015 Oct 21.

Authors

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.

PMID: 26681495
PMCID: PMC5397584
DOI: 10.1016/j.biopsych.2015.10.009

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.

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Conflict of interest statement

The authors report no conflicts of interest.

Figures

**Fig. 1. Q-Q and fold enrichment plots of schizophrenia stratified according to Neanderthal selective sweep score**
Shown are A) quantile-quantile (Q-Q) and B) fold enrichment plots of GWAS summary statistics p-values for schizophrenia (SCZ), stratified based on Neanderthal selective sweep (NSS) score. The human divergent (HD) stratum comprises single nucleotide polymorphisms (SNPs) with negative NSS scores. The regions around these SNPs present fewer derived alleles in Neanderthal than expected given the frequency of derived alleles in humans, and may therefore have undergone recent positive selection in the latter. The non-divergent (ND) stratum comprises all SNPs with positive NSS scores. HD SNPs show a marked leftward (A) and upward (B) deflection from the lines corresponding to All SNPs. This signifies a comparatively higher proportion of low p-values among HD SNPs.

**Fig. 2. Q-Q and fold enrichment plots of three non-schizophrenia phenotypes stratified according to Neanderthal selective sweep scores**
Phenotypes: Crohn’s disease (CD), Height and total cholesterol (TC). A) The quantile-quantile (Q-Q) plots show GWAS summary statistics p-values of SNPs tagging human divergent regions (HD), non-divergent (ND) regions as well as All SNPs. There is no indication of enrichment as seen in SCZ in (Fig. 1). B) The fold enrichment counterparts of the Q-Q plots in A) illustrate the lack of enrichment. The regression analysis however shows significant enrichment for Height. (Table 1).

**Fig. 3. Q-Q and fold enrichment plots showing schizophrenia association enrichment of brain genes with negative Neanderthal selective sweep (NSS) score**
Shown are A) the quantile- quantile (Q-Q) and B) the fold enrichment plots for: SNPs annotated to generic genes (Any); SNPs annotated to genes associated with the brain, as established by an NCBI site search (Brain); SNPs annotated to genes associated with the brain, defined by Kang *et al*. (34) (Neuro); SNPs with negative NSS score and annotated to genes associated with the brain, as established by an NCBI site search (NSSBrain); or to genes defined by Kang *et al*. (34) (NSSNeuro); and all SNPs (All SNPs). The NSS Brain category is enriched (deflected left) compared to the other categories, i.e. presents a higher incidence of associations (lower p-values) with schizophrenia (SCZ). This is confirmed by the Binomial Proportion Test (BPT) comparing Brain and NSS Brain groups (p = 5.5×10⁻³).

**Fig. 4. Replication plot for schizophrenia with and without conditioning on Neanderthal selective sweep score < 0**
SNPs with negative Neanderthal selective sweep score (NSS) score tend to replicate better than baseline SNPs across the 52 schizophrenia (SCZ) meta-analysis sub studies. For example, at a −log(p)-value level of 4 the cumulative replication rate improves from 60% to about 80% when restricting the choice to SNPs with negative NSS score. A negative NSS score seems therefore to be a viable aid to identify non-spurious schizophrenia associations.

See this image and copyright information in PMC

References

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Genetic Markers of Human Evolution Are Enriched in Schizophrenia

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Genetic Markers of Human Evolution Are Enriched in Schizophrenia

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