Neanderthal‐derived genetic variation in living humans relates to schizophrenia diagnosis, to psychotic symptom severity, and to dopamine synthesis
Open accessAbstract
Schizophrenia has been hypothesized to be a human‐specific condition, but experimental approaches to testing this idea have been limited. Because Neanderthals, our closest evolutionary relatives, interbred with modern humans prior to their disappearance from the fossil record, leaving a residual echo that survives in our DNA today, we leveraged new discoveries about ancient hominid DNA to explore this hypothesis in living people in three converging ways. First, in four independent case–control datasets totaling 9,362 individuals, individuals with schizophrenia had less Neanderthal‐derived genetic variation than controls (p = .044). Second, in 49 unmedicated inpatients with schizophrenia, having more Neanderthal admixture predicted less severe positive symptoms (p = .046). Finally, using 18 F‐fluorodopa PET scanning in 172 healthy individuals, having greater Neanderthal introgression was significantly associated with lower dopamine synthesis capacity in the striatum and pons (p's < 2 × 10−5), which is fundamentally important in the pathophysiology and treatment of psychosis. These results may help to elucidate the evolutionary history of a devastating neuropsychiatric disease by supporting the notion of schizophrenia as a human‐specific condition. Additionally, the relationship between Neanderthal admixture and dopamine function suggests a potential mechanism whereby Neanderthal admixture may have affected our gene pool to alter schizophrenia risk and/or course.
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Some previous studies have suggested that evolutionary forces such as positive selection and Neandertal admixture may be linked to mental disorders such as Schizophrenia.
“Some previous studies have suggested that evolutionary forces such as positive selection [41] and Neandertal admixture [42, 43] may be linked to mental disorders such as Schizophrenia.”
From Neandertal introgression partitions the genetic landscape of neuropsychiatric disorders and associated behavioral phenotypes (2022) · cites this paper as [43]
Gregory et al. [37] reported that lower NeanderScores are associated with schizophrenia and, in particular, with the positive symptoms often present in the condition, suggesting Homo sapiens-specific variants, rather than Neanderthal, may be playing a role in susceptibility to the condition.
“For instance, Gregory et al. [37] reported that lower NeanderScores are associated with schizophrenia and, in particular, with the positive symptoms often present in the condition, suggesting Homo sapiens-specific variants, rather than Neanderthal, may be playing a role in susceptibility to the condition.”
From Enrichment of a subset of Neanderthal polymorphisms in autistic probands and siblings (2024) · cites this paper as [37]
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Cites
The Positive and Negative Syndrome Scale (PANSS) for schizophrenia.
Kay, S. R., Fiszbein, A., & Opler, L. A. (1987) · Schizophrenia Bulletin · doi:10.1093/schbul/13.2.261 · Cited by 21,378 · see citing works
Biological insights from 108 schizophrenia-associated genetic loci
Schizophrenia Working Group of the Psychiatric Genomics Consortium (2014) · Nature · doi:10.1038/nature13595 · Cited by 7,577 · see citing works
Graphical Evaluation of Blood-to-Brain Transfer Constants from Multiple-Time Uptake Data
Patlak, C. S., Blasberg, R. G., & Fenstermacher, J. D. (1983) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.1983.1 · Cited by 3,565 · see citing works
The Dopamine Hypothesis of Schizophrenia: Version III--The Final Common Pathway
Howes, O. D., & Kapur, S. (2009) · Schizophrenia Bulletin · doi:10.1093/schbul/sbp006 · Cited by 2,693 · see citing works
Schizophrenia as a Complex Trait: Evidence From a Meta-analysis of Twin Studies
Sullivan, P. F., Kendler, K. S., & Neale, M. C. (2003) · Archives of General Psychiatry · doi:10.1001/archpsyc.60.12.1187 · Cited by 2,356 · see citing works
Schizophrenia: A Concise Overview of Incidence, Prevalence, and Mortality
McGrath, J., Saha, S., Chant, D., & Welham, J. (2008) · Epidemiologic Reviews · doi:10.1093/epirev/mxn001 · Cited by 2,280 · see citing works
The complete genome sequence of a Neanderthal from the Altai Mountains
Prüfer, K., Racimo, F., Patterson, N., Jay, F., Sankararaman, S., Sawyer, S., Heinze, A., Renaud, G., Sudmant, P. H., de Filippo, C., et al. (2014) · Nature · doi:10.1038/nature12886 · Cited by 2,254 · see citing works
A high-coverage genome sequence from an archaic denisovan individual
Meyer, M., Kircher, M., Gansauge, M.-T., Li, H., Racimo, F., Mallick, S., Schraiber, J. G., Jay, F., Prüfer, K., de Filippo, C., et al. (2012) · Science · doi:10.1126/science.1224344 · Cited by 1,967 · see citing works
Patlak, C. S., & Blasberg, R. G. (1985) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.1985.87 · Cited by 1,673 · see citing works
GERAD1 Consortium, Pardiñas, A. F., CRESTAR Consortium, Holmans, P., Pocklington, A. J., Escott-Price, V., Ripke, S., Carrera, N., Legge, S. E., Bishop, S., et al. (2018) · Nature Genetics · doi:10.1038/s41588-018-0059-2 · Cited by 1,552 · see citing works
Data quality control in genetic case-control association studies
Anderson, C. A., Pettersson, F. H., Clarke, G. M., Cardon, L. R., Morris, A. P., & Zondervan, K. T. (2010) · Nature Protocols · doi:10.1038/nprot.2010.116 · Cited by 1,318 · see citing works
The genomic landscape of Neanderthal ancestry in present-day humans
Sankararaman, S., Mallick, S., Dannemann, M., Prüfer, K., Kelso, J., Pääbo, S., Patterson, N., & Reich, D. (2014) · Nature · doi:10.1038/nature12961 · Cited by 1,107 · see citing works
The genetic history of Ice Age Europe
Fu, Q., Posth, C., Hajdinjak, M., Petr, M., Mallick, S., Fernandes, D., Furtwängler, A., Haak, W., Meyer, M., Mittnik, A., et al. (2016) · Nature · doi:10.1038/nature17993 · Cited by 959 · see citing works
Haber, S. N. (2016) · Dialogues in Clinical Neuroscience · doi:10.31887/dcns.2016.18.1/shaber · Cited by 922 · see citing works
Wallwork, R. S., Fortgang, R. G., Hashimoto, R., Weinberger, D. R., & Dickinson, D. (2012) · Schizophrenia Research · doi:10.1016/j.schres.2012.01.031 · Cited by 843 · see citing works
Self-citationFMRI Clustering in AFNI: False-Positive Rates Redux
Cox, R., Chen, G., Glen, D., Reynolds, R., & Taylor, P. (2017) · Brain Connectivity · doi:10.1089/brain.2016.0475 · Cited by 792 · see citing works
A high-coverage Neandertal genome from Vindija Cave in Croatia
Prüfer, K., de Filippo, C., Grote, S., Mafessoni, F., Korlević, P., Hajdinjak, M., Vernot, B., Skov, L., Hsieh, P., Peyrégne, S., et al. (2017) · Science · doi:10.1126/science.aao1887 · Cited by 719 · see citing works
Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia
Meyer-Lindenberg, A., Miletich, R. S., Kohn, P. D., Esposito, G., Carson, R. E., Quarantelli, M., Weinberger, D. R., & Berman, K. F. (2002) · Nature Neuroscience · doi:10.1038/nn804 · Cited by 652 · see citing works
Self-citationResurrecting Surviving Neandertal Lineages from Modern Human Genomes
Vernot, B., & Akey, J. M. (2014) · Science · doi:10.1126/science.1245938 · Cited by 562 · see citing works
Polygenic risk scores for schizophrenia and bipolar disorder predict creativity
Power, R. A., Steinberg, S., Björnsdóttir, G., Rietveld, C. A., Abdellaoui, A., Nivard, M. G., Johannesson, M., Galesloot, T. E., Hottenga, J., Willemsen, G. A. H. M., et al. (2015) · Nature Neuroscience · doi:10.1038/nn.4040 · Cited by 486 · see citing works
The Date of Interbreeding between Neandertals and Modern Humans
Sankararaman, S., Patterson, N., Li, H., Pääbo, S., & Reich, D. (2012) · PLoS Genetics · doi:10.1371/journal.pgen.1002947 · Cited by 460 · see citing works
Crow, T. (2000) · Brain Research Reviews · doi:10.1016/s0165-0173(99)00029-6 · Cited by 387 · cited 2× · see citing works
“2021;186B:329–338. wileyonlinelibrary.com/journal/ajmgb 329 may be related to the emergence of abilities that characterize modern humans, such as language (Crow, 2000), social functioning (Burns, 2006), and/or creativity (Power et al., 2015).”
BackgroundElevated dopa decarboxylase activity in living brain of patients with psychosis
Reith, J., Benkelfat, C., Sherwin, A., Yasuhara, Y., Kuwabara, H., Andermann, F., Bachneff, S., Cumming, P., Diksic, M., & Dyve, S. E. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.24.11651 · Cited by 342 · see citing works
Power, R. A., Kyaga, S., Uher, R., MacCabe, J. H., Långström, N., Landen, M., McGuffin, P., Lewis, C. M., Lichtenstein, P., & Svensson, A. C. (2013) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2013.268 · Cited by 336 · see citing works
The phenotypic legacy of admixture between modern humans and Neandertals
Simonti, C. N., Vernot, B., Bastarache, L., Bottinger, E., Carrell, D. S., Chisholm, R. L., Crosslin, D. R., Hebbring, S. J., Jarvik, G. P., Kullo, I. J., et al. (2016) · Science · doi:10.1126/science.aad2149 · Cited by 330 · see citing works
The Adopted-Away Offspring of Schizophrenics
ROSENTHAL, D., Wender, P. H., Kety, S. S., Welner, J., & D, F. S. M. (1971) · American Journal of Psychiatry · doi:10.1176/ajp.128.3.307 · Cited by 280 · see citing works
[Therapeutic use in psychiatry of phenothiazine of central elective action (4560 RP)].
Delay, J., Deniker, P., & Harl, J. M. (1952) · PubMed · Cited by 244 · see citing works
Mental Illness in the Biological and Adoptive Families of Adopted Schizophrenics
Kety, S. S., ROSENTHAL, D., Wender, P. H., & D, F. S. M. (1971) · American Journal of Psychiatry · doi:10.1176/ajp.128.3.302 · Cited by 235 · see citing works
Reconstructing the Neanderthal brain using computational anatomy
Kochiyama, T., Ogihara, N., Tanabe, H. C., Kondo, O., Amano, H., Hasegawa, K., Suzuki, H., Ponce de León, M. S., Zollikofer, C. P. E., Bastir, M., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-24331-0 · Cited by 156 · see citing works
Xu, K., Schadt, E. E., Pollard, K. S., Roussos, P., & Dudley, J. T. (2015) · Molecular Biology and Evolution · doi:10.1093/molbev/msv031 · Cited by 133 · see citing works
Genetic Markers of Human Evolution Are Enriched in Schizophrenia
Srinivasan, S., Bettella, F., Mattingsdal, M., Wang, Y., Witoelar, A., Schork, A. J., Thompson, W. K., Zuber, V., Winsvold, B. S., Zwart, J.-A., et al. (2016) · Biological Psychiatry · doi:10.1016/j.biopsych.2015.10.009 · Cited by 129 · see citing works
The Rationale and Ethics of Medication-Free Research in Schizophrenia
Carpenter, W. T. (1997) · Archives of General Psychiatry · doi:10.1001/archpsyc.1997.01830170015002 · Cited by 122 · see citing works
The evolutionary paradox and the missing heritability of schizophrenia
van Dongen, J., & Boomsma, D. I. (2013) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.32135 · Cited by 106 · see citing works
Taylor, N. E., Pei, J., Zhang, J., Vlasov, K. Y., Davis, T., Taylor, E., Weng, F., Dort, C. J. V., Solt, K., & Brown, E. N. (2019) · eNeuro · doi:10.1523/eneuro.0018-18.2019 · Cited by 93 · see citing works
Detecting ancient positive selection in humans using extended lineage sorting
Peyrégne, S., Boyle, M. J., Dannemann, M., & Prüfer, K. (2017) · Genome Research · doi:10.1101/gr.219493.116 · Cited by 93 · see citing works
Dickinson, D., Zaidman, S., Giangrande, E. J., Eisenberg, D. P., Gregory, M. D., & Berman, K. F. (2019) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2019.19050527 · Cited by 89 · see citing works
Self-citationNeanderthal-Derived Genetic Variation Shapes Modern Human Cranium and Brain
Gregory, M. D., Kippenhan, J. S., Eisenberg, D. P., Kohn, P. D., Dickinson, D., Mattay, V. S., Chen, Q., Weinberger, D. R., Saad, Z. S., & Berman, K. F. (2017) · Scientific Reports · doi:10.1038/s41598-017-06587-0 · Cited by 69 · see citing works
Self-citationPsychosis: A costly by-product of social brain evolution in Homo sapiens
Burns, J. K. (2006) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2006.01.006 · Cited by 60 · see citing works
Corticostriatal circuitry in regulating diseases characterized by intrusive thinking
Kalivas, B. C., & Kalivas, P. (2016) · Dialogues in Clinical Neuroscience · doi:10.31887/dcns.2016.18.1/pkalivas · Cited by 37 · see citing works
Common Variation in the DOPA Decarboxylase (DDC) Gene and Human Striatal DDC Activity In Vivo
Eisenberg, D. P., Kohn, P. D., Hegarty, C. E., Ianni, A. M., Kolachana, B. S., Gregory, M. D., Masdeu, J. C., & Berman, K. F. (2016) · Neuropsychopharmacology · doi:10.1038/npp.2016.31 · Cited by 24 · see citing works
Self-citationProbing the Association between Early Evolutionary Markers and Schizophrenia
Srinivasan, S., Bettella, F., Hassani, S., Wang, Y., Witoelar, A., Schork, A. J., Thompson, W. K., Collier, D. A., Desikan, R. S., Melle, I. S., et al. (2017) · PLoS ONE · doi:10.1371/journal.pone.0169227 · Cited by 23 · see citing works
Gregory, M. D., Kippenhan, J. S., Kohn, P. D., Eisenberg, D. P., Callicott, J. H., Kolachana, B. S., & Berman, K. F. (2020) · Brain Connectivity · doi:10.1089/brain.2020.0809 · Cited by 23 · see citing works
Self-citationEisenberg, D., Yankowitz, L., Ianni, A. M., Rubinstein, D., Kohn, P., Hegarty, C. E., Gregory, M. D., Apud, J., & Berman, K. (2017) · Neuropsychopharmacology · doi:10.1038/npp.2017.67 · Cited by 20 · see citing works
Self-citationGregory, M. D., Kippenhan, J. S., Callicott, J. H., Rubinstein, D., Mattay, V. S., Coppola, R., & Berman, K. F. (2018) · Cerebral Cortex · doi:10.1093/cercor/bhy344 · Cited by 13 · see citing works
Self-citationNeanderthal and Denisovan ancestry in Papuans: A functional study
Akkuratov, E. E., Gelfand, M. S., & Khrameeva, E. E. (2018) · Journal of Bioinformatics and Computational Biology · doi:10.1142/s0219720018400115 · Cited by 6 · see citing works
Cardno, A. G., & Gottesman, I. I. (2000) · American Journal of Medical Genetics · doi:10.1002/(sici)1096-8628(200021)97:1
Flagged first, then by citations
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Dannemann, M., Milaneschi, Y., Yermakovich, D., Stiglbauer, V., Kariis, H. M., Krebs, K., Friese, M. A., Otte, C., Estonian Biobank Research Team, Esko, T., et al. (2022) · Translational Psychiatry · doi:10.1038/s41398-022-02196-2 · Cited by 23 · see citing works
Cheli, S. (2022) · New Ideas in Psychology · doi:10.1016/j.newideapsych.2022.100993 · Cited by 16 · see citing works
Enrichment of a subset of Neanderthal polymorphisms in autistic probands and siblings
Pauly, R., Johnson, L., Feltus, F. A., & Casanova, E. L. (2024) · Molecular Psychiatry · doi:10.1038/s41380-024-02593-7 · Cited by 7 · see citing works
Mitterœcker, P., & Merola, G. P. (2024) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2024.105636 · Cited by 6 · see citing works
Sandroni, V., & Chaumette, B. (2025) · Genes Brain & Behavior · doi:10.1111/gbb.70013 · Cited by 5 · see citing works
Geneticist who unmasked lives of ancient humans wins medicine Nobel
Callaway, E., & Ledford, H. K. (2022) · Nature · doi:10.1038/d41586-022-03086-9 · Cited by 3 · see citing works
A (Cross-)Cultural Look at Schizotypy
Cheli, S. (2023) · Springer eBooks · doi:10.1007/978-3-031-41788-7_7 · Cited by 2 · see citing works
Chen, Y., Yu, X., Xu, S., Shi, X., Zhang, X., & Sun, C. (2023) · Annals of Human Genetics · doi:10.1111/ahg.12533 · Cited by 2 · see citing works
The construct of schizophrenia as a human-specific condition
Stromeyer, C. (2022) · Schizophrenia Research · doi:10.1016/j.schres.2022.02.023 · Cited by 2 · see citing works
Gregory, M. D., & Berman, K. F. (2022) · Neuropsychopharmacology · doi:10.1038/s41386-022-01396-0 · Cited by 2 · see citing works
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Morez, A., Soltantouyeh, A., Zeloni, R., Carollo, F., Mezzavilla, M., Marnetto, D., & Pagani, L. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.04.03.716297 · Cited by 2 · see citing works
Neanderthals and us: Towards a philosophy of deep history
Zwart, H. A. E., & Soressi, M. (2022) · Internationales Jahrbuch für Philosophische Anthropologie · doi:10.1515/jbpa-2022-0002 · Cited by 1 · see citing works
Núñez, C., Serra‐Arumí, C., Butjosa, A., Amoretti, S., Martínez‐Arán, A., Janssen, J., Mezquida, G., Vieta, E., Andrés-Camazón, P., Cuesta, M. J., et al. (2025) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2025.08.004 · Cited by 1 · see citing works
Adaptive introgression in modern human circadian rhythm genes
Kendall, C., Nooranikhojasteh, A., Debortoli, G., Roberto, V. C. F., de Aquino, M. M., Samson, D. R., Parra, E. J., Viola, B., & Schillaci, M. A. (2025) · npj Biological Timing and Sleep · doi:10.1038/s44323-025-00060-2 · Cited by 1 · see citing works
Chikhi, L., Racine, J., Tournebize, R., & Pocheville, A. (2026) · Evolutionary Biology/Evolutionary biology · doi:10.1007/978-3-032-13925-2_10 · Cited by 1 · see citing works
From Protective Factors to Mechanisms: Charting the Neurobiology of Schizophrenia Resilience
Bittner, R. A., Barnes-Scheufler, C. V., Reif, A., & Qubad, M. (2026) · Schizophrenia Bulletin · doi:10.1093/schbul/sbag146 · Cited by 1 · see citing works
Evolutionary Aspects of Schizotypy
Cheli, S., & Brüne, M. (2023) · Springer eBooks · doi:10.1007/978-3-031-41788-7_2 · Cited by 1 · see citing works
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Goswami, T. (2022) · Indian Journal of Animal Health · doi:10.36062/ijah.2022.spl.14722
How to Elucidate Functional Genomic Differences between Extinct Organisms and Their Extant Relatives
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- Authors
- Gregory, M. D., Eisenberg, D. P., Hamborg, M., Kippenhan, J. S., Kohn, P., Kolachana, B., Dickinson, D., & Berman, K. F.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Gregory, Michael D.
- ORCID
- Venue
- American Journal of Medical Genetics Part B: Neuropsychiatric Genetics
- Publisher
- Wiley
- Published
- 2021-07
- Volume
- 186
- Issue
- 5
- Pages
- 329-338
- ISSN
- 1552-4841 (ISSN-L)
- 1552-485X
- PMC
- PMC8454493
- OpenAlex
- W3197793201
- Cited by
- 24
- References
- 46
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 2 · 2023: 5 · 2022: 8
- FWCI
- 2.69
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Medical Genetics Part B Neuropsychiatric Genetics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (Z99 MH999999)
- National Institute of Mental Health (RC2MH089964, U01MH046276, R01MH059566, U01MH046318, R01MH059571, R01MH060879, R01MH059565, R01MH081800, R01MH060870, U01MH046289, U01MH079469, R01MH061675, ZIAMH002717, R01MH059586, R01MH059588, R01MH067257, U01MH079470, ZIAMH002942, R01MH084098, R01MH059587, ZIAMH002652)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Social Sciences › Anthropology › Pleistocene-Era Hominins and Archaeology
- Keywords
- Neanderthal admixture, schizophrenia, Neanderthal introgression, psychotic symptoms, dopamine synthesis, striatum, positive symptoms, schizophrenia risk
- MeSH terms
- Animals, Dopamine, Humans, Psychotic Disorders, Schizophrenia, Genetic Variation, Hominidae, Neanderthals
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