ArticleSchizophrenia bulletin2016
Recent Positive Selection Drives the Expansion of a Schizophrenia Risk Nonsynonymous Variant at SLC39A8 in Europeans.
Article in Schizophrenia bulletin, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 44 citations in OpenAlex.
- Analysis of whole exome sequencing in severe mental illness hints at selection of brain development and immune related genes.Scientific reports · 2021Trial
- Manganese: biology, physiology and role in disease.Cell discovery · 2026Review
- ZIP8 loss impairs macrophage-mediated phagolysosomal removal of bacteria and is overcome by butyrate supplementation.Communications biology · 2026Article
- Zinc Transporter Gene Variants (SLC30A and SLC39A) in Human Disease: From Metal Homeostasis Disruption to Convergent Signaling Pathways.Human mutation · 2026Review
- The Role of SLC39A8.p.(Ala391Thr) in Schizophrenia Symptom Severity and Cognitive Ability: Cross-Sectional Studies of Schizophrenia and the General UK Population.American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics · 2025Article
- Metal Transporter GeneNutrients · 2025Article
- Human genetic variants in SLC39A8 impact uptake and steady-state metal levels within the cell.Life science alliance · 2025Article
- Cross-ancestry and sex-stratified genome-wide association analyses of amygdala and subnucleus volumes.Nature genetics · 2025Article
- Neuronal SLC39A8 deficiency impairs cerebellar development by altering manganese homeostasis.JCI insight · 2024Article
- SLC39A8.p.(Ala391Thr) is associated with poorer cognitive ability: a cross-sectional study of schizophrenia and the general UK population.medRxiv : the preprint server for health sciences · 2024Article
- Crohn's Disease-Associated Pathogenic Mutation in the Manganese Transporter ZIP8 Shifts the Ileal and Rectal Mucosal Microbiota Implicating Aberrant Bile Acid Metabolism.Inflammatory bowel diseases · 2024Article
- Asian-European differentiation of schizophrenia-associated genes driven by admixture and natural selection.iScience · 2024Article
- Recent natural selection conferred protection against schizophrenia by non-antagonistic pleiotropy.Scientific reports · 2023Article
- Genomic findings in schizophrenia and their implications.Molecular psychiatry · 2023Review
- The schizophrenia-associated missense variant rs13107325 regulates dendritic spine density.Translational psychiatry · 2022Article
- Review
- The schizophrenia-associated variant in SLC39A8 alters protein glycosylation in the mouse brain.Molecular psychiatry · 2022Article
- Translational genomics and beyond in bipolar disorder.Molecular psychiatry · 2021Review
- Glycobiology and schizophrenia: a biological hypothesis emerging from genomic research.Molecular psychiatry · 2020Review
- Pleiotropic ZIP8 A391T implicates abnormal manganese homeostasis in complex human disease.JCI insight · 2020Article
Corrections and comments
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Authors and funding
14 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Natural selection has played important roles in optimizing complex human adaptations. However, schizophrenia poses an evolutionary paradox during human evolution, as the illness has strongly negative effects on fitness, but persists with a prevalence of ~0.5% across global populations. Recent studies have identified numerous risk variations in diverse populations, which might be able to explain the stable and high rate of schizophrenia morbidity in different cultures and regions, but the questions about why the risk alleles derived and maintained in human gene pool still remain unsolved. Here, we studied the evolutionary pattern of a schizophrenia risk variant rs13107325 (P < 5.0 × 10(-8) in Europeans) in the SLC39A8 gene. We found the SNP is monomorphic in Asians and Africans with risk (derived) T-allele totally absent, and further evolutionary analyses showed the T-allele has experienced recent positive selection in Europeans. Subsequent exploratory analyses implicated that the colder environment in Europe was the likely selective pressures, ie, when modern humans migrated "out of Africa" and moved to Europe mainland (a colder and cooler continent than Africa), new alleles derived due to positive selection and protected humans from risk of hypertension and also helped them adapt to the cold environment. The hypothesis was supported by our pleiotropic analyses with hypertension and energy intake as well as obesity in Europeans. Our data thus provides an intriguing example to illustrate a possible mechanism for maintaining schizophrenia risk alleles in the human gene pool, and further supported that schizophrenia is likely a product caused by pleiotropic effect during human evolution.
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