The highly pleiotropic gene SLC39A8 as an opportunity to gain insight into the molecular pathogenesis of schizophrenia
Open accessAbstract
There is a long way from the initial discovery of a genome‐wide significant signal to mechanistic understanding of the association. Identification of the gene and causal polymorphism usually requires an extensive additional effort. The schizophrenia genome‐wide significant locus at 4q24 may be a rare exception to this pattern. As discussed in this review, the association at this locus is most probably driven by a functional missense variant at the metal cations transporter SLC39A8. The variant, rs13107325, is almost exclusive of European populations and is one of the most pleiotropic variants of the genome, being associated at genome‐wide significant level with several additional traits, such as body mass index, Crohn's disease, blood pressure related‐traits, and serum levels of manganese, N‐terminal pro‐B‐type natriuretic peptide and HDL‐cholesterol. SLC39A8 seems to be subject to recent natural selection in Europeans. It is almost ubiquitously expressed and its physiological role is beginning to be elucidated, mainly in relation to immunity. This manuscript presents arguments in favor of the rs13107325 variant as the functional variant responsible for the association of this locus with schizophrenia, reviews the genetic associations with this gene, the evidences of natural selection on the gene, and the known aspects about its structure and physiological functions. Finally, some hypotheses about putative mechanisms for its association with schizophrenia are presented based on this knowledge, including impaired immunity/inflammation, interference with glutamatergic neurotransmission, homeostasis of essential metals in brain, such as iron, zinc or manganese, or neurotoxicity by heavy metals, such as cadmium or lead.
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A common variant in the gene SLC39A8 decreases a person's risk of developing hypertension and Parkinson's disease, but increases their risk of developing schizophrenia, Crohn's disease and obesity.
“A com mon variant in the gene SLC39A8 , for instance, decreases a person's risk of devel oping hypertension and Parkinson's dis ease, but increases their risk of developing schizophrenia, Crohn's disease and obesity 6 .”
From Adopt a moratorium on heritable genome editing (2019) · cites this paper as [6]
Section 3 and the association table report that the SLC39A8 variant is associated with schizophrenia and Crohn’s disease, higher body mass index, and lower blood pressure. The paper lists hypertension and Parkinson’s disease as near-significant associations, but the passages do not establish a reduced risk of Parkinson’s disease; higher body mass index is not itself a demonstrated increase in obesity risk. The claim also states the disease-risk associations more definitively than the paper does. (LLM, conf=0.86)
Experimental — accuracy not yet measuredModifying disease risk by replacing genetic variants with alternative ones is fraught with challenges, because variants that decrease the risk of some diseases often increase the risk of others.
“Modifying disease risk by replacing genetic variants with alternative ones is fraught with challenges, because variants that decrease the risk of some diseases often increase the risk of others.”
From Adopt a moratorium on heritable genome editing (2019) · cites this paper as [6]
Section 1 identifies the Thr allele as increasing schizophrenia risk, while Section 8 says the alternative Ala allele is associated with hypertension risk and describes the variant as a possible example of antagonistic pleiotropy. This supports a disease-risk trade-off for one variant, but the paper does not establish that such trade-offs occur often or discuss the practical challenges of replacing genetic variants. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe nonsynonymous variant in SLC39A8 affects zinc and manganese transport, is highly pleiotropic for complex phenotypes, and may impair inflammation, glutamatergic neurotransmission, and regulation of various metals.
“the nonsynonymous variant in SLC39A8 affects zinc and manganese transport, is highly pleiotropic for complex phenotypes, and may impair inflammation, glutamatergic neurotransmission, and regulation of various metals in the body48.”
From Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use (2019) · cites this paper as [48]
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- Authors
- Costas, J.
- Affiliations
- Instituto de Investigación Sanitaria de Santiago (ES)
- Corresponding author
- Costas, Javier
- ORCID
- Costas, Javier
- Venue
- American Journal of Medical Genetics Part B: Neuropsychiatric Genetics
- Publisher
- Wiley
- Published
- 2017-05-30
- Volume
- 177
- Issue
- 2
- Pages
- 274-283
- ISSN
- 1552-4841 (ISSN-L)
- 1552-485X
- OpenAlex
- W2618782704
- Cited by
- 58
- References
- 77
- Citations by year
- 2026: 4 · 2025: 8 · 2023: 4 · 2022: 12 · 2021: 6 · 2020: 8 · 2019: 11 · 2018: 4 · 2017: 1
- FWCI
- 1.00
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- American Journal of Medical Genetics Part B Neuropsychiatric Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Instituto de Salud Carlos III (PI14/01020)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
- Keywords
- SLC39A8, schizophrenia, pleiotropy, missense mutations, natural selection, immune function, inflammation, glutamatergic neurotransmission, manganese homeostasis, heavy metal neurotoxicity, Crohn's disease, body mass index, blood pressure, HDL cholesterol
- MeSH terms
- Humans, Phenotype, Schizophrenia, Polymorphism, Single Nucleotide, Cation Transport Proteins, Genome-Wide Association Study, Pathology, Molecular, Genetic Pleiotropy
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