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Article ; Online: Coexpression network analysis of the adult brain sheds light on the pathogenic mechanism of DDR1 in schizophrenia and bipolar disorder.

Aranda, Selena / Muntané, Gerard / Vilella, Elisabet

2024 Volume 14, Issue 1, Page(s) 112

Abstract: DDR1 has been linked to schizophrenia (SCZ) and bipolar disorder (BD) in association studies. DDR1 encodes 58 distinct transcripts, which can be translated into five isoforms (DDR1a-e) and are expressed in the brain. However, the transcripts expressed in ...

Abstract	DDR1 has been linked to schizophrenia (SCZ) and bipolar disorder (BD) in association studies. DDR1 encodes 58 distinct transcripts, which can be translated into five isoforms (DDR1a-e) and are expressed in the brain. However, the transcripts expressed in each brain cell type, their functions and their involvement in SCZ and BD remain unknown. Here, to infer the processes in which DDR1 transcripts are involved, we used transcriptomic data from the human brain dorsolateral prefrontal cortex of healthy controls (N = 936) and performed weighted gene coexpression network analysis followed by enrichment analyses. Then, to explore the involvement of DDR1 transcripts in SCZ (N = 563) and BD (N = 222), we studied the association of coexpression modules with disease and performed differential expression and transcript significance analyses. Some DDR1 transcripts were distributed across five coexpression modules identified in healthy controls (M
MeSH term(s)	Adult ; Humans ; Bipolar Disorder/genetics ; Bipolar Disorder/metabolism ; Brain/metabolism ; Discoidin Domain Receptor 1/genetics ; Discoidin Domain Receptor 1/metabolism ; Gene Expression Profiling ; Schizophrenia/genetics ; Schizophrenia/metabolism ; Transcriptome
Chemical Substances	DDR1 protein, human (EC 2.7.10.1) ; Discoidin Domain Receptor 1 (EC 2.7.10.1)
Language	English
Publishing date	2024-02-23
Publishing country	United States
Document type	Journal Article
ZDB-ID	2609311-X
ISSN	2158-3188 ; 2158-3188
ISSN (online)	2158-3188
ISSN	2158-3188
DOI	10.1038/s41398-024-02823-0
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Article ; Online: Coexpression of the discoidin domain receptor 1 gene with oligodendrocyte-related and schizophrenia risk genes in the developing and adult human brain.

Muntané, Gerard / Chillida, Marc / Aranda, Selena / Navarro, Arcadi / Vilella, Elisabet

Brain and behavior

2021 Volume 11, Issue 8, Page(s) e2309

Abstract: Background: Discoidin domain receptor tyrosine kinase 1 (DDR1) is present in multiple types of epithelial cells and is highly expressed in the nervous system. Previous studies have revealed that DDR1 is involved in schizophrenia (SCZ). Although the ... ...

Abstract	Background: Discoidin domain receptor tyrosine kinase 1 (DDR1) is present in multiple types of epithelial cells and is highly expressed in the nervous system. Previous studies have revealed that DDR1 is involved in schizophrenia (SCZ). Although the expression of DDR1 in oligodendrocytes has been described, its role in brain myelination is not well understood. In this study, we aimed to explore the coexpression network of DDR1 in the human brain and to compare the list of DDR1 coexpressing genes with the list of genes containing single nucleotide polymorphisms (SNPs) that are associated with SCZ. Materials and methods: We used a weighted gene coexpression network analysis (WGCNA) of a dataset from four brain areas (the dorsolateral prefrontal cortex, primary motor cortex, hippocampus, and striatum) and from four different intervals (I) of life (I-1 = 10-38 weeks postconception, I-2 ≥0 to < 6 years, I-3 ≥ 6 to < 40 years, and I-4 ≥ 40 years of age). We compared the list of genes that are associated with SCZ in the GWAS Catalog with the list of genes coexpressing with DDR1 in each interval. Results: Our study revealed that DDR1 was coexpressed with oligodendrocyte-related genes mainly in I-2 (adjP = 5.66e-24) and I-3 (adjP = 2.8e-114), which coincided with the coexpression of DDR1 with myelination-related genes (adjP = 9.04e-03 and 2.51e-08, respectively). DDR1 was also coexpressed with astrocyte-related genes in I-1 (adjP = 1.11e-71), I-2 (adjP = 2.12e-20) and I-4 (adjP = 9.93e-52) and with type 2 microglia-related genes in I-1 (adjP = 2.84e-08), I-2 (adjP = 5.68e-16) and I-4 (adjP = 3.66e-10). Moreover, we observed significant enrichment of SCZ susceptibility genes within the coexpression modules containing DDR1 in I-1 and I-4 (P = 1e-04 and 0.0037, respectively), during which the DDR1 module showed the highest association with the astrocytes. Conclusions: Our study confirmed that DDR1 is coexpressed with oligodendrocyte- and myelin-related genes in the human brain but suggests that DDR1 may contribute mainly to SCZ risk through its role in other glial cell types, such as astrocytes.
MeSH term(s)	Brain ; Discoidin Domain Receptor 1/genetics ; Discoidin Domain Receptor 1/metabolism ; Humans ; Oligodendroglia ; Receptor Protein-Tyrosine Kinases/genetics ; Schizophrenia/genetics
Chemical Substances	DDR1 protein, human (EC 2.7.10.1) ; Discoidin Domain Receptor 1 (EC 2.7.10.1) ; Receptor Protein-Tyrosine Kinases (EC 2.7.10.1)
Language	English
Publishing date	2021-07-29
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2623587-0
ISSN	2162-3279 ; 2162-3279
ISSN (online)	2162-3279
ISSN	2162-3279
DOI	10.1002/brb3.2309
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Article ; Online: Polygenic risk scores enhance prediction of body mass index increase in individuals with a first episode of psychosis.

Muntané, Gerard / Vázquez-Bourgon, Javier / Sada, Ester / Martorell, Lourdes / Papiol, Sergi / Bosch, Elena / Navarro, Arcadi / Crespo-Facorro, Benedicto / Vilella, Elisabet

European psychiatry : the journal of the Association of European Psychiatrists

2023 Volume 66, Issue 1, Page(s) e28

Abstract: Background: Individuals with a first episode of psychosis (FEP) show rapid weight gain during the first months of treatment, which is associated with a reduction in general physical health. Although genetics is assumed to be a significant contributor to ...

Abstract	Background: Individuals with a first episode of psychosis (FEP) show rapid weight gain during the first months of treatment, which is associated with a reduction in general physical health. Although genetics is assumed to be a significant contributor to weight gain, its exact role is unknown. Methods: We assembled a population-based FEP cohort of 381 individuals that was split into a Training ( Results: The results confirmed considerable shared genetic susceptibility for the two traits involving 449 near-independent genomic loci. The inclusion of BMI PRSs significantly improved the prediction of ∆BMI at 12 months after the onset of antipsychotic treatment by 49.4% compared to a clinical model. In addition, we demonstrated that the PRS containing pleiotropic information between BMI and SCZ predicted ∆BMI better at 3 (12.2%) and 12 months (53.2%). Conclusions: We prove for the first time that genetic factors play a key role in determining ∆BMI during the FEP. This finding has important clinical implications for the early identification of individuals most vulnerable to weight gain and highlights the importance of examining genetic pleiotropy in the context of medically important comorbidities for predicting future outcomes.
MeSH term(s)	Humans ; Body Mass Index ; Genome-Wide Association Study ; Psychotic Disorders/drug therapy ; Risk Factors ; Weight Gain
Language	English
Publishing date	2023-02-28
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1074337-6
ISSN	1778-3585 ; 0767-399X ; 0924-9338
ISSN (online)	1778-3585
ISSN	0767-399X ; 0924-9338
DOI	10.1192/j.eurpsy.2023.9
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Zs.A 2369: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: CAAStools: a toolbox to identify and test Convergent Amino Acid Substitutions.

Barteri, Fabio / Valenzuela, Alejandro / Farré, Xavier / de Juan, David / Muntané, Gerard / Esteve-Altava, Borja / Navarro, Arcadi

Bioinformatics (Oxford, England)

2023 Volume 39, Issue 10

Abstract: Motivation: Coincidence of Convergent Amino Acid Substitutions (CAAS) with phenotypic convergences allow pinpointing genes and even individual mutations that are likely to be associated with trait variation within their phylogenetic context. Such ... ...

Abstract	Motivation: Coincidence of Convergent Amino Acid Substitutions (CAAS) with phenotypic convergences allow pinpointing genes and even individual mutations that are likely to be associated with trait variation within their phylogenetic context. Such findings can provide useful insights into the genetic architecture of complex phenotypes. Results: Here we introduce CAAStools, a set of bioinformatics tools to identify and validate CAAS in orthologous protein alignments for predefined groups of species representing the phenotypic values targeted by the user. Availability and implementation: CAAStools source code is available at http://github.com/linudz/caastools, along with documentation and examples.
MeSH term(s)	Phylogeny ; Amino Acid Substitution ; Computational Biology ; Software ; Documentation
Language	English
Publishing date	2023-10-16
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1422668-6
ISSN	1367-4811 ; 1367-4803
ISSN (online)	1367-4811
ISSN	1367-4803
DOI	10.1093/bioinformatics/btad623
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Zs.A 2374: Show issues

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Article ; Online: Gradual Increase in Inflammation-Linked Glycoproteins and a Proatherogenic Lipoprotein Profile in the Early Stages of Psychosis as Characterized by

Gallart-Palau, Xavier / Muntané, Gerard / Martorell, Lourdes / Amigó, Núria / Correig, Xavier / Ribalta, Josep / Sánchez-Gistau, Vanessa / Labad, Javier / Vilella, Elisabet

Journal of proteome research

2023 Volume 22, Issue 7, Page(s) 2271–2280

Abstract: Minimally invasive prognostic markers of inflammation and dyslipidemia in individuals with a risk of psychosis, also called "at-risk mental state" (ARMS), or in the first episode of psychosis (FEP) are of utmost clinical importance to prevent ... ...

Abstract	Minimally invasive prognostic markers of inflammation and dyslipidemia in individuals with a risk of psychosis, also called "at-risk mental state" (ARMS), or in the first episode of psychosis (FEP) are of utmost clinical importance to prevent cardiovascular disorders. We analyzed the plasma concentration of inflammation-linked glycoproteins (Glycs) and lipoprotein subclasses by proton nuclear magnetic resonance (
MeSH term(s)	Humans ; Proton Magnetic Resonance Spectroscopy ; Inflammation/metabolism ; Lipoproteins ; Psychotic Disorders/diagnosis ; Magnetic Resonance Spectroscopy ; Biomarkers ; Glycoproteins
Chemical Substances	Lipoproteins ; Biomarkers ; Glycoproteins
Language	English
Publishing date	2023-06-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2078618-9
ISSN	1535-3907 ; 1535-3893
ISSN (online)	1535-3907
ISSN	1535-3893
DOI	10.1021/acs.jproteome.2c00847
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Article ; Online: Comprehensive summary of mitochondrial DNA alterations in the postmortem human brain: A systematic review.

Valiente-Pallejà, Alba / Tortajada, Juan / Bulduk, Bengisu K / Vilella, Elisabet / Garrabou, Glòria / Muntané, Gerard / Martorell, Lourdes

EBioMedicine

2022 Volume 76, Page(s) 103815

Abstract: Background: Mitochondrial DNA (mtDNA) encodes 37 genes necessary for synthesizing 13 essential subunits of the oxidative phosphorylation system. mtDNA alterations are known to cause mitochondrial disease (MitD), a clinically heterogeneous group of ... ...

Abstract	Background: Mitochondrial DNA (mtDNA) encodes 37 genes necessary for synthesizing 13 essential subunits of the oxidative phosphorylation system. mtDNA alterations are known to cause mitochondrial disease (MitD), a clinically heterogeneous group of disorders that often present with neuropsychiatric symptoms. Understanding the nature and frequency of mtDNA alterations in health and disease could be a cornerstone in disentangling the relationship between biochemical findings and clinical symptoms of brain disorders. This systematic review aimed to summarize the mtDNA alterations in human brain tissue reported to date that have implications for further research on the pathophysiological significance of mtDNA alterations in brain functioning. Methods: We searched the PubMed and Embase databases using distinct terms related to postmortem human brain and mtDNA up to June 10, 2021. Reports were eligible if they were empirical studies analysing mtDNA in postmortem human brains. Findings: A total of 158 of 637 studies fulfilled the inclusion criteria and were clustered into the following groups: MitD (48 entries), neurological diseases (NeuD, 55 entries), psychiatric diseases (PsyD, 15 entries), a miscellaneous group with controls and other clinical diseases (5 entries), ageing (20 entries), and technical issues (5 entries). Ten entries were ascribed to more than one group. Pathogenic single nucleotide variants (pSNVs), both homo- or heteroplasmic variants, have been widely reported in MitD, with heteroplasmy levels varying among brain regions; however, pSNVs are rarer in NeuD, PsyD and ageing. A lower mtDNA copy number (CN) in disease was described in most, but not all, of the identified studies. mtDNA deletions were identified in individuals in the four clinical categories and ageing. Notably, brain samples showed significantly more mtDNA deletions and at higher heteroplasmy percentages than blood samples, and several of the deletions present in the brain were not detected in the blood. Finally, mtDNA heteroplasmy, mtDNA CN and the deletion levels varied depending on the brain region studied. Interpretation: mtDNA alterations are well known to affect human tissues, including the brain. In general, we found that studies of MitD, NeuD, PsyD, and ageing were highly variable in terms of the type of disease or ageing process investigated, number of screened individuals, studied brain regions and technology used. In NeuD and PsyD, no particular type of mtDNA alteration could be unequivocally assigned to any specific disease or diagnostic group. However, the presence of mtDNA deletions and mtDNA CN variation imply a role for mtDNA in NeuD and PsyD. Heteroplasmy levels and threshold effects, affected brain regions, and mitotic segregation patterns of mtDNA alterations may be involved in the complex inheritance of NeuD and PsyD and in the ageing process. Therefore, more information is needed regarding the type of mtDNA alteration, the affected brain regions, the heteroplasmy levels, and their relationship with clinical phenotypes and the ageing process. Funding: Hospital Universitari Institut Pere Mata; Institut d'Investigació Sanitària Pere Virgili; Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (PI18/00514).
MeSH term(s)	Brain ; DNA, Mitochondrial/genetics ; Humans ; Mitochondria/genetics ; Mitochondrial Diseases/genetics ; Mutation
Chemical Substances	DNA, Mitochondrial
Language	English
Publishing date	2022-01-24
Publishing country	Netherlands
Document type	Journal Article ; Systematic Review
ZDB-ID	2851331-9
ISSN	2352-3964
ISSN (online)	2352-3964
DOI	10.1016/j.ebiom.2022.103815
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Article ; Online: Increased blood lactate levels during exercise and mitochondrial DNA alterations converge on mitochondrial dysfunction in schizophrenia.

Valiente-Pallejà, Alba / Torrell, Helena / Alonso, Yolanda / Vilella, Elisabet / Muntané, Gerard / Martorell, Lourdes

Schizophrenia research

2020 Volume 220, Page(s) 61–68

Abstract: Background: Mitochondrial dysfunction and an elevation of lactate are observed in patients with schizophrenia (SZ). However, it is unknown whether mitochondrial dysfunction is associated with the presence of mitochondrial DNA (mtDNA) alterations and ... ...

Abstract	Background: Mitochondrial dysfunction and an elevation of lactate are observed in patients with schizophrenia (SZ). However, it is unknown whether mitochondrial dysfunction is associated with the presence of mitochondrial DNA (mtDNA) alterations and comorbid clinical conditions. We aimed to identify systemic mitochondrial abnormalities in blood samples of patients with SZ that may have a high impact on the brain due to its high bioenergetic requirements. Methods: Case/control study between 57 patients with SZ and 33 healthy controls (HCs). We measured lactate levels at baseline, during 15 min of exercise (at 5, 10 and 15 min) and at rest. We also evaluated the presence of clinical conditions associated with mitochondrial disorders (CAMDs), measured the neutrophil to lymphocyte ratio (NLR, a subclinical inflammatory marker), and analyzed mtDNA variation and copy number. Results: Linear models adjusting for covariates showed that patients with SZ exhibited higher elevation of lactate than HCs during exercise but not at baseline or at rest. In accordance, patients showed higher number of CAMDs and lower mtDNA copy number. Interestingly, CAMDs correlated with both lactate levels and mtDNA copy number, which in turn correlated with the NLR. Finally, we identified 13 putative pathogenic variants in the mtDNA of 11 participants with SZ not present in HCs, together with a lactate elevation during exercise that was significantly higher in these 11 carriers than in the noncarriers. Conclusions: These results are consistent with systemic mitochondrial malfunctioning in SZ and pinpoint lactate metabolism and mtDNA as targets for potential therapeutic treatments.
MeSH term(s)	DNA Copy Number Variations/genetics ; DNA, Mitochondrial/genetics ; Humans ; Lactates ; Mitochondria/genetics ; Mitochondrial Diseases/genetics ; Schizophrenia/genetics
Chemical Substances	DNA, Mitochondrial ; Lactates
Language	English
Publishing date	2020-04-21
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639422-x
ISSN	1573-2509 ; 0920-9964
ISSN (online)	1573-2509
ISSN	0920-9964
DOI	10.1016/j.schres.2020.03.070
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Zs.A 2351: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: The shared genetic architecture of schizophrenia, bipolar disorder and lifespan.

Muntané, Gerard / Farré, Xavier / Bosch, Elena / Martorell, Lourdes / Navarro, Arcadi / Vilella, Elisabet

Human genetics

2020 Volume 140, Issue 3, Page(s) 441–455

Abstract: Psychiatric disorders such as Schizophrenia (SCZ) and Bipolar Disorder (BD) represent an evolutionary paradox, as they exhibit strong negative effects on fitness, such as decreased fecundity and early mortality, yet they persist at a worldwide prevalence ...

Abstract	Psychiatric disorders such as Schizophrenia (SCZ) and Bipolar Disorder (BD) represent an evolutionary paradox, as they exhibit strong negative effects on fitness, such as decreased fecundity and early mortality, yet they persist at a worldwide prevalence of approximately 1%. Molecular mechanisms affecting lifespan, which may be widely common among complex diseases with fitness effects, can be studied by the integrated analysis of data from genome-wide association studies (GWAS) of human longevity together with any disease of interest. Here, we report the first of such studies, focusing on the genetic overlap-pleiotropy-between two psychiatric disorders with shortened lifespan, SCZ and BD, and human parental lifespan (PLS) as a surrogate of life expectancy. Our results are twofold: first, we demonstrate extensive polygenic overlap between SCZ and PLS and to a lesser extent between BD and PLS. Second, we identified novel loci shared between PLS and SCZ (n = 39), and BD (n = 8). Whereas most of the identified SCZ (66%) and BD (62%) pleiotropic risk alleles were associated with reduced lifespan, we also detected some antagonistic protective alleles associated to shorter lifespans. In fact, top-associated SNPs with SCZ seems to explain longevity variance explained (LVE) better than many other life-threatening diseases, including Type 2 diabetes and most cancers, probably due to a high overlap with smoking-related pathways. Overall, our study provides evidence of a genetic burden driven through premature mortality among people with SCZ, which can have profound implications for understanding, and potentially treating, the mortality gap associated with this psychiatric disorder.
MeSH term(s)	Bipolar Disorder/genetics ; Case-Control Studies ; Evolution, Molecular ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Humans ; Linkage Disequilibrium ; Longevity/genetics ; Polymorphism, Single Nucleotide ; Schizophrenia/genetics
Language	English
Publishing date	2020-08-09
Publishing country	Germany
Document type	Journal Article
ZDB-ID	223009-4
ISSN	1432-1203 ; 0340-6717
ISSN (online)	1432-1203
ISSN	0340-6717
DOI	10.1007/s00439-020-02213-8
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Zs.A 256: Show issues

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Article ; Online: DDR1 and Its Ligand, Collagen IV, Are Involved in In Vitro Oligodendrocyte Maturation.

Silva, Maria Elena / Hernández-Andrade, Matías / Abasolo, Nerea / Espinoza-Cruells, Cristóbal / Mansilla, Josselyne B / Reyes, Carolina R / Aranda, Selena / Esteban, Yaiza / Rodriguez-Calvo, Ricardo / Martorell, Lourdes / Muntané, Gerard / Rivera, Francisco J / Vilella, Elisabet

International journal of molecular sciences

2023 Volume 24, Issue 2

Abstract: Discoidin domain receptor 1 (DDR1) is a tyrosine kinase receptor expressed in epithelial cells from different tissues in which collagen binding activates pleiotropic functions. In the brain, DDR1 is mainly expressed in oligodendrocytes (OLs), the ... ...

Abstract	Discoidin domain receptor 1 (DDR1) is a tyrosine kinase receptor expressed in epithelial cells from different tissues in which collagen binding activates pleiotropic functions. In the brain, DDR1 is mainly expressed in oligodendrocytes (OLs), the function of which is unclear. Whether collagen can activate DDR1 in OLs has not been studied. Here, we assessed the expression of DDR1 during in vitro OL differentiation, including collagen IV incubation, and the capability of collagen IV to induce DDR1 phosphorylation. Experiments were performed using two in vitro models of OL differentiation: OLs derived from adult rat neural stem cells (NSCs) and the HOG16 human oligodendroglial cell line. Immunocytofluorescence, western blotting, and ELISA were performed to analyze these questions. The differentiation of OLs from NSCs was addressed using oligodendrocyte transcription factor 2 (Olig2) and myelin basic protein (MBP). In HOG16 OLs, collagen IV induced DDR1 phosphorylation through slow and sustained kinetics. In NSC-derived OLs, DDR1 was found in a high proportion of differentiating cells (MBP+/Olig2+), but its protein expression was decreased in later stages. The addition of collagen IV did not change the number of DDR1+/MBP+ cells but did accelerate OL branching. Here, we provide the first demonstration that collagen IV mediates the phosphorylation of DDR1 in HOG16 cells and that the in vitro co-expression of DDR1 and MBP is associated with accelerated branching during the differentiation of primary OLs.
MeSH term(s)	Rats ; Humans ; Animals ; Discoidin Domain Receptor 1/metabolism ; Ligands ; Receptor Protein-Tyrosine Kinases ; Collagen Type IV/metabolism ; Oligodendroglia/metabolism
Chemical Substances	Discoidin Domain Receptor 1 (EC 2.7.10.1) ; Ligands ; Receptor Protein-Tyrosine Kinases (EC 2.7.10.1) ; Collagen Type IV ; DDR1 protein, human (EC 2.7.10.1)
Language	English
Publishing date	2023-01-16
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms24021742
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Article ; Online: Human genetic adaptation related to cellular zinc homeostasis.

Roca-Umbert, Ana / Garcia-Calleja, Jorge / Vogel-González, Marina / Fierro-Villegas, Alejandro / Ill-Raga, Gerard / Herrera-Fernández, Víctor / Bosnjak, Anja / Muntané, Gerard / Gutiérrez, Esteban / Campelo, Felix / Vicente, Rubén / Bosch, Elena

PLoS genetics

2023 Volume 19, Issue 9, Page(s) e1010950

Abstract: SLC30A9 encodes a ubiquitously zinc transporter (ZnT9) and has been consistently suggested as a candidate for positive selection in humans. However, no direct adaptive molecular phenotype has been demonstrated. Our results provide evidence for ... ...

Abstract	SLC30A9 encodes a ubiquitously zinc transporter (ZnT9) and has been consistently suggested as a candidate for positive selection in humans. However, no direct adaptive molecular phenotype has been demonstrated. Our results provide evidence for directional selection operating in two major complementary haplotypes in Africa and East Asia. These haplotypes are associated with differential gene expression but also differ in the Met50Val substitution (rs1047626) in ZnT9, which we show is found in homozygosis in the Denisovan genome and displays accompanying signatures suggestive of archaic introgression. Although we found no significant differences in systemic zinc content between individuals with different rs1047626 genotypes, we demonstrate that the expression of the derived isoform (ZnT9 50Val) in HEK293 cells shows a gain of function when compared with the ancestral (ZnT9 50Met) variant. Notably, the ZnT9 50Val variant was found associated with differences in zinc handling by the mitochondria and endoplasmic reticulum, with an impact on mitochondrial metabolism. Given the essential role of the mitochondria in skeletal muscle and since the derived allele at rs1047626 is known to be associated with greater susceptibility to several neuropsychiatric traits, we propose that adaptation to cold may have driven this selection event, while also impacting predisposition to neuropsychiatric disorders in modern humans.
MeSH term(s)	Animals ; Humans ; HEK293 Cells ; Hominidae/genetics ; Homeostasis/genetics ; Zinc ; Human Genetics ; Selection, Genetic ; Haplotypes ; Genome, Human
Chemical Substances	Zinc (J41CSQ7QDS)
Language	English
Publishing date	2023-09-25
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2186725-2
ISSN	1553-7404 ; 1553-7390
ISSN (online)	1553-7404
ISSN	1553-7390
DOI	10.1371/journal.pgen.1010950
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