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1. Human genetic adaptation related to cellular zinc homeostasis

Author

Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Ministerio de Ciencia e Innovación (España), Generalitat de Catalunya, Fundació Privada Cellex, Fundación Privada Mir-Puig, Instituto de Salud Carlos III, European Commission, Muntané, Gerard [0000-0003-1541-8365], Bosch, Elena [0000-0003-2848-103X], 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, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Ministerio de Ciencia e Innovación (España), Generalitat de Catalunya, Fundació Privada Cellex, Fundación Privada Mir-Puig, Instituto de Salud Carlos III, European Commission, Muntané, Gerard [0000-0003-1541-8365], Bosch, Elena [0000-0003-2848-103X], 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, and Bosch, Elena

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.

Published
2023

2. Identifying signatures of positive selection in human populations from North Africa

Author

Agencia Estatal de Investigación (España), European Commission, Ministerio de Ciencia, Innovación y Universidades (España), Ministerio de Ciencia e Innovación (España), Generalitat de Catalunya, Lucas-Sanchez, Marcel [0000-0001-6741-3959], Comas, David [0000-0002-5075-0956], Bosch, Elena [0000-0003-2848-103X], Caro-Consuegra, Rocio, Lucas-Sanchez, Marcel, Comas, David, Bosch, Elena, Agencia Estatal de Investigación (España), European Commission, Ministerio de Ciencia, Innovación y Universidades (España), Ministerio de Ciencia e Innovación (España), Generalitat de Catalunya, Lucas-Sanchez, Marcel [0000-0001-6741-3959], Comas, David [0000-0002-5075-0956], Bosch, Elena [0000-0003-2848-103X], Caro-Consuegra, Rocio, Lucas-Sanchez, Marcel, Comas, David, and Bosch, Elena

Abstract

Because of its location, North Africa (NA) has witnessed continuous demographic movements with an impact on the genomes of present-day human populations. Genomic data describe a complex scenario with varying proportions of at least four main ancestry components: Maghrebi, Middle Eastern-, European-, and West-and-East-African-like. However, the footprint of positive selection in NA has not been studied. Here, we compile genome-wide genotyping data from 190 North Africans and individuals from surrounding populations, investigate for signatures of positive selection using allele frequencies and linkage disequilibrium-based methods and infer ancestry proportions to discern adaptive admixture from post-admixture selection events. Our results show private candidate genes for selection in NA involved in insulin processing (KIF5A), immune function (KIF5A, IL1RN, TLR3), and haemoglobin phenotypes (BCL11A). We also detect signatures of positive selection related to skin pigmentation (SLC24A5, KITLG), and immunity function (IL1R1, CD44, JAK1) shared with European populations and candidate genes associated with haemoglobin phenotypes (HPSE2, HBE1, HBG2), other immune-related (DOCK2) traits, and insulin processing (GLIS3) traits shared with West and East African populations. Finally, the SLC8A1 gene, which codifies for a sodium-calcium exchanger, was the only candidate identified under post-admixture selection in Western NA.

Published
2023

3. Polygenic risk scores enhance prediction of body mass index increase in individuals with a first episode of psychosis

Author

Agència de Gestió d'Ajuts Universitaris i de Recerca, Instituto de Salud Carlos III, Plan Nacional sobre Drogas (España), Fundació Seny, Fundación Marques de Valdecilla, Ministerio de Economía y Competitividad (España), European Commission, Instituto de Investigación Marqués de Valdecilla, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Generalitat de Catalunya, Muntané, Gerard [0000-0003-1541-8365], Bosch, Elena [0000-0003-2848-103X], Navarro, Arcadi [0000-0003-2162-8246], Crespo-Facorro, Benedicto [0000-0003-0033-7132], Muntané, Gerard, Vázquez-Bourgon, Javier, Sada-Fuente, Ester, Martorell, Lourdes, Papiol, Sergi, Bosch, Elena, Navarro, Arcadi, Crespo-Facorro, Benedicto, Vilella, Elisabet, Agència de Gestió d'Ajuts Universitaris i de Recerca, Instituto de Salud Carlos III, Plan Nacional sobre Drogas (España), Fundació Seny, Fundación Marques de Valdecilla, Ministerio de Economía y Competitividad (España), European Commission, Instituto de Investigación Marqués de Valdecilla, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Generalitat de Catalunya, Muntané, Gerard [0000-0003-1541-8365], Bosch, Elena [0000-0003-2848-103X], Navarro, Arcadi [0000-0003-2162-8246], Crespo-Facorro, Benedicto [0000-0003-0033-7132], Muntané, Gerard, Vázquez-Bourgon, Javier, Sada-Fuente, Ester, Martorell, Lourdes, Papiol, Sergi, Bosch, Elena, Navarro, Arcadi, Crespo-Facorro, Benedicto, and Vilella, Elisabet

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 (n = 224) set and a Validation (n = 157) set to calculate the polygenic risk score (PRS) in a two-step process. In parallel, we obtained reference genome-wide association studies for body mass index (BMI) and schizophrenia (SCZ) to examine the pleiotropic landscape between the two traits. BMI PRSs were added to linear models that included sociodemographic and clinical variables to predict BMI increase (∆BMI) in the Validation set., [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.

Published
2023

4. DDR1 methylation is associated with bipolar disorder and the isoform expression and methylation of myelin genes

Author

García- Ruiz, Beatriz [0000-0001-9552-949X], Castro de Moura, Manuel [0000-0002-8488-5306], Muntané, Gerard [0000-0003-1541-8365], Martorell, Lourdes [0000-0003-4999-2197], Bosch, Elena [0000-0003-2848-103X], Esteller, Manel [0000-0003-4490-6093], Canales-Rodríguez, Erick Jorge [0000-0001-6421-2633], Pomarol-Clotet, Edith [0000-0002-8159-8563], Jiménez, Esther [0000-0001-6929-6207], Vieta, Eduard [0000-0002-0548-0053], Vilella, Elisabet [0000-0002-1887-5919], García-Ruiz, Beatriz, Castro de Moura, Manuel, Muntané, Gerard, Martorell, Lourdes, Bosch, Elena, Esteller, Manel, Canales-Rodríguez, Erick Jorge, Pomarol-Clotet, Edith, Jiménez, Esther, Vieta, Eduard, Vilella, Elisabet, García- Ruiz, Beatriz [0000-0001-9552-949X], Castro de Moura, Manuel [0000-0002-8488-5306], Muntané, Gerard [0000-0003-1541-8365], Martorell, Lourdes [0000-0003-4999-2197], Bosch, Elena [0000-0003-2848-103X], Esteller, Manel [0000-0003-4490-6093], Canales-Rodríguez, Erick Jorge [0000-0001-6421-2633], Pomarol-Clotet, Edith [0000-0002-8159-8563], Jiménez, Esther [0000-0001-6929-6207], Vieta, Eduard [0000-0002-0548-0053], Vilella, Elisabet [0000-0002-1887-5919], García-Ruiz, Beatriz, Castro de Moura, Manuel, Muntané, Gerard, Martorell, Lourdes, Bosch, Elena, Esteller, Manel, Canales-Rodríguez, Erick Jorge, Pomarol-Clotet, Edith, Jiménez, Esther, Vieta, Eduard, and Vilella, Elisabet

Abstract

[Aim] To investigate DDR1 methylation in the brains of bipolar disorder (BD) patients and its association with DDR1 mRNA levels and comethylation with myelin genes., [Materials & methods] Genome-wide profiling of DNA methylation (Infinium MethylationEPIC BeadChip) corrected for glial composition and DDR1 gene expression analysis in the occipital cortices of individuals with BD (n = 15) and healthy controls (n = 15) were conducted., [Results] DDR1 5-methylcytosine levels were increased and directly associated with DDR1b mRNA expression in the brains of BD patients. We also observed that DDR1 was comethylated with a group of myelin genes., [Conclusion] DDR1 is hypermethylated in BD brain tissue and is associated with isoform expression. Additionally, DDR1 comethylation with myelin genes supports the role of this receptor in myelination.

Published
2021

5. Macrophage-specific MHC II expression is regulated by a remote Ciita enhancer controlled by NFAT5

Author

Ministerio de Economía y Competitividad (España), Fundació La Marató de TV3, Generalitat de Catalunya, Ministerio de Educación, Cultura y Deporte (España), Fundació Catalunya-La Pedrera, Institución Catalana de Investigación y Estudios Avanzados, Buxadé, María [0000-0002-3020-8393], Riera-Borrull, Marta [0000-0003-4670-7290], López-Cotarelo, Pilar [0000-0003-1578-0110], Redondo, Juan Miguel [000-0001-5779-9122], Bosch, Elena [0000-0003-2848-103X], Buxadé, María, Huerga Encabo, Héctor, Riera-Borrull, Marta, Quintana-Gallardo, Lucía, López-Cotarelo, Pilar, Tellechea, Mónica, Martínez-Martínez, Sara, Redondo, Juan Miguel, Martín Caballero, Juan, Flores, Juana María, Bosch, Elena, Rodríguez-Fernández, José Luis, Aramburu, Jose, López-Rodríguez, Cristina, Ministerio de Economía y Competitividad (España), Fundació La Marató de TV3, Generalitat de Catalunya, Ministerio de Educación, Cultura y Deporte (España), Fundació Catalunya-La Pedrera, Institución Catalana de Investigación y Estudios Avanzados, Buxadé, María [0000-0002-3020-8393], Riera-Borrull, Marta [0000-0003-4670-7290], López-Cotarelo, Pilar [0000-0003-1578-0110], Redondo, Juan Miguel [000-0001-5779-9122], Bosch, Elena [0000-0003-2848-103X], Buxadé, María, Huerga Encabo, Héctor, Riera-Borrull, Marta, Quintana-Gallardo, Lucía, López-Cotarelo, Pilar, Tellechea, Mónica, Martínez-Martínez, Sara, Redondo, Juan Miguel, Martín Caballero, Juan, Flores, Juana María, Bosch, Elena, Rodríguez-Fernández, José Luis, Aramburu, Jose, and López-Rodríguez, Cristina

Abstract

MHCII in antigen-presenting cells (APCs) is a key regulator of adaptive immune responses. Expression of MHCII genes is controlled by the transcription coactivator CIITA, itself regulated through cell type-specific promoters. Here we show that the transcription factor NFAT5 is needed for expression of Ciita and MHCII in macrophages, but not in dendritic cells and other APCs. NFAT5-deficient macrophages showed defective activation of MHCII-dependent responses in CD4(+) T lymphocytes and attenuated capacity to elicit graft rejection in vivo. Ultrasequencing analysis of NFAT5-immunoprecipitated chromatin uncovered an NFAT5-regulated region distally upstream of Ciita. This region was required for CIITA and hence MHCII expression, exhibited NFAT5-dependent characteristics of active enhancers such as H3K27 acetylation marks, and required NFAT5 to interact with Ciita myeloid promoter I. Our results uncover an NFAT5-regulated mechanism that maintains CIITA and MHCII expression in macrophages and thus modulates their T lymphocyte priming capacity.

Published
2018

6. DDR1 methylation is associated with bipolar disorder and the isoform expression and methylation of myelin genes

Author

Edith Pomarol-Clotet, Elisabet Vilella, Gerard Muntané, Elena Bosch, Beatriz Garcia-Ruiz, Erick J. Canales-Rodríguez, Manel Esteller, Lourdes Martorell, Manuel Castro de Moura, Eduard Vieta, Esther Jiménez, García- Ruiz, Beatriz, Castro de Moura, Manuel, Muntané, Gerard, Martorell, Lourdes, Bosch, Elena, Esteller, Manel, Canales-Rodríguez, Erick Jorge, Pomarol-Clotet, Edith, Jiménez, Esther, Vieta, Eduard, Vilella, Elisabet, García- Ruiz, Beatriz [0000-0001-9552-949X], Castro de Moura, Manuel [0000-0002-8488-5306], Muntané, Gerard [0000-0003-1541-8365], Martorell, Lourdes [0000-0003-4999-2197], Bosch, Elena [0000-0003-2848-103X], Esteller, Manel [0000-0003-4490-6093], Canales-Rodríguez, Erick Jorge [0000-0001-6421-2633], Pomarol-Clotet, Edith [0000-0002-8159-8563], Jiménez, Esther [0000-0001-6929-6207], Vieta, Eduard [0000-0002-0548-0053], and Vilella, Elisabet [0000-0002-1887-5919]

Subjects
Gene isoform, Cancer Research, Bipolar disorder, Human brain, Biology, Methylation, Myelin genes, Myelin, Gene expression, Genetics, medicine, human brain, Gene, bipolar disorder, DDR1, Discoidin domain receptor 1, Molecular biology, discoidin domain receptor 1, medicine.anatomical_structure, DNA methylation, gene expression, methylation, myelin genes
Abstract

[Aim] To investigate DDR1 methylation in the brains of bipolar disorder (BD) patients and its association with DDR1 mRNA levels and comethylation with myelin genes., [Materials & methods] Genome-wide profiling of DNA methylation (Infinium MethylationEPIC BeadChip) corrected for glial composition and DDR1 gene expression analysis in the occipital cortices of individuals with BD (n = 15) and healthy controls (n = 15) were conducted., [Results] DDR1 5-methylcytosine levels were increased and directly associated with DDR1b mRNA expression in the brains of BD patients. We also observed that DDR1 was comethylated with a group of myelin genes., [Conclusion] DDR1 is hypermethylated in BD brain tissue and is associated with isoform expression. Additionally, DDR1 comethylation with myelin genes supports the role of this receptor in myelination.

Published
2021

7. Macrophage-specific MHCII expression is regulated by a remote Ciita enhancer controlled by NFAT5

Author

Pilar López-Cotarelo, Juan Martín-Caballero, Juan Miguel Redondo, Marta Riera-Borrull, Elena Bosch, Juana M. Flores, Cristina López-Rodríguez, Jose Aramburu, Sara Martínez-Martínez, José Luis Rodríguez-Fernández, Hector Huerga Encabo, Mónica Tellechea, Lucía Quintana-Gallardo, Maria Buxadé, Ministerio de Economía y Competitividad (España), Fundació La Marató de TV3, Generalitat de Catalunya, Ministerio de Educación, Cultura y Deporte (España), Fundació Catalunya-La Pedrera, Institución Catalana de Investigación y Estudios Avanzados, Buxadé, María, Riera-Borrull, Marta, López-Cotarelo, Pilar, Redondo, Juan Miguel, Bosch, Elena, Buxadé, María [0000-0002-3020-8393], Riera-Borrull, Marta [0000-0003-4670-7290], López-Cotarelo, Pilar [0000-0003-1578-0110], Redondo, Juan Miguel [000-0001-5779-9122], and Bosch, Elena [0000-0003-2848-103X]

Subjects
CD4-Positive T-Lymphocytes, 0301 basic medicine, Major histocompatibility, Immunology, Priming (immunology), chemical and pharmacologic phenomena, Adipose-tissue macrophages, Article, Mice, 03 medical and health sciences, CD4(+) T-cells, 0302 clinical medicine, NFAT5, medicine, CIITA, Animals, Immunology and Allergy, Gene-expression, Enhancer, Transcription factor, Research Articles, Gene Rearrangement, Mice, Knockout, Bare lymphocyte syndrome, Chemistry, Macrophages, Histocompatibility Antigens Class II, Nuclear Proteins, Allograft-rejection, Promoter, NF-Kappa-B, respiratory system, medicine.disease, IFN-Gamma, Cell biology, Transcription factor NFAT5, Enhancer Elements, Genetic, 030104 developmental biology, Gene Expression Regulation, Transcription Coactivator, Trans-Activators, Class-II transactivator, Transcription Factors, 030215 immunology
Abstract

25 p.-5 fig.-5 fig. supl.-2 tab. supl., MHCII in antigen-presenting cells (APCs) is a key regulator of adaptive immune responses. Expression of MHCII genes is controlled by the transcription coactivator CIITA, itself regulated through cell type-specific promoters. Here we show that the transcription factor NFAT5 is needed for expression of Ciita and MHCII in macrophages, but not in dendritic cells and other APCs. NFAT5-deficient macrophages showed defective activation of MHCII-dependent responses in CD4(+) T lymphocytes and attenuated capacity to elicit graft rejection in vivo. Ultrasequencing analysis of NFAT5-immunoprecipitated chromatin uncovered an NFAT5-regulated region distally upstream of Ciita. This region was required for CIITA and hence MHCII expression, exhibited NFAT5-dependent characteristics of active enhancers such as H3K27 acetylation marks, and required NFAT5 to interact with Ciita myeloid promoter I. Our results uncover an NFAT5-regulated mechanism that maintains CIITA and MHCII expression in macrophages and thus modulates their T lymphocyte priming capacity., This work was supported by the Spanish Ministry of Economy and Competitiveness (MINECO), Agencia Estatal de Investigación, and European Regional Development Fund(SAF2012-36535, SAF2015-71363-R, and BFU2016-77961-P), and Fundació la Marató de TV3 (1225-30 and 201619-30). We also acknowledge funding support from Generalitat de Catalunya(2014SGR1153, 2017SGR888, and 2017SGR702) and MINECO through the “Unidad de Excelencia María de Maeztu” funded by MINECO (MDM-2014-0370). H. Huerga Encabo was supported by a predoctoral fellowship of the Spanish Ministerio de Educación, Cultura y Deporte (FPU13/01798). M. Tellechea was supported by fellowships from Fundació Catalunya-La Pedrera(2011) and Generalitat de Catalunya (FI-DGR program 2013). C. López-Rodríguez is a recipient of an ICREA Acadèmia award from Institució Catalana de Recerca i Estudis Avançats (ICREA,Generalitat de Catalunya)

Published
2018

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