%0 Journal Article %J Pharmaceutics %D 2023 %T A Comprehensive Analysis of 21 Actionable Pharmacogenes in the Spanish Population: From Genetic Characterisation to Clinical Impact. %A Núñez-Torres, Rocío %A Pita, Guillermo %A Peña-Chilet, Maria %A López-López, Daniel %A Zamora, Jorge %A Roldán, Gema %A Herráez, Belén %A Alvarez, Nuria %A Alonso, María Rosario %A Dopazo, Joaquin %A González-Neira, Anna %X

The implementation of pharmacogenetics (PGx) is a main milestones of precision medicine nowadays in order to achieve safer and more effective therapies. Nevertheless, the implementation of PGx diagnostics is extremely slow and unequal worldwide, in part due to a lack of ethnic PGx information. We analysed genetic data from 3006 Spanish individuals obtained by different high-throughput (HT) techniques. Allele frequencies were determined in our population for the main 21 actionable PGx genes associated with therapeutical changes. We found that 98% of the Spanish population harbours at least one allele associated with a therapeutical change and, thus, there would be a need for a therapeutical change in a mean of 3.31 of the 64 associated drugs. We also identified 326 putative deleterious variants that were not previously related with PGx in 18 out of the 21 main PGx genes evaluated and a total of 7122 putative deleterious variants for the 1045 PGx genes described. Additionally, we performed a comparison of the main HT diagnostic techniques, revealing that after whole genome sequencing, genotyping with the PGx HT array is the most suitable solution for PGx diagnostics. Finally, all this information was integrated in the Collaborative Spanish Variant Server to be available to and updated by the scientific community.

%B Pharmaceutics %V 15 %8 2023 Apr 19 %G eng %N 4 %R 10.3390/pharmaceutics15041286 %0 Journal Article %J Hum Genomics %D 2023 %T A crowdsourcing database for the copy-number variation of the Spanish population. %A López-López, Daniel %A Roldán, Gema %A Fernandez-Rueda, Jose L %A Bostelmann, Gerrit %A Carmona, Rosario %A Aquino, Virginia %A Perez-Florido, Javier %A Ortuno, Francisco %A Pita, Guillermo %A Núñez-Torres, Rocío %A González-Neira, Anna %A Peña-Chilet, Maria %A Dopazo, Joaquin %X

BACKGROUND: Despite being a very common type of genetic variation, the distribution of copy-number variations (CNVs) in the population is still poorly understood. The knowledge of the genetic variability, especially at the level of the local population, is a critical factor for distinguishing pathogenic from non-pathogenic variation in the discovery of new disease variants.

RESULTS: Here, we present the SPAnish Copy Number Alterations Collaborative Server (SPACNACS), which currently contains copy number variation profiles obtained from more than 400 genomes and exomes of unrelated Spanish individuals. By means of a collaborative crowdsourcing effort whole genome and whole exome sequencing data, produced by local genomic projects and for other purposes, is continuously collected. Once checked both, the Spanish ancestry and the lack of kinship with other individuals in the SPACNACS, the CNVs are inferred for these sequences and they are used to populate the database. A web interface allows querying the database with different filters that include ICD10 upper categories. This allows discarding samples from the disease under study and obtaining pseudo-control CNV profiles from the local population. We also show here additional studies on the local impact of CNVs in some phenotypes and on pharmacogenomic variants. SPACNACS can be accessed at: http://csvs.clinbioinfosspa.es/spacnacs/ .

CONCLUSION: SPACNACS facilitates disease gene discovery by providing detailed information of the local variability of the population and exemplifies how to reuse genomic data produced for other purposes to build a local reference database.

%B Hum Genomics %V 17 %P 20 %8 2023 Mar 09 %G eng %N 1 %R 10.1186/s40246-023-00466-8 %0 Journal Article %J Hum Mol Genet %D 2022 %T Novel genes and sex differences in COVID-19 severity. %A Cruz, Raquel %A Almeida, Silvia Diz-de %A Heredia, Miguel López %A Quintela, Inés %A Ceballos, Francisco C %A Pita, Guillermo %A Lorenzo-Salazar, José M %A González-Montelongo, Rafaela %A Gago-Domínguez, Manuela %A Porras, Marta Sevilla %A Castaño, Jair Antonio Tenorio %A Nevado, Julián %A Aguado, Jose María %A Aguilar, Carlos %A Aguilera-Albesa, Sergio %A Almadana, Virginia %A Almoguera, Berta %A Alvarez, Nuria %A Andreu-Bernabeu, Álvaro %A Arana-Arri, Eunate %A Arango, Celso %A Arranz, María J %A Artiga, Maria-Jesus %A Baptista-Rosas, Raúl C %A Barreda-Sánchez, María %A Belhassen-Garcia, Moncef %A Bezerra, Joao F %A Bezerra, Marcos A C %A Boix-Palop, Lucía %A Brión, Maria %A Brugada, Ramón %A Bustos, Matilde %A Calderón, Enrique J %A Carbonell, Cristina %A Castano, Luis %A Castelao, Jose E %A Conde-Vicente, Rosa %A Cordero-Lorenzana, M Lourdes %A Cortes-Sanchez, Jose L %A Corton, Marta %A Darnaude, M Teresa %A De Martino-Rodríguez, Alba %A Campo-Pérez, Victor %A Bustamante, Aranzazu Diaz %A Domínguez-Garrido, Elena %A Luchessi, André D %A Eirós, Rocío %A Sanabria, Gladys Mercedes Estigarribia %A Fariñas, María Carmen %A Fernández-Robelo, Uxía %A Fernández-Rodríguez, Amanda %A Fernández-Villa, Tania %A Gil-Fournier, Belén %A Gómez-Arrue, Javier %A Álvarez, Beatriz González %A Quirós, Fernan Gonzalez Bernaldo %A González-Peñas, Javier %A Gutiérrez-Bautista, Juan F %A Herrero, María José %A Herrero-Gonzalez, Antonio %A Jimenez-Sousa, María A %A Lattig, María Claudia %A Borja, Anabel Liger %A Lopez-Rodriguez, Rosario %A Mancebo, Esther %A Martín-López, Caridad %A Martín, Vicente %A Martinez-Nieto, Oscar %A Martinez-Lopez, Iciar %A Martinez-Resendez, Michel F %A Martinez-Perez, Ángel %A Mazzeu, Juliana A %A Macías, Eleuterio Merayo %A Minguez, Pablo %A Cuerda, Victor Moreno %A Silbiger, Vivian N %A Oliveira, Silviene F %A Ortega-Paino, Eva %A Parellada, Mara %A Paz-Artal, Estela %A Santos, Ney P C %A Pérez-Matute, Patricia %A Perez, Patricia %A Pérez-Tomás, M Elena %A Perucho, Teresa %A Pinsach-Abuin, Mel Lina %A Pompa-Mera, Ericka N %A Porras-Hurtado, Gloria L %A Pujol, Aurora %A León, Soraya Ramiro %A Resino, Salvador %A Fernandes, Marianne R %A Rodríguez-Ruiz, Emilio %A Rodriguez-Artalejo, Fernando %A Rodriguez-Garcia, José A %A Ruiz-Cabello, Francisco %A Ruiz-Hornillos, Javier %A Ryan, Pablo %A Soria, José Manuel %A Souto, Juan Carlos %A Tamayo, Eduardo %A Tamayo-Velasco, Alvaro %A Taracido-Fernandez, Juan Carlos %A Teper, Alejandro %A Torres-Tobar, Lilian %A Urioste, Miguel %A Valencia-Ramos, Juan %A Yáñez, Zuleima %A Zarate, Ruth %A Nakanishi, Tomoko %A Pigazzini, Sara %A Degenhardt, Frauke %A Butler-Laporte, Guillaume %A Maya-Miles, Douglas %A Bujanda, Luis %A Bouysran, Youssef %A Palom, Adriana %A Ellinghaus, David %A Martínez-Bueno, Manuel %A Rolker, Selina %A Amitrano, Sara %A Roade, Luisa %A Fava, Francesca %A Spinner, Christoph D %A Prati, Daniele %A Bernardo, David %A García, Federico %A Darcis, Gilles %A Fernández-Cadenas, Israel %A Holter, Jan Cato %A Banales, Jesus M %A Frithiof, Robert %A Duga, Stefano %A Asselta, Rosanna %A Pereira, Alexandre C %A Romero-Gómez, Manuel %A Nafría-Jiménez, Beatriz %A Hov, Johannes R %A Migeotte, Isabelle %A Renieri, Alessandra %A Planas, Anna M %A Ludwig, Kerstin U %A Buti, Maria %A Rahmouni, Souad %A Alarcón-Riquelme, Marta E %A Schulte, Eva C %A Franke, Andre %A Karlsen, Tom H %A Valenti, Luca %A Zeberg, Hugo %A Richards, Brent %A Ganna, Andrea %A Boada, Mercè %A Rojas, Itziar %A Ruiz, Agustín %A Sánchez, Pascual %A Real, Luis Miguel %A Guillén-Navarro, Encarna %A Ayuso, Carmen %A González-Neira, Anna %A Riancho, José A %A Rojas-Martinez, Augusto %A Flores, Carlos %A Lapunzina, Pablo %A Carracedo, Ángel %X

Here we describe the results of a genome-wide study conducted in 11 939 COVID-19 positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (p < 5x10-8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (p = 1.3x10-22 and p = 8.1x10-12, respectively), and for variants in 9q21.32 near TLE1 only among females (p = 4.4x10-8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (p = 2.7x10-8) and ARHGAP33 (p = 1.3x10-8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, p = 4.1x10-8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥ 60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.

%B Hum Mol Genet %8 2022 Jun 16 %G eng %R 10.1093/hmg/ddac132 %0 Journal Article %J Nucleic Acids Res %D 2021 %T CSVS, a crowdsourcing database of the Spanish population genetic variability. %A Peña-Chilet, Maria %A Roldán, Gema %A Perez-Florido, Javier %A Ortuno, Francisco M %A Carmona, Rosario %A Aquino, Virginia %A López-López, Daniel %A Loucera, Carlos %A Fernandez-Rueda, Jose L %A Gallego, Asunción %A Garcia-Garcia, Francisco %A González-Neira, Anna %A Pita, Guillermo %A Núñez-Torres, Rocío %A Santoyo-López, Javier %A Ayuso, Carmen %A Minguez, Pablo %A Avila-Fernandez, Almudena %A Corton, Marta %A Moreno-Pelayo, Miguel Ángel %A Morin, Matías %A Gallego-Martinez, Alvaro %A Lopez-Escamez, Jose A %A Borrego, Salud %A Antiňolo, Guillermo %A Amigo, Jorge %A Salgado-Garrido, Josefa %A Pasalodos-Sanchez, Sara %A Morte, Beatriz %A Carracedo, Ángel %A Alonso, Ángel %A Dopazo, Joaquin %K Alleles %K Chromosome Mapping %K Crowdsourcing %K Databases, Genetic %K Exome %K Gene Frequency %K Genetic Variation %K Genetics, Population %K Genome, Human %K Genomics %K Humans %K Internet %K Precision Medicine %K Software %K Spain %X

The knowledge of the genetic variability of the local population is of utmost importance in personalized medicine and has been revealed as a critical factor for the discovery of new disease variants. Here, we present the Collaborative Spanish Variability Server (CSVS), which currently contains more than 2000 genomes and exomes of unrelated Spanish individuals. This database has been generated in a collaborative crowdsourcing effort collecting sequencing data produced by local genomic projects and for other purposes. Sequences have been grouped by ICD10 upper categories. A web interface allows querying the database removing one or more ICD10 categories. In this way, aggregated counts of allele frequencies of the pseudo-control Spanish population can be obtained for diseases belonging to the category removed. Interestingly, in addition to pseudo-control studies, some population studies can be made, as, for example, prevalence of pharmacogenomic variants, etc. In addition, this genomic data has been used to define the first Spanish Genome Reference Panel (SGRP1.0) for imputation. This is the first local repository of variability entirely produced by a crowdsourcing effort and constitutes an example for future initiatives to characterize local variability worldwide. CSVS is also part of the GA4GH Beacon network. CSVS can be accessed at: http://csvs.babelomics.org/.

%B Nucleic Acids Res %V 49 %P D1130-D1137 %8 2021 01 08 %G eng %N D1 %1 https://www.ncbi.nlm.nih.gov/pubmed/32990755?dopt=Abstract %R 10.1093/nar/gkaa794 %0 Journal Article %J International journal of data mining and bioinformatics %D 2012 %T Select your SNPs (SYSNPs): a web tool for automatic and massive selection of SNPs. %A Lorente-Galdos, Belén %A Medina, Ignacio %A Morcillo-Suarez, Carlos %A Heredia, Txema %A Carreño-Torres, Angel %A Sangrós, Ricardo %A Alegre, Josep %A Pita, Guillermo %A Vellalta, Gemma %A Malats, Nuria %A Pisano, David G %A Joaquín Dopazo %A Navarro, Arcadi %X Association studies are the choice approach in the discovery of the genomic basis of complex traits. To carry out such analysis, researchers frequently need to (1) select optimally informative sets of Single Nucleotide Polymorphisms (SNPs) in candidate regions and (2) annotate the results of associations found by means of genome-wide SNP arrays. These are complex tasks, since many criteria have to be considered, including the SNPs’ functional properties, technological information and haplotype frequencies in given populations. SYSNPs implements algorithms that allow for efficient and simultaneous consideration of all the relevant criteria to obtain sets of SNPs that properly cover arbitrarily large lists of genes or genomic regions. Complementarily, SYSNPs allows for comprehensive functional annotation of SNPs linked to any given marker SNP. SYSNPs dramatically reduces the effort needed for SNP selection from days of searching various databases to a few minutes using a simple browser. %B International journal of data mining and bioinformatics %V 6 %P 324-34 %8 2012 %G eng %U http://inderscience.metapress.com/content/f76740x8071u513n/