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Article ; Online: Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2.

Pérez-Jurado, Luis A / Cáceres, Alejandro / Balagué-Dobón, Laura / Esko, Tonu / López de Heredia, Miguel / Quintela, Inés / Cruz, Raquel / Lapunzina, Pablo / Carracedo, Ángel / González, Juan R

Communications biology

2024 Volume 7, Issue 1, Page(s) 202

Abstract: The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals ...

Abstract	The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people.
MeSH term(s)	Male ; Humans ; Aged ; SARS-CoV-2/genetics ; Mosaicism ; COVID-19/genetics ; Chromosomes, Human, Y ; Aging
Language	English
Publishing date	2024-02-19
Publishing country	England
Document type	Journal Article
ISSN	2399-3642
ISSN (online)	2399-3642
DOI	10.1038/s42003-024-05805-6
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Article ; Online: A Genome-Wide Association Study of Small Cell Lung Cancer.

Enjo-Barreiro, José Ramón / Ruano-Ravina, Alberto / Diz-de-Almeida, Silvia / Cruz, Raquel / Quintela, Inés / Rey-Brandariz, Julia / Carracedo, Ángel / Kelsey, Karl / Provencio, Mariano / Barros-Dios, Juan / Varela-Lema, Leonor / Pérez-Ríos, Mónica

Archivos de bronconeumologia

2023 Volume 59, Issue 10, Page(s) 645–650

Abstract: Introduction: Small cell lung cancer (SCLC) comprises 10-15% of all lung cancer cases and is the most aggressive histological type. Survival is poor and the molecular landscape of this disease is extraordinarily complex. The objective of this paper was ... ...

Abstract	Introduction: Small cell lung cancer (SCLC) comprises 10-15% of all lung cancer cases and is the most aggressive histological type. Survival is poor and the molecular landscape of this disease is extraordinarily complex. The objective of this paper was to perform a Genome-Wide Association Study (GWAS) of this disease using a case-control study specifically designed for small cell lung cancer (SCLC). Methods: Incident cases were consecutively recruited from 8 hospitals from different regions of Spain. Controls were recruited from the same hospitals using a frequency sampling based on age and sex distribution of cases. Biological samples were obtained along with detailed information on cases and controls lifestyle, including tobacco and radon exposure. Results: We included 271 SCLC cases and 557 controls. We found evidence (p-values<10 Conclusion: This study provides biological evidence for pathways related to SCLC, offering novel loci for further research.
MeSH term(s)	Humans ; Small Cell Lung Carcinoma/epidemiology ; Small Cell Lung Carcinoma/genetics ; Genome-Wide Association Study ; Case-Control Studies ; Lung Neoplasms/epidemiology ; Lung Neoplasms/genetics ; Spain/epidemiology
Language	Spanish
Publishing date	2023-07-15
Publishing country	Spain
Document type	Journal Article
ZDB-ID	733126-5
ISSN	1579-2129 ; 0300-2896
ISSN (online)	1579-2129
ISSN	0300-2896
DOI	10.1016/j.arbres.2023.07.008
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Article: Differential admixture in Latin American populations and its impact on the study of colorectal cancer.

Colistro, Valentina / Mut, Patricia / Hidalgo, Pedro C / Carracedo, Angel / Quintela, Inés / Rojas-Martínez, Augusto / Sans, Mónica

Genetics and molecular biology

2020 Volume 43, Issue 4, Page(s) e20200143

Abstract: Genome-wide association studies focused on searching genes responsible for several diseases. Admixture mapping studies proposed a more efficient alternative capable of detecting polymorphisms contributing with a small effect on the disease risk. This ... ...

Abstract	Genome-wide association studies focused on searching genes responsible for several diseases. Admixture mapping studies proposed a more efficient alternative capable of detecting polymorphisms contributing with a small effect on the disease risk. This method focuses on the higher values of linkage disequilibrium in admixed populations. To test this, we analyzed 10 genomic regions previously defined as related with colorectal cancer among nine populations and studied the variation pattern of haplotypic structures and heterozygosity values on seven categories of SNPs. Both analyses showed differences among chromosomal regions and studied populations. Admixed Latin-American samples generally show intermediate values. Heterozygosity of the SNPs grouped in categories varies more in each gene than in each population. African related populations have more blocks per chromosomal region, coherently with their antiquity. In sum, some similarities were found among Latin American populations, but each chromosomal region showed a particular behavior, despite the fact that the study refers to genes and regions related with one particular complex disease. This study strongly suggests the necessity of developing statistical methods to deal with di- or tri-hybrid populations, as well as to carefully analyze the different historic and demographic scenarios, and the different characteristics of particular chromosomal regions and evolutionary forces.
Language	English
Publishing date	2020-11-13
Publishing country	Brazil
Document type	Journal Article
ZDB-ID	1445712-x
ISSN	1678-4685 ; 1415-4757
ISSN (online)	1678-4685
ISSN	1415-4757
DOI	10.1590/1678-4685-GMB-2020-0143
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Article ; Online: Assessment of genotyping tools applied in genetic susceptibility studies of periodontal disease: A systematic review.

de Coo, Alicia / Quintela, Inés / Blanco, Juan / Diz, Pedro / Carracedo, Ángel

Archives of oral biology

2018 Volume 92, Page(s) 38–50

Abstract: Objective: A systematic review to evaluate the various genotyping tools and study strategies employed to define genetic susceptibility to periodontitis.: Methods: The review was performed in accordance with Preferred Reporting Items for Systematic ... ...

Abstract	Objective: A systematic review to evaluate the various genotyping tools and study strategies employed to define genetic susceptibility to periodontitis. Methods: The review was performed in accordance with Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines. The search for publications referring to the genetic bases of periodontal disease was performed on the MEDLINE-PubMed and Cochrane Library databases, on trials registers, and on the web pages of regulatory agencies. Results: We found 2439 potentially eligible articles, of which only 25 satisfied the established inclusion criteria and were processed for data extraction. The review revealed marked heterogeneity between studies, caused in part by the lack of a universally accepted definition for periodontitis phenotypes and by the variety of genotyping tools available. The most commonly used technique was genotyping candidate genes. Conclusion: The few rigorous studies that have been published on genetic susceptibility to periodontitis are subject to severe methodological bias due to their design and the genotyping tools employed. Despite their limitations, candidate gene studies continue to be the predominant methodological approach, rather than genome-wide association studies. Further studies must be designed using a universally accepted, validated diagnostic criterion for periodontitis, analysing multiple genes and polymorphisms in combination with rare variants.
MeSH term(s)	Genetic Predisposition to Disease ; Genome-Wide Association Study ; Genotype ; Humans ; Periodontal Diseases/genetics ; Phenotype ; Polymorphism, Single Nucleotide
Language	English
Publishing date	2018-04-30
Publishing country	England
Document type	Journal Article ; Systematic Review
ZDB-ID	80227-x
ISSN	1879-1506 ; 0003-9969
ISSN (online)	1879-1506
ISSN	0003-9969
DOI	10.1016/j.archoralbio.2018.04.012
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Article ; Online: Genetic Susceptibility to Periodontal Disease in Down Syndrome: A Case-Control Study.

Fernández, María / de Coo, Alicia / Quintela, Inés / García, Eliane / Diniz-Freitas, Márcio / Limeres, Jacobo / Diz, Pedro / Blanco, Juan / Carracedo, Ángel / Cruz, Raquel

International journal of molecular sciences

2021 Volume 22, Issue 12

Abstract: Severe periodontitis is prevalent in Down syndrome (DS). This study aimed to identify genetic variations associated with periodontitis in individuals with DS. The study group was distributed into DS patients with periodontitis ( ...

Abstract	Severe periodontitis is prevalent in Down syndrome (DS). This study aimed to identify genetic variations associated with periodontitis in individuals with DS. The study group was distributed into DS patients with periodontitis (
MeSH term(s)	Adolescent ; Adult ; Case-Control Studies ; Child ; Down Syndrome/complications ; Female ; Genetic Markers ; Genetic Predisposition to Disease ; Genotype ; Humans ; Male ; Middle Aged ; Periodontal Diseases/etiology ; Periodontal Diseases/pathology ; Saliva/metabolism ; Young Adult
Chemical Substances	Genetic Markers
Language	English
Publishing date	2021-06-10
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/ijms22126274
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Article ; Online: Patterns of genetic differentiation and the footprints of historical migrations in the Iberian Peninsula.

Bycroft, Clare / Fernandez-Rozadilla, Ceres / Ruiz-Ponte, Clara / Quintela, Inés / Carracedo, Ángel / Donnelly, Peter / Myers, Simon

Nature communications

2019 Volume 10, Issue 1, Page(s) 551

Abstract: The Iberian Peninsula is linguistically diverse and has a complex demographic history, including a centuries-long period of Muslim rule. Here, we study the fine-scale genetic structure of its population, and the genetic impacts of historical events, ... ...

Abstract	The Iberian Peninsula is linguistically diverse and has a complex demographic history, including a centuries-long period of Muslim rule. Here, we study the fine-scale genetic structure of its population, and the genetic impacts of historical events, leveraging powerful, haplotype-based statistical methods to analyse 1413 individuals from across Spain. We detect extensive fine-scale population structure at extremely fine scales (below 10 Km) in some regions, including Galicia. We identify a major east-west axis of genetic differentiation, and evidence of historical north to south population movement. We find regionally varying fractions of north-west African ancestry (0-11%) in modern-day Iberians, related to an admixture event involving European-like and north-west African-like source populations. We date this event to 860-1120 CE, implying greater genetic impacts in the early half of Muslim rule in Iberia. Together, our results indicate clear genetic impacts of population movements associated with both the Muslim conquest and the subsequent Reconquista.
MeSH term(s)	Cluster Analysis ; Genetics, Population ; Geography ; Human Migration ; Humans ; Phylogeny ; Spain
Language	English
Publishing date	2019-02-01
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-018-08272-w
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Article ; Online: Enhanced localization of genetic samples through linkage-disequilibrium correction.

Baran, Yael / Quintela, Inés / Carracedo, Angel / Pasaniuc, Bogdan / Halperin, Eran

American journal of human genetics

2013 Volume 92, Issue 6, Page(s) 882–894

Abstract: Characterizing the spatial patterns of genetic diversity in human populations has a wide range of applications, from detecting genetic mutations associated with disease to inferring human history. Current approaches, including the widely used principal- ... ...

Abstract	Characterizing the spatial patterns of genetic diversity in human populations has a wide range of applications, from detecting genetic mutations associated with disease to inferring human history. Current approaches, including the widely used principal-component analysis, are not suited for the analysis of linked markers, and local and long-range linkage disequilibrium (LD) can dramatically reduce the accuracy of spatial localization when unaccounted for. To overcome this, we have introduced an approach that performs spatial localization of individuals on the basis of their genetic data and explicitly models LD among markers by using a multivariate normal distribution. By leveraging external reference panels, we derive closed-form solutions to the optimization procedure to achieve a computationally efficient method that can handle large data sets. We validate the method on empirical data from a large sample of European individuals from the POPRES data set, as well as on a large sample of individuals of Spanish ancestry. First, we show that by modeling LD, we achieve accuracy superior to that of existing methods. Importantly, whereas other methods show decreased performance when dense marker panels are used in the inference, our approach improves in accuracy as more markers become available. Second, we show that accurate localization of genetic data can be achieved with only a part of the genome, and this could potentially enable the spatial localization of admixed samples that have a fraction of their genome originating from a given continent. Finally, we demonstrate that our approach is resistant to distortions resulting from long-range LD regions; such distortions can dramatically bias the results when unaccounted for.
MeSH term(s)	Algorithms ; Genetic Markers ; Genetics, Population ; Genome, Human ; Humans ; Linkage Disequilibrium ; Models, Genetic ; Phylogeography/methods ; Polymorphism, Single Nucleotide ; Principal Component Analysis ; Software ; Spain
Chemical Substances	Genetic Markers
Language	English
Publishing date	2013-05-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	219384-x
ISSN	1537-6605 ; 0002-9297
ISSN (online)	1537-6605
ISSN	0002-9297
DOI	10.1016/j.ajhg.2013.04.023
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Article ; Online: Identification of autosomal cis expression quantitative trait methylation (cis eQTMs) in children's blood.

eLife

2022 Volume 11

Abstract: Background: The identification of expression quantitative trait methylation (eQTMs), defined as associations between DNA methylation levels and gene expression, might help the biological interpretation of epigenome-wide association studies (EWAS). We ... ...

Abstract	Background: The identification of expression quantitative trait methylation (eQTMs), defined as associations between DNA methylation levels and gene expression, might help the biological interpretation of epigenome-wide association studies (EWAS). We aimed to identify autosomal cis eQTMs in children's blood, using data from 832 children of the Human Early Life Exposome (HELIX) project. Methods: Blood DNA methylation and gene expression were measured with the Illumina 450K and the Affymetrix HTA v2 arrays, respectively. The relationship between methylation levels and expression of nearby genes (1 Mb window centered at the transcription start site, TSS) was assessed by fitting 13.6 M linear regressions adjusting for sex, age, cohort, and blood cell composition. Results: We identified 39,749 blood autosomal cis eQTMs, representing 21,966 unique CpGs (eCpGs, 5.7% of total CpGs) and 8,886 unique transcript clusters (eGenes, 15.3% of total transcript clusters, equivalent to genes). In 87.9% of these cis eQTMs, the eCpG was located at <250 kb from eGene's TSS; and 58.8% of all eQTMs showed an inverse relationship between the methylation and expression levels. Only around half of the autosomal cis-eQTMs eGenes could be captured through annotation of the eCpG to the closest gene. eCpGs had less measurement error and were enriched for active blood regulatory regions and for CpGs reported to be associated with environmental exposures or phenotypic traits. In 40.4% of the eQTMs, the CpG and the eGene were both associated with at least one genetic variant. The overlap of autosomal cis eQTMs in children's blood with those described in adults was small (13.8%), and age-shared cis eQTMs tended to be proximal to the TSS and enriched for genetic variants. Conclusions: This catalogue of autosomal cis eQTMs in children's blood can help the biological interpretation of EWAS findings and is publicly available at https://helixomics.isglobal.org/ and at Dryad (doi:10.5061/dryad.fxpnvx0t0). Funding: The study has received funding from the European Community's Seventh Framework Programme (FP7/2007-206) under grant agreement no 308333 (HELIX project); the H2020-EU.3.1.2. - Preventing Disease Programme under grant agreement no 874583 (ATHLETE project); from the European Union's Horizon 2020 research and innovation programme under grant agreement no 733206 (LIFECYCLE project), and from the European Joint Programming Initiative "A Healthy Diet for a Healthy Life" (JPI HDHL and Instituto de Salud Carlos III) under the grant agreement no AC18/00006 (NutriPROGRAM project). The genotyping was supported by the projects PI17/01225 and PI17/01935, funded by the Instituto de Salud Carlos III and co-funded by European Union (ERDF, "A way to make Europe") and the Centro Nacional de Genotipado-CEGEN (PRB2-ISCIII). BiB received core infrastructure funding from the Wellcome Trust (WT101597MA) and a joint grant from the UK Medical Research Council (MRC) and Economic and Social Science Research Council (ESRC) (MR/N024397/1). INMA data collections were supported by grants from the Instituto de Salud Carlos III, CIBERESP, and the Generalitat de Catalunya-CIRIT. KANC was funded by the grant of the Lithuanian Agency for Science Innovation and Technology (6-04-2014_31V-66). The Norwegian Mother, Father and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research. The Rhea project was financially supported by European projects (EU FP6-2003-Food-3-NewGeneris, EU FP6. STREP Hiwate, EU FP7 ENV.2007.1.2.2.2. Project No 211250 Escape, EU FP7-2008-ENV-1.2.1.4 Envirogenomarkers, EU FP7-HEALTH-2009- single stage CHICOS, EU FP7 ENV.2008.1.2.1.6. Proposal No 226285 ENRIECO, EU- FP7- HEALTH-2012 Proposal No 308333 HELIX), and the Greek Ministry of Health (Program of Prevention of obesity and neurodevelopmental disorders in preschool children, in Heraklion district, Crete, Greece: 2011-2014; "Rhea Plus": Primary Prevention Program of Environmental Risk Factors for Reproductive Health, and Child Health: 2012-15). We acknowledge support from the Spanish Ministry of Science and Innovation through the "Centro de Excelencia Severo Ochoa 2019-2023" Program (CEX2018-000806-S), and support from the Generalitat de Catalunya through the CERCA Program. MV-U and CR-A were supported by a FI fellowship from the Catalan Government (FI-DGR 2015 and #016FI_B 00272). MC received funding from Instituto Carlos III (Ministry of Economy and Competitiveness) (CD12/00563 and MS16/00128).
MeSH term(s)	Adult ; Child, Preschool ; Cohort Studies ; DNA Methylation ; Epigenome ; Europe ; Humans ; Phenotype
Language	English
Publishing date	2022-03-18
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.65310
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Article ; Online: Clinical characterization of a male patient with the recently described 8q21.11 microdeletion syndrome.

Quintela, Ines / Barros, Francisco / Castro-Gago, Manuel / Carracedo, Angel / Eiris, Jesus

American journal of medical genetics. Part A

2015 Volume 167, Issue 6, Page(s) 1369–1373

Abstract: The 8q21.11 microdeletion syndrome (OMIM # 614230) has been recently described and is primarily characterized by intellectual disability and facial dysmorphism. We describe here a male patient of 9 years 9 months of age with moderate intellectual ... ...

Abstract	The 8q21.11 microdeletion syndrome (OMIM # 614230) has been recently described and is primarily characterized by intellectual disability and facial dysmorphism. We describe here a male patient of 9 years 9 months of age with moderate intellectual disability and dysmorphic facial features. A high resolution copy number variation analysis, performed with the Affymetrix Cytogenetics Whole-Genome 2.7 M SNP array, allowed the identification of a heterozygous 7.069 Mb microdeletion at chromosome 8q21.11-q21.13. Clinical comparison of our patient with literature shows many similarities. However, the whole facial appearance of our patient, especially the elongated rather than rounded face and the absence of a wide nasal bridge and epicanthal folds, confers him a phenotype similar only to a subset, but not to the majority, of the hitherto described patients.
MeSH term(s)	Abnormalities, Multiple/diagnosis ; Abnormalities, Multiple/genetics ; Abnormalities, Multiple/pathology ; Child ; Chromosomes, Human, Pair 8 ; DNA Copy Number Variations ; Facies ; Heterozygote ; Humans ; Intellectual Disability/diagnosis ; Intellectual Disability/genetics ; Intellectual Disability/pathology ; Male ; Monosomy ; Oligonucleotide Array Sequence Analysis ; Phenotype ; Syndrome
Language	English
Publishing date	2015-04-21
Publishing country	United States
Document type	Case Reports ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1493479-6
ISSN	1552-4833 ; 1552-4825
ISSN (online)	1552-4833
ISSN	1552-4825
DOI	10.1002/ajmg.a.37038
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Article ; Online: A maternally inherited 16p13.11-p12.3 duplication concomitant with a de novo SOX5 deletion in a male patient with global developmental delay, disruptive and obsessive behaviors and minor dysmorphic features.

Quintela, Ines / Barros, Francisco / Lago-Leston, Ramon / Castro-Gago, Manuel / Carracedo, Angel / Eiris, Jesus

American journal of medical genetics. Part A

2015 Volume 167, Issue 6, Page(s) 1315–1322

Abstract: We detail here the clinical description and the family genetic study of a male patient with global developmental delay, disruptive and obsessive behaviors and minor dysmorphic features and a combination of two rare genetic variants: a maternally ... ...

Abstract	We detail here the clinical description and the family genetic study of a male patient with global developmental delay, disruptive and obsessive behaviors and minor dysmorphic features and a combination of two rare genetic variants: a maternally inherited 16p13.11-p12.3 duplication and a de novo 12p12.1 deletion affecting SOX5. The 16p13.11 microduplication has been implicated in several neurodevelopmental and behavioral disorders and is characterized by variable expressivity and incomplete penetrance. The causes of this variation in phenotypic expression are not fully clear, representing a challenge in genetic diagnosis and counseling. However, several authors have proposed the two-hit model as one of the underlying mechanisms for this phenotypic heterogeneity. Our data could also support this two-hit model in which the 16p13.11-p12.3 duplication might contribute to the phenotype, not only as a single event but also in association with the SOX5 deletion. The SOX5 gene plays important roles in various developmental processes and has been associated with several neurodevelopmental disorders, mainly intellectual disability, developmental delay and language and/or speech delay as well as with behavior problems and dysmorphic features. However, many of the physical features and behavioral manifestations as well as language deficiencies present in our patient are consistent with those previously reported for SOX5 deletions. Patients carrying multiple genomic variants, as the one presented here, illustrate the difficulty in analyzing genotypes when the contribution of each variant results in overlapping phenotypes and/or, alternatively, in the modification of the clinical manifestations defined by the coexisting variant.
MeSH term(s)	Child ; Chromosome Duplication ; Chromosomes, Human, Pair 16 ; Developmental Disabilities/genetics ; Developmental Disabilities/pathology ; Developmental Disabilities/physiopathology ; Facies ; Gene Deletion ; Genotype ; Humans ; Language Development Disorders/genetics ; Language Development Disorders/pathology ; Language Development Disorders/physiopathology ; Male ; Models, Genetic ; Obsessive Behavior/genetics ; Obsessive Behavior/pathology ; Obsessive Behavior/physiopathology ; Pedigree ; Phenotype ; SOXD Transcription Factors/genetics
Chemical Substances	SOX5 protein, human ; SOXD Transcription Factors
Language	English
Publishing date	2015-04-02
Publishing country	United States
Document type	Case Reports ; Journal Article
ZDB-ID	1493479-6
ISSN	1552-4833 ; 1552-4825
ISSN (online)	1552-4833
ISSN	1552-4825
DOI	10.1002/ajmg.a.36909
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