Bases genéticas de la discapacidad intelectual y los trastornos del espectro autista: aplicación de las nuevas tecnologías al análisis de variantes del número de copias (CNVs)

La discapacidad intelectual (DI) es un trastorno del neurodesarrollo complejo y fenotípicamente heterogéneo caracterizado por deficiencias significativas en el funcionamiento intelectual y en las habilidades adaptativas de inicio en el período del desarrollo. El trastorno del espectro autista (TEA) es un trastorno del neurodesarrollo caracterizado por deficiencias en las habilidades para la comunicación, en la interacción social y en el desarrollo del lenguaje y por la presencia de intereses restringidos y/o comportamientos estereotipados repetitivos. La etiología de estos trastornos incluye tanto factores ambientales como genéticos, pero una proporción significativa de los pacientes permanece sin un diagnóstico genético definitivo. En este estudio, evaluamos la utilidad de paneles de SNPs del genoma completo de alta densidad en la detección de variantes del número de copias (CNVs) clínicamente relevantes en pacientes con DI y/o TEA. Además, proporcionamos datos moleculares y descripciones clínicas detalladas de pacientes con CNVs patogénicas y/o potencialmente patogénicas

Enhanced localization of genetic samples through linkage-disequilibrium correction

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

Patterns of genetic differentiation and the footprints of historical migrations in the Iberian Peninsula

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.We acknowledge support from the Wellcome Trust (203141/Z/16/Z, 090532/Z/09/Z, 098387/Z/12/Z, 095552/Z/11/Z, 212284/Z/18/Z) and Fondo de Investigación Sanitaria (Grants PI13/01136 and PI16/01057)S

Genomic characterization of host factors related to SARS-CoV-2 infection in people with dementia and control populations: the GR@ACE/DEGESCO study

Emerging studies have suggested several chromosomal regions as potential host genetic factors involved in the susceptibility to SARS-CoV-2 infection and disease outcome. We nested a COVID-19 genome-wide association study using the GR@ACE/DEGESCO study, searching for susceptibility factors associated with COVID-19 disease. To this end, we compared 221 COVID-19 confirmed cases with 17,035 individuals in whom the COVID-19 disease status was unknown. Then, we performed a meta-analysis with the publicly available data from the COVID-19 Host Genetics Initiative. Because the APOE locus has been suggested as a potential modifier of COVID-19 disease, we added sensitivity analyses stratifying by dementia status or by disease severity. We confirmed the existence of the 3p21.31 region (LZTFL1, SLC6A20) implicated in the susceptibility to SARS-CoV-2 infection and TYK2 gene might be involved in COVID-19 severity. Nevertheless, no statistically significant association was observed in the COVID-19 fatal outcome or in the stratified analyses (dementia-only and non-dementia strata) for the APOE locus not supporting its involvement in SARS-CoV-2 pathobiology or COVID-19 prognosis

Genetic Susceptibility to Periodontal Disease in Down Syndrome: A Case-Control Study

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 (n = 50) and DS patients with healthy periodontium (n = 36). All samples were genotyped with the “Axiom Spanish Biobank” array, which contains 757,836 markers. An association analysis at the individual marker level using logistic regression, as well as at the gene level applying the sequence kernel association test (SKAT) was performed. The most significant genes were included in a pathway analysis using the free DAVID software. C12orf74 (rs4315121, p = 9.85 × 10−5, OR = 8.84), LOC101930064 (rs4814890, p = 9.61 × 10−5, OR = 0.13), KBTBD12 (rs1549874, p = 8.27 × 10−5, OR = 0.08), PIWIL1 (rs11060842, p = 7.82 × 10−5, OR = 9.05) and C16orf82 (rs62030877, p = 8.92 × 10−5, OR = 0.14) showed a higher probability in the individual analysis. The analysis at the gene level highlighted PIWIL, MIR9-2, LHCGR, TPR and BCR. At the signaling pathway level, PI3K-Akt, long-term depression and FoxO achieved nominal significance (p = 1.3 × 10−2, p = 5.1 × 10−3, p = 1.2 × 10−2, respectively). In summary, various metabolic pathways are involved in the pathogenesis of periodontitis in DS, including PI3K-Akt, which regulates cell proliferation and inflammatory responseThe genotyping service was carried out at CeGen-PRB3-ISCIII; it is supported by grant PT13/0001, ISCIII-SGEFI/FEDERS

Clonal chromosomal mosaicism and loss of chromosome Y in men are risk factors for SARS-CoV-2 vulnerability in the elderly

* SCOURGE Cohort Group Javier Abellan15,16; René Acosta-Isaac17; Jose María Aguado18,19,20,21; Carlos Aguilar22; Sergio Aguilera-Albesa23,24; Abdolah Ahmadi Sabbagh25; Jorge Alba26; Sergiu Albu27,28,29; Karla A.M. Alcalá-Gallardo30; Julia Alcoba-Florez31; Sergio Alcolea Batres32; Holmes Rafael AlgarinLara33,34; Virginia Almadana35; Kelliane A. Medeiros36,37; Julia Almeida38,39; Berta Almoguera40,3; María R. Alonso41; Nuria Alvarez41; Rodolfo Alvarez-Sala Walther32; Yady Álvarez-Benítez33,34; Felipe Álvarez-Navia42,43; Katiusse A. dos Santos44; Álvaro Andreu-Bernabeu45,20; Maria Rosa Antonijoan46; Eleno Martínez-Aquino47; Eunate Arana-Arri48,49; Carlos Aranda50,51; Celso Arango45,52,20; Carolina Araque53,54; Nathalia K. Araujo55; Ana C. Arcanjo56,57,58; Ana Arnaiz59,60; Francisco Arnalich Fernández61; María J. Arranz62; José Ramon Arribas Lopez61; Maria-Jesus Artiga63; Yubelly Avello-Malaver64; Carmen Ayuso40,3; Belén Ballina Martín25; Raúl C. BaptistaRosas65,66,67; Ana María Baldion64; Andrea Barranco-Díaz34; María Barreda- Sánchez68,69; Viviana Barrera-Penagos64; Moncef Belhassen-Garcia70,43; David Bernal-Bello71; Enrique Bernal68; Joao F. Bezerra72; Marcos A.C. Bezerra73; Natalia Blanca-López74; Rafael Blancas75; Lucía Boix-Palop76; Alberto Borobia77; Elsa Bravo78; María Brion79,80; Óscar Brochado-Kith81; Ramón Brugada82,83,80,84; Matilde Bustos85; Alfonso Cabello86; Alejandro Cáceres4,5; Juan J. Caceres-Agra87; Esther Calbo76; Enrique J. Calderón88,6,89; Shirley Camacho90; Francisco C. Ceballos81; Yolanda Cañadas51; Cristina Carbonell42,43; Servando Cardona-Huerta91; Maria Sanchez Carpintero50,51; Carlos Carpio Segura32; José Antonio Carrillo-Avila92; Marcela C. Campos56; Carlos Casasnovas93,94,3; Luis Castano48,95,3,96,97; Carlos F. Castaño50,51; Jose E. Castelao98; Aranzazu Castellano Candalija99; María A. Castillo90; Walter G. ChavesSantiago100,54; Sylena Chiquillo-Gómez33,34; Marco A. Cid-Lopez30; Oscar CienfuegosJimenez91; Rosa Conde-Vicente101; Gabriela C.R. Cunha102; M. Lourdes Cordero-Lorenzana103; Dolores Corella104,105; Almudena Corrales106,107; Jose L. Cortes-Sanchez91,108; Marta Corton40,3; Karla S.C. Souza109; Fabiola T.C. Silva56; Raquel Cruz8,3,9,10; Luisa Cuesta110; Nathali A.C. Tavares111; Maria C.C. Carvalho112; David Dalmau62,76; Raquel C.S. Dantas-Komatsu113; M. Teresa Darnaude114; Raimundo de Andrés115; Carmen de Juan116; Juan De la Cruz Troca117,118,6; Carmen de la Horra89; Ana B. de la Hoz48; Alba De Martino-Rodríguez119,120; Marina S. Cruz121; Julianna Lys de Sousa Alves Neri122; Victor del Campo-Pérez123; Juan Delgado-Cuesta124; Aranzazu Diaz de Bustamante114; Anderson Díaz-Pérez34; Beatriz Dietl76; Silvia Diz-de Almeida3,10; Manoella do Monte Alves125,126; Elena Domínguez-Garrido127; Lidia S. Rosa128; Andre D. Luchessi129; Jose Echave-Sustaeta130; Rocío Eiros131; César O. EncisoOlivera53,54; Gabriela Escudero132; Pedro Pablo España133; Gladys Mercedes Estigarribia Sanabria134; María Carmen Fariñas59,60,135; Ramón Fernández59,136; Lidia FernandezCaballero40,3; Ana Fernández-Cruz137; Silvia Fernández Ferrero25; Yolanda Fernández Martínez25; María J. Fernandez-Nestosa138; Uxía Fernández-Robelo139; Amanda FernándezRodríguez81; Marta Fernández-Sampedro59,135,60; Ruth Fernández40,3; Tania Fernández-Villa140; Carmen Fernéndez Capitán99; Antonio Augusto F. Carioca141; Patricia Flores-Pérez142; Lácides Fuenmayor-Hernández34; Marta Fuertes Núñez25; Victoria Fumadó143; Ignacio Gadea144; Lidia Gagliardi50,51; Manuela Gago-Domínguez13,9; Natalia Gallego11; Cristina Galoppo145; Ana García-Soidán146; Carlos Garcia Cerrada15,16; Aitor García-de-Vicuña48,95; Josefina GarciaGarcía68; Irene García-García77; Carmen García-Ibarbia59,135,60; Andrés C. García-Montero147; Leticia García50,51; Mercedes García50,51; María Carmen García Torrejón148,16; Inés García40,3; Elisa García-Vázquez68; Emiliano Garza-Frias91; Angela Gentile145; Belén Gil-Fournier149; Jéssica N.G. de Araújo150; Mario Gómez-Duque100,54; Javier Gómez-Arrue119,120; Luis Gómez Carrera32; María Gómez García151; Ángela Gómez Sacristán152; Juan R. González4,5,6,14; Anna González-Neira41; Beatriz González Álvarez119,120; Fernan Gonzalez Bernaldo de Quirós153; Rafaela González-Montelongo154; Javier González-Peñas45,20,52; Manuel Gonzalez-Sagrado101; Hugo Gonzalo Benito155; Oscar Gorgojo-Galindo156; Miguel Górgolas86; Florencia Guaragna145; Jessica G. Chaux54; Encarna Guillen-Navarro68,157,158,159; Beatriz Guillen-Guio106; Pablo Guisado-Vasco130; Luz D. Gutierrez-Castañeda160,54; Juan F. Gutiérrez-Bautista161; Sara HeiliFrades162; Rafael H. Jacomo163; Estefania Hernandez164; Cristina Hernández Moro25; Luis D. Hernandez-Ortega165,166; Guillermo Hernández-Pérez42; Rebeca Hernández-Vaquero167; Belen Herraez41; M. Teresa Herranz68; María Herrera50,51; María José Herrero168,169; Antonio HerreroGonzalez170; Juan P. Horcajada171,172,28,173; Natale Imaz-Ayo48; Maider IntxaustiUrrutibeaskoa174; Antonio Íñigo-Campos154; María Íñiguez175; Rubén Jara68; Ángel Jiménez50,51; Ignacio Jiménez-Alfaro176; Pilar Jiménez161; María A. Jimenez-Sousa81; Iolanda Jordan177,178,6; Rocío Laguna-Goya179,180; Daniel Laorden32; María Lasa-Lazaro179,180; María Claudia Lattig90,181; Ailen Lauriente145; Anabel Liger Borja182; Lucía Llanos183; Amparo López-Bernús42,43; Miguel It is made available under a CC-BY-NC-ND 4.0 International license . (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. medRxiv preprint doi: https://doi.org/10.1101/2020.04.19.20071357; this version posted February 18, 2022. The copyright holder for this preprint López de Heredia3 ; Esther Lopez-Garcia117,118,6,184; Eduardo López Granados185,186,3; Rosario Lopez-Rodriguez40,3; Miguel A. López-Ruz187,188,189; Leonardo Lorente190; José M. LorenzoSalazar154; José E. Lozano191; María Lozano-Espinosa182; Ignacio Mahillo192,193,107; Esther Mancebo179,180; Carmen Mar133; Cristina Marcelo Calvo99; Alba Marcos-Delgado194; Miguel Marcos42,43; Alicia Marín Candon77; Pablo Mariscal Aguilar32; Laura Martin-Pedraza74; Marta Martin-Fernandez195; Caridad Martín-López182; José-Ángel Martín-Oterino42,43; María Dolores Martín196; Vicente Martín194,6; María M. Martín197; María Martín-Vicente81; Amalia Martinez198; Óscar Martínez-González75; Ricardo Martínez164; Pedro Martinez-Paz155; Covadonga M. DiazCaneja45,52,20; Oscar Martinez-Nieto64,181; Iciar Martinez-Lopez199,200; Michel F. MartinezResendez91; Silvia Martínez59,135; Juan José Martinez94,3; Angel Martinez-Perez201; Andrea Martínez-Ramas40,3; Violeta Martínez Robles25; Laura Marzal40,3; Juliana F. Mazzeu202,203,204; Francisco J. Medrano88,6,89; Xose M. Meijome205,206; Natalia Mejuto-Montero207; Ingrid Mendes3 ; Alice L. Duarte109; Ana Méndez-Echevarria208; Humberto Mendoza Charris78,34; Eleuterio Merayo Macías209; Fátima Mercadillo210; Arieh R. Mercado-Sesma165,166; Pablo Minguez40,3; Elena Molina-Roldán211; Antonio J J. Molina194; Juan José Montoya164; Susana M.T. Pinho36,212,213; Patricia Moreira-Escriche116; Xenia Morelos-Arnedo78,34; Rocío Moreno3 ; Victor Moreno Cuerda15,16; Antonio Moreno-Docón68; Junior Moreno-Escalante34; Alberto Moreno Fernández99; Patricia Muñoz García214,107,20; Pablo Neira145; Julian Nevado3,11,12; Israel NietoGañán146; Vivian N. Silbiger129; Rocio Nuñez- Torres41; Antònia Obrador-Hevia215,216; J. Gonzalo Ocejo-Vinyals59,135; Virginia Olivar145; Silviene F. Oliveira56,217,204,218; Lorena Ondo40,3; Alberto Orfao38,39; Eva Ortega-Paino63; Luis Ortega219; Rocio Ortiz-Lopez91; Fernando Ortiz-Flores59,135; José A. Oteo26,175; Manuel Pacheco164; Fredy Javier Pacheco-Miranda34; Irene Padilla Conejo25; Sonia Panadero-Fajardo92; Mara Parellada45,52,20; Roberto Pariente-Rodríguez146; Vicente Friaza6,89; Estela Paz-Artal179,180,220; Germán Peces-Barba221,107; Miguel S. Pedromingo Kus222; Celia Perales144; Ney P.C. Santos223; Genilson P. Guegel224; Perez Maria Jazmin145; Alexandra Perez82,80; Patricia Pérez-Matute175; César Pérez225; Gustavo Perez-de-Nanclares48,95; Felipe Pérez-García226,227; Patricia Perez228; Luis A. Pérez-Jurado1,2,3; M. Elena Pérez-Tomás68; Teresa Perucho229; Lisbeth A. Pichardo25; Adriana P. Ribeiro36,37,213; Mel·lina Pinsach-Abuin82,80; Luz Adriana Pinzón100,54; Jeane F.P. Medeiros230; Guillermo Pita41; Francesc Pla-Junca231,3; Laura Planas-Serra94,3; Ericka N. Pompa-Mera232; Gloria L. Porras-Hurtado164; Aurora Pujol94,3,233; María Eugenia Quevedo Chávez33,34; Maria Angeles Quijada46,234; Inés Quintela8 ; Soraya Ramiro León149; Pedro Rascado Sedes235; Joana F.R. Nunes56; Delia Recalde119,120; Emma Recio-Fernández175; Salvador Resino81; Renata R. Sousa213,236; Carlos S. RivadeneiraChamorro54; Diana Roa-Agudelo64; Montserrat Robelo Pardo235; Marianne R. Fernandes223,237; María A. Rodriguez-Hernandez85; Agustí Rodriguez-Palmero238,94; Emilio Rodríguez-Ruiz235,9; Marilyn Johanna Rodriguez54; Fernando Rodriguez-Artalejo117,118,6,184; Marena RodríguezFerrer34; Carlos Rodriguez-Gallego239,240; José A. Rodriguez-Garcia25; Belén Rodríguez Maya15; Antonio Rodriguez-Nicolas161; German Ezequiel Rodriguez Novoa145; Paula A. RodriguezUrrego64; Federico Rojo241,242; Andrea Romero-Coronado34; Rubén Morilla89,243; Filomeno Rondón García25; Antonio Rosales-Castillo244; Cladelis Rubio245; María Rubio Olivera50,51; Francisco Ruiz-Cabello161,188,246; Eva Ruiz-Casares229; Juan J. Ruiz-Cubillan59,135; Javier RuizHornillos247,51,248; Montserrat Ruiz94,3; Pablo Ryan249,250,251; Hector D. Salamanca53,54; Lorena Salazar-García90; Giorgina Gabriela Salgueiro Origlia 99; Anna Sangil76; Olga SánchezPernaute252; Pedro-Luis Sánchez131,43; Antonio J. Sánchez López253; Clara Sánchez-Pablo131; María Concepción Sánchez Prados32; Javier Sánchez Real25; Jorge Sánchez Redondo15,254; Cristina Sancho- Sainz174; Esther Sande255; Arnoldo Santos225; Agatha Schlüter94,3; Sonia Segovia231,256,257; Alex Serra-Llovich62; Fernando Sevil Puras22; Marta Sevilla Porras3,11; Miguel A. Sicolo258,259; Cristina Silván Fuentes3 ; Vitor M.S. Moraes260; Vanessa S. Souza102; Jordi SoléViolán261,107; José Manuel Soria201; Jose V. Sorlí104,105; Nayara S. Silva262; Juan Carlos Souto17; John J. Sprockel100,54; José Javier Suárez-Rama8 ; David A. Suarez-Zamora64; Xiana TaboadaFraga207; Eduardo Tamayo263,156; Alvaro Tamayo-Velasco264; Juan Carlos TaracidoFernandez170; Romero H.T. Vasconcelos111; Carlos Tellería119,120; Thássia M.T. Carratto260; Jair Antonio Tenorio Castaño3,11,12; Alejandro Teper145; Izabel M.T. Araujo109; Juan Torres-Macho265; Lilian Torres-Tobar266; Ronald P. Torres Gutiérrez222; Jesús Troya249; Miguel Urioste210; Juan Valencia-Ramos267; Agustín Valido35,268; Juan Pablo Vargas Gallo269,270; Belén Varón271; Tomas Vega272; Santiago Velasco-Quirce273; Valentina Vélez-Santamaría93,94; Virginia Víctor50,51; Julia Vidán Estévez25; Gabriela V. Silva109; Miriam Vieitez-Santiago59,135; Carlos Vilches274; Lavinia Villalobos25; Felipe Villar221; Judit Villar-Garcia275,276,277; Cristina Villaverde3,40; Pablo VillosladaBlanco175; Ana Virseda-Berdices81; Tatiana X. Costa278; Zuleima Yáñez34; Antonio Zapatero Gaviria279; Ruth Zarate280; Sandra Zazo241; Carlos Flores106,107,154; José A. Riancho59,60,135; Augusto Rojas-Martinez281; Pablo Lapunzina3,11,12; Ángel Carracedo3,8,9,10,13The ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) has 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 events (CME) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (CME 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, CME 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.The authors acknowledge support from the Catalan Department of Economy and Knowledge (SGR2017/1974, SGR2017/801) and the Spanish Ministry of Science “Programa de Excelencia María de Maeztu” (MDM-2014-0370) and “Centro de Excelencia Severo Ochoa” (CEX2018-000806-S), the Fondo Europeo de Desarrollo Regional, UE (RTI2018-100789-B-I00) and the Estonian Research Council (PUT1660). Authors also receive support from the Generalitat de Catalunya through the CERCA Program.N

In utero and childhood exposure to tobacco smoke and multi-layer molecular signatures in children

Background The adverse health effects of early life exposure to tobacco smoking have been widely reported. In spite of this, the underlying molecular mechanisms of in utero and postnatal exposure to tobacco smoke are only partially understood. Here, we aimed to identify multi-layer molecular signatures associated with exposure to tobacco smoke in these two exposure windows. Methods We investigated the associations of maternal smoking during pregnancy and childhood secondhand smoke (SHS) exposure with molecular features measured in 1203 European children (mean age 8.1 years) from the Human Early Life Exposome (HELIX) project. Molecular features, covering 4 layers, included blood DNA methylation and gene and miRNA transcription, plasma proteins, and sera and urinary metabolites. Results Maternal smoking during pregnancy was associated with DNA methylation changes at 18 loci in child blood. DNA methylation at 5 of these loci was related to expression of the nearby genes. However, the expression of these genes themselves was only weakly associated with maternal smoking. Conversely, childhood SHS was not associated with blood DNA methylation or transcription patterns, but with reduced levels of several serum metabolites and with increased plasma PAI1 (plasminogen activator inhibitor-1), a protein that inhibits fibrinolysis. Some of the in utero and childhood smoking-related molecular marks showed dose-response trends, with stronger effects with higher dose or longer duration of the exposure. Conclusion In this first study covering multi-layer molecular features, pregnancy and childhood exposure to tobacco smoke were associated with distinct molecular phenotypes in children. The persistent and dose-dependent changes in the methylome make CpGs good candidates to develop biomarkers of past exposure. Moreover, compared to methylation, the weak association of maternal smoking in pregnancy with gene expression suggests different reversal rates and a methylation-based memory to past exposures. Finally, certain metabolites and protein markers evidenced potential early biological effects of postnatal SHS, such as fibrinolysis

Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease.Fil: Dalmasso, Maria Carolina. Gobierno de la Provincia de la Pampa. Ministerio Publico. Laboratorio de Genetica Forense.; Argentina. Universitat zu Köln; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Confluencia; ArgentinaFil: de Rojas, Itziar. Universitat Internacional de Catalunya; España. Instituto de Salud Carlos Iii (isciii); EspañaFil: Moreno Grau, Sonia. Universitat Internacional de Catalunya; España. Instituto de Salud Carlos Iii (isciii); EspañaFil: Tesi, Niccolo. Vrije Universiteit Amsterdam; Países Bajos. Delft University of Technology; Países BajosFil: Grenier Boley, Benjamin. Universite Lille; FranciaFil: Andrade, Victor. Universitat zu Köln; Alemania. Universitat Bonn; AlemaniaFil: Pedersen, Nancy L.. Karolinska Huddinge Hospital. Karolinska Institutet; SueciaFil: Stringa, Najada. University of Amsterdam; Países BajosFil: Zettergren, Anna. University of Gothenburg; SueciaFil: Hernández, Isabel. Universitat Internacional de Catalunya; España. Instituto de Salud Carlos Iii (isciii); EspañaFil: Montrreal, Laura. Universitat Internacional de Catalunya; EspañaFil: Antúnez, Carmen. Hospital Clínico Universitario Virgen de la Arrixaca; EspañaFil: Antonell, Anna. Universidad de Barcelona; EspañaFil: Tankard, Rick M.. Murdoch University; AustraliaFil: Bis, Joshua C.. University of Washington; Estados UnidosFil: Sims, Rebecca. Cardiff University; Reino UnidoFil: Bellenguez, Céline. Universite Lille; FranciaFil: Quintela, Inés. Universidad de Santiago de Compostela; EspañaFil: González Perez, Antonio. Centro Andaluz de Estudios Bioinformáticos; EspañaFil: Calero, Miguel. Instituto de Salud Carlos Iii (isciii); España. Fundación Reina Sofia; EspañaFil: Franco Macías, Emilio. Universidad de Sevilla; EspañaFil: Macías, Juan. Hospital Universitario de Valme; EspañaFil: Blesa, Rafael. Instituto de Salud Carlos Iii (isciii); España. Universitat Autònoma de Barcelona; EspañaFil: Cervera Carles, Laura. Instituto de Salud Carlos Iii (isciii); España. Universitat Autònoma de Barcelona; EspañaFil: Menéndez González, Manuel. Universidad de Oviedo; EspañaFil: Frank García, Ana. Instituto de Salud Carlos Iii (isciii); España. Universidad Autónoma de Madrid; España. Instituto de Investigacion del Hospital de la Paz.; España. Hospital Universitario La Paz; EspañaFil: Royo, Jose Luís. Universidad de Málaga; EspañaFil: Moreno, Fermin. Instituto de Salud Carlos Iii (isciii); España. Hospital Universitario Donostia; España. Instituto Biodonostia; EspañaFil: Huerto Vilas, Raquel. Hospital Universitari Santa Maria de Lleida; España. Institut de Recerca Biomedica de Lleida; EspañaFil: Baquero, Miquel. Hospital Universitari i Politècnic La Fe; Españ

Severe manifestations of SARS-CoV-2 in children and adolescents: from COVID-19 pneumonia to multisystem inflammatory syndrome: a multicentre study in pediatric intensive care units in Spain

Background Multisystem inflammatory syndrome temporally associated with COVID-19 (MIS-C) has been described as a novel and often severe presentation of SARS-CoV-2 infection in children. We aimed to describe the characteristics of children admitted to Pediatric Intensive Care Units (PICUs) presenting with MIS-C in comparison with those admitted with SARS-CoV-2 infection with other features such as COVID-19 pneumonia. Methods A multicentric prospective national registry including 47 PICUs was carried out. Data from children admitted with confirmed SARS-CoV-2 infection or fulfilling MIS-C criteria (with or without SARS-CoV-2 PCR confirmation) were collected. Clinical, laboratory and therapeutic features between MIS-C and non-MIS-C patients were compared. Results Seventy-four children were recruited. Sixty-one percent met MIS-C definition. MIS-C patients were older than non-MIS-C patients (p = 0.002): 9.4 years (IQR 5.5-11.8) vs 3.4 years (IQR 0.4-9.4). A higher proportion of them had no previous medical history of interest (88.2% vs 51.7%, p = 0.005). Non-MIS-C patients presented more frequently with respiratory distress (60.7% vs 13.3%, p < 0.001). MIS-C patients showed higher prevalence of fever (95.6% vs 64.3%, p < 0.001), diarrhea (66.7% vs 11.5%, p < 0.001), vomits (71.1% vs 23.1%, p = 0.001), fatigue (65.9% vs 36%, p = 0.016), shock (84.4% vs 13.8%, p < 0.001) and cardiac dysfunction (53.3% vs 10.3%, p = 0.001). MIS-C group had a lower lymphocyte count (p < 0.001) and LDH (p = 0.001) but higher neutrophil count (p = 0.045), neutrophil/lymphocyte ratio (p < 0.001), C-reactive protein (p < 0.001) and procalcitonin (p < 0.001). Patients in the MIS-C group were less likely to receive invasive ventilation (13.3% vs 41.4%, p = 0.005) but were more often treated with vasoactive drugs (66.7% vs 24.1%, p < 0.001), corticosteroids (80% vs 44.8%, p = 0.003) and immunoglobulins (51.1% vs 6.9%, p < 0.001). Most patients were discharged from PICU by the end of data collection with a median length of stay of 5 days (IQR 2.5-8 days) in the MIS-C group. Three patients died, none of them belonged to the MIS-C group. Conclusions MIS-C seems to be the most frequent presentation among critically ill children with SARS-CoV-2 infection. MIS-C patients are older and usually healthy. They show a higher prevalence of gastrointestinal symptoms and shock and are more likely to receive vasoactive drugs and immunomodulators and less likely to need mechanical ventilation than non-MIS-C patients

Long runs of homozygosity are associated with Alzheimer's disease

Altres ajuts: The Genome Research at Fundació ACE project (GR@ACE) is supported by Fundación bancaria "La Caixa," Grifols SA and Fundació ACE. L.M.R. is supported by Consejería de Salud de la Junta de Andalucía (Grant PI-0001/2017).Long runs of homozygosity (ROH) are contiguous stretches of homozygous genotypes, which are a footprint of inbreeding and recessive inheritance. The presence of recessive loci is suggested for Alzheimer's disease (AD); however, their search has been poorly assessed to date. To investigate homozygosity in AD, here we performed a fine-scale ROH analysis using 10 independent cohorts of European ancestry (11,919 AD cases and 9181 controls.) We detected an increase of homozygosity in AD cases compared to controls [ β (CI 95%) = 0.070 (0.037-0.104); P = 3.91 × 10 −5 ; β (CI95%) = 0.043 (0.009-0.076); P = 0.013]. ROHs increasing the risk of AD (OR > 1) were significantly overrepresented compared to ROHs increasing protection (p < 2.20 × 10 −16). A significant ROH association with AD risk was detected upstream the HS3ST1 locus (chr4:11,189,482‒11,305,456), (β (CI 95%) = 1.09 (0.48 ‒ 1.48), p value = 9.03 × 10 −4), previously related to AD. Next, to search for recessive candidate variants in ROHs, we constructed a homozygosity map of inbred AD cases extracted from an outbred population and explored ROH regions in whole-exome sequencing data (N = 1449). We detected a candidate marker, rs117458494, mapped in the SPON1 locus, which has been previously associated with amyloid metabolism. Here, we provide a research framework to look for recessive variants in AD using outbred populations. Our results showed that AD cases have enriched homozygosity, suggesting that recessive effects may explain a proportion of AD heritability