Both rare and common genetic variants contribute to autism in the Faroe Islands

Autor: Laurence Cuisset, Alexandre Mathieu, Thierry Bienvenu, Jónrit Halling, Coralie Carton, Rannva Biskupstoe, Nathalie Lemière, Thomas Kergrohen, Guðrið Andorsdóttir, Claire S. Leblond, Tormodur Stora, Freddy Cliquet, Jean-François Deleuze, Thomas Bourgeron, Eva Billstedt, Julien Buratti, Guillaume Huguet, Christopher Gillberg, Anne Boland
Přispěvatelé: Génétique Humaine et Fonctions Cognitives, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Gènes, Synapses et Cognition (CNRS - UMR3571 ), Université Paris Diderot, Sorbonne Paris Cité, Paris, France, Université Paris Diderot - Paris 7 (UPD7), Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Service de Génétique et Biologie Moléculaires [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de psychiatrie et neurosciences (U894 / UMS 1266), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), National Hospital of the Faroe Islands [Tórshavn, Faroe Islands], Genetic Biobank of the Faroes [Tórshavn, Faroe Islands], Ministry of Health and The Interior [Faroe Islands], University of the Faroe Islands, University of Gothenburg (GU), Gillberg Neuropsychiatry Centre [Göteborg, Sueden], Institute of Neuroscience and Physiology [Göteborg]-University of Gothenburg (GU), University of Glasgow, This work was supported by the Institut Pasteur, Centre National de la Recherche Scientifique, the Assistance Publique—Hôpitaux de Paris, the University Paris Diderot, the Simons Foundation, the Fondation pour la Recherche Médicale [DBI20141231310], the European Commission Horizon 2020 [COSYN], The human brain project, the European Commission Innovative Medicines Initiative [EU-AIMS no. 115300], the Cognacq-Jay foundation, the Bettencourt-Schueller foundation, the Orange foundation, the FondaMental foundation, the Conny-Maeva foundation, and the Agence Nationale de la Recherche (ANR) [SynPathy]. This research was supported by the Laboratory of Excellence GENMED (Medical Genomics) grant no. ANR-10-LABX-0013, Bio-Psy and by the INCEPTION program ANR-16-CONV-0005, all managed by the ANR part of the Investment for the Future program., We would like to thank all the participants of the epidemiological and genetic cohorts, the 'progeny' database, Julien Fumey for his R tutorial (https://bioinfo-fr.net/creer-sa-carte-geographique-avec-r), Fabrice de Chaumont for his help with python and Thomas Rolland for his feedback on the revised manuscript., ANR-16-CONV-0005,INCEPTION,Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs(2016), ANR-10-LABX-0013,GENMED,Medical Genomics(2010), ANR-15-NEUR-0007,SynPathy,Key Determinants of Synaptic Excitation-Inhibition Imbalance in Autism Spectrum Disorders - From Genetic Animal Models to Human Patients(2015), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre de Psychiatrie et Neurosciences (U894), MATHIEU, Alexandre, Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs - - INCEPTION2016 - ANR-16-CONV-0005 - CONV - VALID, Medical Genomics - - GENMED2010 - ANR-10-LABX-0013 - LABX - VALID, Key Determinants of Synaptic Excitation-Inhibition Imbalance in Autism Spectrum Disorders - From Genetic Animal Models to Human Patients - - SynPathy2015 - ANR-15-NEUR-0007 - NEURON II - VALID
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Zdroj: npj Genomic Medicine
npj Genomic Medicine, Springer Nature, 2019, 4 (1), ⟨10.1038/s41525-018-0075-2⟩
NPJ Genomic Medicine
npj Genomic Medicine, 2019, 4 (1), ⟨10.1038/s41525-018-0075-2⟩
npj Genomic Medicine, Vol 4, Iss 1, Pp 1-10 (2019)
ISSN: 2056-7944
Popis: The number of genes associated with autism is increasing, but few studies have been performed on epidemiological cohorts and in isolated populations. Here, we investigated 357 individuals from the Faroe Islands including 36 individuals with autism, 136 of their relatives and 185 non-autism controls. Data from SNP array and whole exome sequencing revealed that individuals with autism had a higher burden of rare exonic copy-number variants altering autism associated genes (deletions (p = 0.0352) or duplications (p = 0.0352)), higher inbreeding status (p = 0.023) and a higher load of rare homozygous deleterious variants (p = 0.011) compared to controls. Our analysis supports the role of several genes/loci associated with autism (e.g., NRXN1, ADNP, 22q11 deletion) and identified new truncating (e.g., GRIK2, ROBO1, NINL, and IMMP2L) or recessive deleterious variants (e.g., KIRREL3 and CNTNAP2) affecting autism-associated genes. It also revealed three genes involved in synaptic plasticity, RIMS4, KALRN, and PLA2G4A, carrying de novo deleterious variants in individuals with autism without intellectual disability. In summary, our analysis provides a better understanding of the genetic architecture of autism in isolated populations by highlighting the role of both common and rare gene variants and pointing at new autism-risk genes. It also indicates that more knowledge about how multiple genetic hits affect neuronal function will be necessary to fully understand the genetic architecture of autism.
Genetic correlates of autism in natives of remote islands A study of the genetic architecture of autism among people living on the remote Faroe Islands highlights the role of both common and rare gene variants to autism. Claire Leblond from the Institut Pasteur in Paris, France, and colleagues profiled the genetics of 357 Faroese individuals, including 36 with autism, 136 of their relatives and 185 non-autistic controls. Similar to the findings of genetic studies of autism from elsewhere, the researchers discovered rare structural variants in known autism-associated genes and a few new candidate genes linked to brain function. However, unlike studies from larger mainland populations, they also showed that inbreeding on these remote islands increased the likelihood of carrying two copies of the point mutations that contribute to autism.
Databáze: OpenAIRE
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