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

• Published in: npj Genomic Medicine
• Main Authors: Leblond, Claire, Cliquet, Freddy, Carton, Coralie, Huguet, Guillaume, Mathieu, Alexandre, Kergrohen, Thomas, Buratti, Julien, Lemière, Nathalie, Cuisset, Laurence, Bienvenu, Thierry, Boland, Anne, Deleuze, Jean-François, Stora, Tormodur, Biskupstoe, Rannva, Halling, Jónrit, Andorsdóttir, Guðrið, Billstedt, Eva, Gillberg, Christopher, Bourgeron, Thomas
• Other Authors: Génétique Humaine et Fonctions Cognitives, Institut Pasteur Paris -Centre National de la Recherche Scientifique (CNRS), Gènes, Synapses et Cognition, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur Paris, 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)
• Format: Article in Journal/Newspaper
• Language: English
• Published: HAL CCSD 2019
• Subjects: Autism spectrum disorders; [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics; Faroe Islands
• Online Access: https://hal-pasteur.archives-ouvertes.fr/pasteur-02562551; https://hal-pasteur.archives-ouvertes.fr/pasteur-02562551/document; https://hal-pasteur.archives-ouvertes.fr/pasteur-02562551/file/Both%20rare%20and%20common%20genetic%20variants%20contribute%20to%20autism%20in%20the%20Faroe%20Islands.pdf; https://doi.org/10.1038/s41525-018-0075-2

International audience 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.