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

Claire Leblond (1, 2, 3, 4) , Freddy Cliquet (1, 2, 3, 4) , Coralie Carton (1, 2, 3, 4) , Guillaume Huguet (1, 2, 3, 4) , Alexandre Mathieu (1, 2, 3, 4) , Thomas Kergrohen (1, 2, 3, 4) , Julien Buratti (1, 2, 3, 4) , Nathalie Lemière (1, 2, 3, 4) , Laurence Cuisset (5) , Thierry Bienvenu (5, 6) , Anne Boland (7, 8) , Jean-François Deleuze (8, 7) , Tormodur Stora (9) , Rannva Biskupstoe (10) , Jónrit Halling (11) , Guðrið Andorsdóttir (12, 10) , Eva Billstedt (13, 14) , Christopher Gillberg (1, 9, 14, 15) , Thomas Bourgeron (1, 2, 3, 4, 14)

1 Génétique Humaine et Fonctions Cognitives
2 CNRS - UMR3571 - Gènes, Synapses et Cognition
3 Université Paris Diderot, Sorbonne Paris Cité, Paris, France
4 C3BI - Centre de Bioinformatique, Biostatistique et Biologie Intégrative
5 Service de Génétique et Biologie Moléculaires [CHU Cochin]
6 U894 / UMS 1266 - Institut de psychiatrie et neurosciences
7 CNG - Centre National de Génotypage
8 JACOB - Institut de Biologie François JACOB
9 National Hospital of the Faroe Islands [Tórshavn, Faroe Islands]
10 Genetic Biobank of the Faroes [Tórshavn, Faroe Islands]
11 University of the Faroe Islands
12 Ministry of Health and The Interior [Faroe Islands]
13 GU - University of Gothenburg
14 Gillberg Neuropsychiatry Centre [Göteborg, Sueden]
15 University of Glasgow

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.

Keywords: Autism spectrum disorders

Domains: Human genetics

Claire Leblond, Freddy Cliquet, Coralie Carton, Guillaume Huguet, Alexandre Mathieu, et al.. Both rare and common genetic variants contribute to autism in the Faroe Islands. npj Genomic Medicine, 2019, 4 (1), ⟨10.1038/s41525-018-0075-2⟩. ⟨pasteur-02562551⟩