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NPJ Genom Med. 2019 Jan 21;4:1. doi: 10.1038/s41525-018-0075-2. eCollection 2019.

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

Leblond CS#1,2,3,4, Cliquet F#1,2,3,4, Carton C#1,2,3,4, Huguet G1,2,3,4, Mathieu A1,2,3,4, Kergrohen T1,2,3,4, Buratti J1,2,3,4, Lemière N1,2,3,4, Cuisset L5, Bienvenu T5,6, Boland A7, Deleuze JF7, Stora T8, Biskupstoe R9, Halling J10, Andorsdóttir G9, Billstedt E11, Gillberg C1,8,11,12, Bourgeron T1,2,3,4,11.

Author information

1
1Human Genetics and Cognitive Functions Unit, Institut Pasteur, Paris, France.
2
2CNRS UMR 3571 Genes, Synapses and Cognition, Institut Pasteur, Paris, France.
3
3University Paris Diderot, Sorbonne Paris Cité, Paris, France.
4
Centre de Bioinformatique, Biostatistique et Biologie Intégrative, Paris, France.
5
5Laboratoire de Génétique et Biologie Moléculaires, Hôpital Cochin, HUPC, Paris, France.
6
6INSERM U894, Institut de Psychiatrie et de Neurosciences de Paris, Paris, France.
7
7Centre National de Recherche en Génomique Humaine (CNRGH), Institut de Biologie François Jacob, CEA, Université Paris-Saclay, Evry, France.
8
Department of Psychiatry, National Hospital Faroe Islands, Tórshavn, Faroe Islands.
9
Ministry of Health Genetic Biobank of the Faroes Tórshavn Faeroe Islands, Tórshavn, Faroe Islands.
10
10Faculty of Science and Technology, The University of the Faroe Islands, Tórshavn, Faroe Islands.
11
11Gillberg Neuropsychiatry Centre, Institute of Neuroscience and Physiology, Gothenburg University, Gothenburg, Sweden.
12
12University of Glasgow, Glasgow, Scotland UK.
#
Contributed equally

Abstract

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.

Conflict of interest statement

The authors declare no competing interests.

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