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

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.

Pairwise common variant meta-analyses of schizophrenia with other psychiatric disorders reveals shared and distinct gene and gene-set associations

“…OCD did not display a significant association with this gene-set, as perhaps would be expected, however, the small sample size of its GWAS may account for this. Deleterious rare variation within these regions has also shown to be enriched for schizophrenia and ASD, consolidating the multi-faceted nature of genomic risk for these disorders (3, 37).…”

Kirrel3-mediated synapse formation is attenuated by disease-associated missense variants

“…Kirrel3 is an emerging hotspot for rare variants linked to neurodevelopmental disorders (Bhalla et al, 2008; Kaminsky et al, 2011; Ben-David and Shifman, 2012; Guerin et al, 2012; Michaelson et al, 2012; Neale et al, 2012; Talkowski et al, 2012; Iossifov et al, 2014; Rubeis et al, 2014; Wang et al, 2016; Yuen et al, 2016; Li et al, 2017; Guo et al, 2019; Leblond, et al, 2019). Here we provide the first functional evidence demonstrating that Kirrel3 variants could cause disease.…”

“…1A) that undergoes homophilic trans-cellular binding (Sellin et al, 2002; Gerke et al, 2005; Martin et al, 2015). Importantly, copy number variations and missense variants in Kirrel3 are repeatedly associated with neurodevelopmental disorders including ASD and intellectual disability (ID) (Table 1) (Bhalla et al, 2008; Kaminsky et al, 2011; Ben-David and Shifman, 2012; Guerin et al, 2012; Michaelson et al, 2012; Neale et al, 2012; Talkowski et al, 2012; Iossifov et al, 2014; Rubeis et al, 2014; Wang et al, 2016; Yuen et al, 2016; Li et al, 2017; Guo et al, 2019; Leblond, et al, 2019). There are currently at least 17 missense variants identified from multiple, independent studies lending credence to the possibility that altering Kirrel3 function leads to ASD and ID.…”

Genetic and Epigenetic Etiology Underlying Autism Spectrum Disorder

“…The loss of one or more of the 15 genes found in the 17q12 region causes ASD and schizophrenia, and the more genes that are deleted, the more brain development and function becomes affected [172]. The chromosomal CNV by 22q11 deletion, which causes 22q11.2 deletion syndromes, shows higher susceptibility for ASD than the general population at about 23%-50% [166].…”