Parent-Of-Origin Effects in Autism Identified through Genome-Wide Linkage Analysis of 16,000 SNPs

Abstract

BackgroundAutism is a common heritable neurodevelopmental disorder with complex etiology. Several genome-wide linkage and association scans have been carried out to identify regions harboring genes related to autism or autism spectrum disorders, with mixed results. Given the overlap in autism features with genetic abnormalities known to be associated with imprinting, one possible reason for lack of consistency would be the influence of parent-of-origin effects that may mask the ability to detect linkage and association.Methods and FindingsWe have performed a genome-wide linkage scan that accounts for potential parent-of-origin effects using 16,311 SNPs among families from the Autism Genetic Resource Exchange (AGRE) and the National Institute of Mental Health (NIMH) autism repository. We report parametric (GH, Genehunter) and allele-sharing linkage (Aspex) results using a broad spectrum disorder case definition. Paternal-origin genome-wide statistically significant linkage was observed on chromosomes 4 (LODGH = 3.79, empirical p<0.005 and LODAspex = 2.96, p = 0.008), 15 (LODGH = 3.09, empirical p<0.005 and LODAspex = 3.62, empirical p = 0.003) and 20 (LODGH = 3.36, empirical p<0.005 and LODAspex = 3.38, empirical p = 0.006).ConclusionsThese regions may harbor imprinted sites associated with the development of autism and offer fruitful domains for molecular investigation into the role of epigenetic mechanisms in autism.

Common DNA methylation alterations in multiple brain regions in autism

“…Interestingly, this DMR is also located within an imprinted region of the genome. Imprinting 63 and parent-of-origin specific effects 15, 16 have been previously implicated in ASD.…”

“…Direct evidence 14 comes from identification of ASD-associated chromosomal abnormalities in imprinted regions, ASD linkage and association in areas of known imprinting, and evidence of parent-of-origin effects in association and linkage signals 15, 16 . Additional support stems from the observation of autistic features, sometimes reaching the diagnostic threshold, in individuals affected with known epigenetic disorders such as Angelman, fragile X, and Rett Syndromes.…”

The role of genomic imprinting in biology and disease: an expanding view

“…How overexpression of UBE3A could lead to psychosis remains to be established 90,105,106 . In addition, several psychiatric disorders with social impairments, including autism spectrum disorders, have shown linkage to imprinted regions or cytogenetic abnormalities that are predicted to disrupt imprinted gene expression 90,107,108 .…”

The Human Imprintome: Regulatory Mechanisms, Methods of Ascertainment, and Roles in Disease Susceptibility

“…Most telling are multiple recent studies on parent-of-origin effects, and the connection between imprinted genes and rare copy number variants observed in autism and schizophrenia (Depienne et al 2009; Fradin et al 2010; Guffanti et al 2011; Hogart et al 2009; Ingason et al 2011; Kato et al 2008). These studies often focus on copy number variants in 15q11–15q13, the PWS critical region, known to contain an imprinted gene cluster.…”