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.
Highlights
Autism is a neurodevelopmental disorder that is manifested in early childhood and is characterized by impairments in reciprocal social interactions and language, and a restricted range of behaviors and interests
The genetic disorders Prader-Willi and Angelman syndromes, which result from defects in imprinting or the loss of expression of imprinted genes in the chromosomal region 15q11-q13 [11] are associated with autistic features and diagnoses [12,13,14,15,16], and maternally transmitted abnormalities of chromosome 15 have been detected in autistic patients [12,17,18]
Autism Genetic Resource Exchange (AGRE) families with a child diagnosed with an Autism Spectrum Disorder (ASD) based on evaluation by the Autism Diagnostic Interview-Revised (ADI-R) [24] were recruited from across the US
Summary
We 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)
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