B653 - Genomewide analysis of autism/autism spectrum disorder related quantitive traits in the ALSPAC cohort - 09/05/2008

B number: 
Principal applicant name: 
Dr Beate Glaser (University of Bristol, UK)
Prof George Davey Smith (University of Bristol, UK), Prof Jean Golding (University of Bristol, UK)
Title of project: 
Genomewide analysis of autism/autism spectrum disorder related quantitive traits in the ALSPAC cohort
Proposal summary: 

Autism is a severe and heritable condition, which belongs together with Pervasive Developmental Disorder NOS, Rett's syndrome, Asperger syndrome and Childhood Disintegrative Disorder to the group of autism spectrum disorders (ASD) (American Psychiatric Association, 1994). ASD usually starts in early childhood and all ASD show strong impairment in reciprocal social interaction. Additionally, syndrome-specific impairment in communication or stereotyped behaviour, interests and activities may be present (American Psychiatric Association, 1994)(WHO, 1992). Associated with ASD are often abnormalities in the development of cognitive skills (mental retardation) and behavioural symptoms like hyperactivity, attention deficits, impulsivity, aggressiveness, self-injury and temper tantrums. (American Psychiatric Association, 1994)(WHO, 1992).

Defined mutations, genetic syndromes and de novo copy number variations account together for approximately 10-20% of ASD cases (Abrahams & Geschwind, 2008). Twin and family studies have however provided additional support for a complex genetic disease aetiology underlying ASD such as shown by the increased similarity of cognitive and behavioural features among relatives (Abrahams & Geschwind, 2008). High heritability estimates for social impairments, communication impairments, and restricted repetitive behaviors and interests have been observed, although the co-variation between these domains was modest (Ronald, Happe, Price, Baron-Cohen, & Plomin, 2006). By contrast, evidence for overlapping genetic influences on comorbid autistic and ADHD behaviours was found in a recent community-based twin sample (Ronald, Simonoff, Kuntsi, Asherson, & Plomin, 2008). These findings suggest an oligogenic disease model for ASD with synergistic action of multiple loci, an assumption that is also supported by distinct linkage signals for ASD endophenotypes (Abrahams & Geschwind, 2008).

Given the importance of common genetic variation in ASD risk, we propose a genome wide association study of autism spectrum disorder related traits in ALSPAC. We furthermore propose that common genetic variation, which is related to autism spectrum disorder quantitative traits, will occur in genes in which more severe mutations will lead to autism.

We will investigate single, multi-marker and epistatic effects using the software Plink, STATA and R. Single marker effects will also be followed up longitudinally. We furthermore aim to identify clusters of endophenotype-related genotypes using hierarchical clustering and PCA. We will investigate homozygocity and segmental sharing across associated genomic regions using Plink and in house developed Perl software.

Date proposal received: 
Friday, 9 May, 2008
Date proposal approved: 
Friday, 9 May, 2008
Primary keyword: