Association between a high-risk autism locus on 5p14 and social communication spectrum phenotypes in the general population.
OBJECTIVE
Recent genome-wide analysis identified a genetic variant on 5p14.1 (rs4307059), which is associated with risk for autism spectrum disorder. This study investigated whether rs4307059 also operates as a quantitative trait locus underlying a broader autism phenotype in the general population, focusing specifically on the social communication aspect of the spectrum.


METHODS
Study participants were 7,313 children from the Avon Longitudinal Study of Parents and Children. Single-trait and joint-trait genotype associations were investigated for 29 measures related to language and communication, verbal intelligence, social interaction, and behavioral adjustment, assessed between ages 3 and 12 years. Analyses were performed in one-sided or directed mode and adjusted for multiple testing, trait interrelatedness, and random genotype dropout.


RESULTS
Single phenotype analyses showed that an increased load of rs4307059 risk allele is associated with stereotyped conversation and lower pragmatic communication skills, as measured by the Children's Communication Checklist (at a mean age of 9.7 years). In addition a trend toward a higher frequency of identification of special educational needs (at a mean age of 11.8 years) was observed. Variation at rs4307059 was also associated with the phenotypic profile of studied traits. This joint signal was fully explained neither by single-trait associations nor by overall behavioral adjustment problems but suggested a combined effect, which manifested through multiple sub-threshold social, communicative, and cognitive impairments.


CONCLUSIONS
Our results suggest that common variation at 5p14.1 is associated with social communication spectrum phenotypes in the general population and support the role of rs4307059 as a quantitative trait locus for autism spectrum disorder.
St Pourcain
Beate
B
Medical Research Council Centre for Causal Analyses in Translational Epidemiology, University of Bristol, Bristol, UK. beate.stpourcain@bristol.ac.uk
Wang
Kai
K
Glessner
Joseph T
JT
Golding
Jean
J
Steer
Colin
C
Ring
Susan M
SM
Skuse
David H
DH
Grant
Struan F A
SF
Hakonarson
Hakon
H
Smith
George D
GD
Davey Smith
George
G
D000483:Alleles; D002648:Child; D002659:Child Development Disorders, Pervasive / Q000175:diagnosis / Q000235:genetics* / Q000628:therapy; D002675:Child, Preschool; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics*; D015331:Cohort Studies; D003147:Communication Disorders / Q000175:diagnosis / Q000235:genetics* / Q000628:therapy; D004519:Education, Special; D005260:Female; D056426:Genetic Loci / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007360:Intelligence / Q000235:genetics; D007859:Learning Disabilities / Q000175:diagnosis / Q000235:genetics / Q000628:therapy; D008137:Longitudinal Studies; D008297:Male; D019965:Neurocognitive Disorders / Q000175:diagnosis / Q000235:genetics* / Q000628:therapy; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics; D012919:Social Behavior; D013239:Stereotyped Behavior; D006113:United Kingdom