A large‐scale screen for coding variants in SERT/SLC6A4 in autism spectrum disorders

In the current study we explored the hypothesis that rare variants in SLC6A4 contribute to autism susceptibility and to rigid‐compulsive behaviors in autism. We made use of a large number of unrelated cases with autism spectrum disorders (∼350) and controls (∼420) and screened for rare exonic variants in SLC6A4 by a high‐throughput method followed by sequencing. We observed no difference in the frequency of such variants in the two groups, irrespective of how we defined the rare variants. Furthermore, we did not observe an association of rare coding variants in SLC6A4 with rigid‐compulsive traits scores in the cases. These results do not support a significant role for rare coding variants in SLC6A4 in autism spectrum disorders, nor do they support a significant role for SLC6A4 in rigid‐compulsive traits in these disorders.

[1]  D. Murphy,et al.  Functional SLITRK1 var321, varCDfs and SLC6A4 G56A variants and susceptibility to obsessive-compulsive disorder , 2006, Molecular Psychiatry.

[2]  Catherine Lord,et al.  5-HTTLPR Genotype-Specific Phenotype in Children and Adolescents With Autism. , 2006, The American journal of psychiatry.

[3]  Randy D Blakely,et al.  Human serotonin transporter variants display altered sensitivity to protein kinase G and p38 mitogen-activated protein kinase. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[4]  J. Sutcliffe,et al.  Allelic heterogeneity at the serotonin transporter locus (SLC6A4) confers susceptibility to autism and rigid-compulsive behaviors. , 2005, American journal of human genetics.

[5]  B. Leventhal,et al.  The serotonin system in autism. , 1996, Current opinion in pediatrics.

[6]  T. Bourgeron,et al.  Support for the association between the rare functional variant I425V of the serotonin transporter gene and susceptibility to obsessive compulsive disorder , 2005, Molecular Psychiatry.

[7]  J. Buxbaum,et al.  Lack of Evidence for Association of the Serotonin Transporter Gene SLC6A4 with Autism , 2006, Biological Psychiatry.

[8]  D. Reich,et al.  Detecting association in a case‐control study while correcting for population stratification , 2001, Genetic epidemiology.

[9]  F. McMahon,et al.  SERT Ileu425Val in autism, Asperger syndrome and obsessive–compulsive disorder , 2008, Psychiatric genetics.

[10]  V. Willour,et al.  Rare plus common SERT variants in obsessive-compulsive disorder , 2007, Molecular Psychiatry.

[11]  G. Dawson,et al.  Autism and the serotonin transporter: the long and short of it , 2005, Molecular Psychiatry.

[12]  Chiara Sabatti,et al.  Overrepresentation of rare variants in a specific ethnic group may confuse interpretation of association analyses. , 2006, Human molecular genetics.

[13]  Ronald W. Davis,et al.  Multiplexed variation scanning for 1,000 amplicons in hundreds of patients using mismatch repair detection (MRD) on tag arrays. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[14]  M. Gill,et al.  Serotonin transporter gene and autism: a haplotype analysis in an Irish autistic population , 2004, Molecular Psychiatry.

[15]  J. Sutcliffe,et al.  Linkage and association analysis at the serotonin transporter (SLC6A4) locus in a rigid‐compulsive subset of autism , 2004, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[16]  T. Gilliam,et al.  Hardy-Weinberg disequilibrium identified genotyping error of the serotonin transporter (SLC6A4) promoter polymorphism. , 2006, Psychiatric genetics.

[17]  B. Greenberg,et al.  Serotonin transporter missense mutation associated with a complex neuropsychiatric phenotype , 2003, Molecular Psychiatry.

[18]  Stephen J. Guter,et al.  Transmission disequilibrium mapping at the serotonin transporter gene (SLC6A4) region in autistic disorder , 2002, Molecular Psychiatry.