An autism susceptibility locus (AUTS1, MIM♯608636) has been identified in chromosome 7q31. NrCAM is a candidate gene for AUTS1 because it is expressed in the brain and encodes a receptor involved in nervous system development. Polymorphisms in NrCAM have been reported to be associated with autism susceptibility and with substance abuse, implicating NrCAM in reward circuitry. Self-stimulatory, perseverative behavior in autism might be due to defects in reward circuitry. In addition, models of drug addiction have also borrowed from models of obsessive–compulsive behavior designed to reduce anxiety. Thus, our goals were to replicate previous associations of NrCAM with autism, making use of a large cohort, and to clarify whether NrCAM was associated with a specific endophenotype of autism in the repetitive behaviors and stereotyped interests domains.
We genotyped six NrCAM single nucleotide polymorphisms in 352 families and we tested for association between these polymorphisms and autism in the entire cohort and in two subsets, one with severe obsessive–compulsive behaviors and one with pronounced self-stimulatory behaviors.
We found no association between single nucleotide polymorphisms of NrCAM and autism in our large cohort, or in the severe obsessive–compulsive behavior and self-stimulatory behavior subsets. However, we observed a significant overtransmission (21 transmitted vs 6 nontransmitted, χ2=12.054, P=0.0005) of the haplotype G-G-A-G-C-A of rs722519-rs1269622-rs405945-rs6958498-rs401433-rs439587 in the severe obsessive–compulsive behavior subset, likely driven by the G-C haplotype of rs6958498-rs401433, which itself showed significant overtransmission (31 transmitted vs 13 nontransmitted, χ2=8.844, P=0.003).
Overtransmission of particular haplotypes of NrCAM, that may relate to the expression level of NrCAM in the brain, appeared to be associated with autism in the severe obsessive–compulsive behavior subset.
Departments of aPsychiatry
bPharmacology and Biological Chemistry
cNeuroscience, and Human Genetics
dSeaver Autism Research Center, Mount Sinai School of Medicine, New York, New York, USA
Correspondence and requests for reprints to Dr Joseph D. Buxbaum, Department of Psychiatry, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1668, New York, NY 10029, USA
Tel: +1 212 659 8862; fax: +1 212 828 4221; e-mail: email@example.com
Sponsorship: This work is supported by the Seaver Foundation and by the National Institutes of Health through a Studies to Advance Autism Research and Treatment (STAART) grant (MH066673). Takeshi Sakurai is a Seaver Fellow.
*These authors contributed equally to the work.
Present address: Nicolas Ramoz, INSERM U675, IFR2, Faculté X Bichat, 75018 Paris, France.
Received 5 December 2005 Accepted 28 June 2006