Association analysis of the NrCAM gene in autism and in subsets of families with severe obsessive-compulsive or self-stimulatory behaviors

Takeshi Sakurai, Nicolas Ramoz, Jennifer G. Reichert, Thomas E. Corwin, Lauren Kryzak, Christopher J. Smith, Jeremy M. Silverman, Eric Hollander, Joseph D. Buxbaum

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

OBJECTIVES: 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. METHODS: 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. RESULTS: 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, χ=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, χ=8.844, P=0.003). CONCLUSIONS: 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.

Original languageEnglish (US)
Pages (from-to)251-257
Number of pages7
JournalPsychiatric Genetics
Volume16
Issue number6
DOIs
StatePublished - Dec 2006
Externally publishedYes

Fingerprint

Autistic Disorder
Compulsive Behavior
Obsessive Behavior
Genes
Haplotypes
Reward
Substance-Related Disorders
Single Nucleotide Polymorphism
Endophenotypes
Stereotyped Behavior
Brain
Nervous System
Anxiety
Chromosomes

Keywords

  • 7q31
  • Autism disorder
  • AUTS1
  • Behaviors
  • Brain
  • Cell adhesion molecule
  • Drug addiction
  • Receptor

ASJC Scopus subject areas

  • Genetics(clinical)
  • Psychiatry and Mental health
  • Genetics
  • Neuroscience(all)

Cite this

Association analysis of the NrCAM gene in autism and in subsets of families with severe obsessive-compulsive or self-stimulatory behaviors. / Sakurai, Takeshi; Ramoz, Nicolas; Reichert, Jennifer G.; Corwin, Thomas E.; Kryzak, Lauren; Smith, Christopher J.; Silverman, Jeremy M.; Hollander, Eric; Buxbaum, Joseph D.

In: Psychiatric Genetics, Vol. 16, No. 6, 12.2006, p. 251-257.

Research output: Contribution to journalArticle

Sakurai, Takeshi ; Ramoz, Nicolas ; Reichert, Jennifer G. ; Corwin, Thomas E. ; Kryzak, Lauren ; Smith, Christopher J. ; Silverman, Jeremy M. ; Hollander, Eric ; Buxbaum, Joseph D. / Association analysis of the NrCAM gene in autism and in subsets of families with severe obsessive-compulsive or self-stimulatory behaviors. In: Psychiatric Genetics. 2006 ; Vol. 16, No. 6. pp. 251-257.
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abstract = "OBJECTIVES: 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. METHODS: 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. RESULTS: 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, χ=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, χ=8.844, P=0.003). CONCLUSIONS: 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.",
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AU - Ramoz, Nicolas

AU - Reichert, Jennifer G.

AU - Corwin, Thomas E.

AU - Kryzak, Lauren

AU - Smith, Christopher J.

AU - Silverman, Jeremy M.

AU - Hollander, Eric

AU - Buxbaum, Joseph D.

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N2 - OBJECTIVES: 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. METHODS: 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. RESULTS: 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, χ=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, χ=8.844, P=0.003). CONCLUSIONS: 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.

AB - OBJECTIVES: 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. METHODS: 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. RESULTS: 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, χ=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, χ=8.844, P=0.003). CONCLUSIONS: 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.

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