Association Between Autism Spectrum Disorders (ASD) In VCFS Patients and SNPs In PRODH and COMT

Background: Velocardiofacial syndrome (VCFS; 22q11.2 deletion syndrome) results from a microdeletion of the 11.2 band of one copy of chromosome 22. Notably, 11% to 33% of VCFS patients have narrowly defined autism and up to about 40% have Autism Spectrum Disorders (ASD) (based on the ADI-R). Genes in the 22q11.2 region have diverse functions and many are expressed in the brain. These genes may play a role in brain development, neurotransmitter levels, and myelination.  COMT (catecholamine-O-methyl transferase), for example, participates in the degradation of catecholamines (including dopamine), and affects the dopamine levels in the prefrontal cortex. Notably, the low-activity allele of COMT has been associated with social cognition impairments in VCFS patients. PRODH (proline dehydrogenase (oxidase)), another gene that is deleted on one copy of the 22q11.2 region, participates in the degradation of the amino acid proline, and the low-activity alleles of PRODH may be associated with ASD and mental retardation.

Objectives: Our goal was to explore the association between SNPs (single nucleotide polymorphisms) in COMT and PRODH on the remaining copy of chromosome 22, and ASD in VCFS patients.

Methods: We selected to study rs4680 in COMT and rs367766 (a surrogate marker in linkage disequilibrium with rs4819756 (r²=0.833, for HapMap-CEU)) in PRODH. As part of a larger study, we genotyped rs4680 and rs367766, and conducted the ADI-R.  We classified subjects as having ASD if they met criteria for qualitative impairments in reciprocal social interaction, and for deficits in either communication or repetitive behaviors and stereotyped patterns (or both).  We had 60 patients on which we had both rs4680 and rs367766 genotypes, and ASD categorization. We conducted Fisher's exact tests and calculated odds ratios to look for associations between the SNPs and ASD.

Results: We found a significant association of ASD with rs367766 (Fisher's Exact test: p=0.006; OR=7.4 (95% CI=1.9-28.6)).  In addition, COMT and PRODH showed an interaction, such that VCFS patients with both low-activity COMT and low-activity PRODH alleles (rs4680A and rs367766C, surrogate marker for rs4819756A, respectively) seemed more likely to have ASD, as compared to VCFS patients with high-activity COMT and high-activity PRODH alleles (Fisher's Exact test: p=0.003; OR=16 (95% CI=2.6-100.1)).

Conclusions: The combination of low-activity alleles of COMT and PRODH appear to be associated with ASD in VCFS patients, and might be a risk factor for the development of ASD in the VCFS population.  Further studies could explore whether low-activity alleles of PRODH and COMT may be associated with ASD in the general population as well (ie, in individuals without a 22q11.2 deletion).