Abstract # 127:

Scheduled for Friday, August 18, 2006 03:20 PM-03:40 PM: Session 13 (Regency East #1) Oral Presentation

Multiple Novel DRD4 and TPH2 Polymorphisms in the Rhesus Macaque: Association with Impulsive and Aggressive Behavior?

T. K. Newman1, J. R. Wendland2, C. S. Barr1, J. D. Higley1 and D. Goldman1
1NIAAA/NIH, 5625 Fishers Lane Room 3S-32, Room 3S-32, Laboratory of Neurogenetics, Rockville, MD 20852, USA, 2NIMH/NIH
     Few behavior related candidate genes (e.g., MAOA and SERT) contain functional polymorphisms that are orthologous across most catarrhines. We have sequenced and screened the rhesus macaque (Macaca mulatta) DRD4 (rhDRD4) and TPH2 (rhTPH2) genes (both associated with behavioral phenotypes in humans) for novel variants, and here we present evidence for an association between impulsive/aggressive behavior and rhDRD4 promoter haplotypes. Twenty-four subjects (12 m, 12 f) were selected from a pool of 168 assessed for impulsivity and aggression (IA) using an intruder challenge test. To date, we have identified 18 SNPs and a putatively functional 152bp insertion/deletion in the 3’ UTR in the rhTPH2 gene. In this dataset, rhTPH2 variants were not associated with IA. In the rhDRD4 gene, we identified 8 SNPs within the promoter region that, based on 48 chromosomes, form two major haplotypes (A&B). In subjects with high IA scores, the frequency of haplotype B was .66 (F = 5.53, p = 0.028). The rhDRD4 5’ flanking region shares a number of features with the human DRD4 promoter: 1) It’s highly polymorphic, averaging 1 SNP per 200bp, 2) rich in CpG dinucleotides, 3) contains numerous putative Sp1 sites, and 4) lacks TATA and CAAT boxes. Several SNPs occur in Sp1 and CpG sites, and thus may be of functional significance. Our results emphasize the value of cross-species comparative analysis of functional gene regions.