On the basis of our previous identified linkage regions for nicotine dependence (ND), we selected seven and four single nucleotide polymorphisms (SNPs) in the b-arrestins 1 (ARRB1) and 2 (ARRB2), respectively, to determine the associations of the two genes with ND in a total of 2037 subjects from 602 nuclear families of European American (EA) and African American (AA) origin. ND was assessed by Smoking Quantity (SQ), the Heaviness of Smoking Index (HSI) and the Fagerströ m Test for ND (FTND) score. Individual SNP analysis indicated that SNPs rs472112 within ARRB1 and rs4790694 within ARRB2 in the EA sample was significantly associated with HSI and FTND score, and the association of rs4790694 for ARRB2 remained significant after correction for multiple testing. Haplotype analysis revealed that haplotype C-G-C-G-G-T within ARRB1 at a frequency of 20%, formed by SNPs rs528833, rs1320709, rs480174, rs5786130, rs611908 and rs472112, was positively associated with HSI and FTND in EAs. We also found a haplotype within ARRB2, C-C-A-T at a frequency of 10.7%, formed by SNPs rs3786047, rs4522461, rs1045280 and rs4790694, that showed a significant positive association with HSI and FTND in the EA sample. No significant associations for either individual SNPs or major haplotype of both ARRB1 and ARRB2 were found in the AA sample. Further, the strength of these associations increased after removing the SQ component from HSI and FTND scores in both the EA and AA samples, suggesting that ARRB1 and ARRB2 play an important role in biological processes involved in the regulation of smoking urgency (that is time to smoke first cigarette). In summary, our results provide the first evidence of a significant association for ARRB1 and ARRB2 variants with ND in an EA sample. Molecular Psychiatry (2008) 13, 398-406; doi:10.1038/sj.mp.4002036; published online 19 June 2007Keywords: haplotype; SNP; ARRB1; ARRB2; association analysis; nicotine dependence Introduction Tobacco use is a leading preventable cause of death in the United States, with one in every five deaths attributable to smoking. 1 Nicotine is believed to be the primary addictive component of cigarette smoke. Nicotine dependence (ND) is a complex quantitative trait that is influenced by both genetic and environmental factors. 2 A number of linkage and association studies have identified susceptibility genes for ND; 3,4 however, few association studies of candidate genes and/or linkage analyses for susceptibility loci have been replicated in independent samples. 3,5 Previously, we identified several chromosomal regions that are likely to harbor susceptibility loci for ND in the Framingham Heart Study (FSH) and Mid-South Tobacco Family (MSTF) samples, including one region on chromosome 11q13 and one on chromosome 17p13, 3,[6][7][8] where the two genes of interest, b-arrestins 1 and 2 (ARRB1 and ARRB2), are located, 9,10 respectively. b-arrestins are key negative regulators and scaffolds for G-protein-coupled receptor (GPCR) signaling, one of the most fundamental cellular signal ...