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Linkage and association studies in African- and Caucasian-American populations demonstrate that SHC3 is a novel susceptibility locus for nicotine dependence

Molecular Psychiatry volume 12, pages 462–473 (2007)Cite this article

Abstract

Our previous linkage study demonstrated that the 9q22–q23 chromosome region showed a ‘suggestive’ linkage to nicotine dependence (ND) in the Framingham Heart Study population. In this study, we provide further evidence for the linkage of this region to ND in an independent sample. Within this region, the gene encoding Src homology 2 domain-containing transforming protein C3 (SHC3) represents a plausible candidate for association with ND, assessed by smoking quantity (SQ), the Heaviness of Smoking Index (HSI) and the Fagerström Test for ND (FTND). We utilized 11 single-nucleotide polymorphisms within SHC3 to examine the association with ND in 602 nuclear families of either African-American (AA) or European-American (EA) origin. Individual SNP-based analysis indicated three SNPs for AAs and one for EAs were significantly associated with at least one ND measure. Haplotype analysis revealed that the haplotypes A-C-T-A-T-A of rs12519–rs3750399–rs4877042–rs2297313–rs1547696–rs1331188, with a frequency of 27.8 and 17.6%, and C-T-A-G-T of rs3750399–rs4877042–rs2297313–rs3818668–rs1547696, at a frequency of 44.7 and 30.6% in the AA and Combined samples, respectively, were significantly inversely associated with the ND measures. In the EA sample, another haplotype with a frequency of 10.6%, A-G-T-G of rs1331188–rs1556384–rs4534195–rs1411836, showed a significant inverse association with ND measures. These associations remained significant after Bonferroni correction. We further demonstrated the SHC3 contributed 40.1–59.2% (depending on the ND measures) of the linkage signals detected on chromosome 9. As further support, we found that nicotine administered through infusion increased the Shc3 mRNA level by 60% in the rat striatum, and decreased it by 22% in the nucleus accumbens (NA). At the protein level, Shc3 was decreased by 38.0% in the NA and showed no change in the striatum. Together, these findings strongly implicate SHC3 in the etiology of ND, which represents an important biological candidate for further investigation.

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Acknowledgements

This project is funded by NIH Grants DA-12844 and DA-13783 to MDL. We thank the Center for Inherited Disease Research (CIDR) for performing the MSTF genome scan. Detailed information on laboratory methods and markers can be found at http://www.cidr.jhmi.edu. Some of the results of this paper were obtained using the program S.A.G.E. (v. 5.0), which is supported by a US Public Health Service Resource Grant (RR03655) from the National Center for Research Resources. We also thank the Rutgers University Cell and DNA Repository, the contractor for the NIDA Center for Genetic Studies, co-directed by Dr Jay Tischfield and Dr John Rice.

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Authors and Affiliations

  1. Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, VA, USA

    M D Li, D Sun, X-Y Lou & J Beuten

  2. Department of Animal Genetics and Breeding and Key Laboratory of Animal Genetics and Breeding of the Ministry of Agriculture, China Agricultural University, Beijing, PR China

    D Sun

  3. ACT Center for Tobacco Treatment, Education and Research, University of Mississippi Medical Center, Jackson, MS, USA

    T J Payne

  4. Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA

    J Z Ma

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Correspondence to M D Li.

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Li, M., Sun, D., Lou, XY. et al. Linkage and association studies in African- and Caucasian-American populations demonstrate that SHC3 is a novel susceptibility locus for nicotine dependence. Mol Psychiatry 12, 462–473 (2007). https://doi.org/10.1038/sj.mp.4001933

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