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Identification of additional variants within the human dopamine transporter gene provides further evidence for an association with bipolar disorder in two independent samples

Molecular Psychiatry volume 11, pages 125–133 (2006)Cite this article

Abstract

The dopamine transporter (DAT) is the site of action of stimulants, and variations in the human DAT gene (DAT1) have been associated with susceptibility to several psychiatric disorders including attention deficit hyperactivity disorder (ADHD) and bipolar disorder. We have previously reported the association of bipolar disorder to novel SNPs in the 3′ end of DAT1. We now report the identification of 20 additional SNPs in DAT1 for a total of 63 variants. We also report evidence for association to bipolar disorder in a second independent sample of families. Eight newly identified SNPs and 14 previously identified SNPs were analyzed in two independent samples of 50 and 70 families each using the transmission disequilibrium test. Two of the eight new SNPs, one in intron 8 and one in intron 13, were found to be moderately associated with bipolar disorder, each in one of the two independent samples. Analysis of haplotypes comprised of all 22 SNPs in sliding windows of five adjacent SNPs revealed an association to the region near introns 7 and 8 in both samples (empirical P-values 0.002 and 0.001, respectively, for the same window). The haplotype block structure observed in the gene in our previous study was confirmed in this sample with greater resolution allowing for discrimination of a third haplotype block in the middle of the gene. Together, these data are consistent with the presence of multiple variants in DAT1 that convey susceptibility to bipolar disorder.

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Acknowledgements

We are grateful to the family members who participated in this study. This work was supported by grants to JRK from NIH (MH47612, MH59567, MH68503, DA13769), the Department of Veterans Affairs and by the UCSD General Clinical Research Center (M01 RR00827). JRK is a founder and holds equity in Psynomics Inc. We would like to thank A Dessa Sadovnick, Ronald Remick, Susan McElroy, and Paul Keck for contributing a portion of the samples analyzed. Data and biomaterials were collected in four projects that participated in the NIMH Bipolar Disorder Genetics Initiative. From 1991–1998, the Principal Investigators and Co-investigators were: Indiana University, Indianapolis, IN, UO1 MH46282, John Nurnberger, MD, PhD, Marvin Miller, MD, and Elizabeth Bowman, MD; Washington University, St Louis, MO, UO1 MH46280, Theodore Reich, MD, Allison Goate, PhD, and John Rice, PhD; Johns Hopkins University, Baltimore, MD UO1 MH46274, J Raymond DePaulo, Jr, MD, Sylvia Simpson, MD, MPH, and Cohn Stine, PhD; NIMH Intramural Research Program, Clinical Neurogenetics Branch, Bethesda, MD, Elliot Gershon, MD, Diane Kazuba, BA, and Elizabeth Maxwell, MSW.

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Authors and Affiliations

  1. Department of Psychiatry, University of California at San Diego, La Jolla, CA, USA

    T A Greenwood, N J Schork & J R Kelsoe

  2. Department of Computer Science and Engineering, University of California at San Diego, La Jolla, CA, USA

    E Eskin

  3. San Diego VA Health Care System, San Diego, CA, USA

    J R Kelsoe

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  1. T A Greenwood
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Correspondence to J R Kelsoe.

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Greenwood, T., Schork, N., Eskin, E. et al. Identification of additional variants within the human dopamine transporter gene provides further evidence for an association with bipolar disorder in two independent samples. Mol Psychiatry 11, 125–133 (2006). https://doi.org/10.1038/sj.mp.4001764

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