Abstract
The dopamine transporter gene (DAT) has been implicated in a variety of disorders, including bipolar disorder, attention-deficit hyperactivity disorder, cocaine-induced paranoia, Tourette's syndrome, and Parkinson's disease. As no clear functional polymorphism has been identified to date, studies rely on linkage disequilibrium (LD) to assess the possible genetic contribution of DAT to the various disorders. A better understanding of the complex structure of LD across the gene is thus critical for an accurate interpretation of the results of such studies, and may facilitate the mapping of the actual functional variants. In the process of characterizing the extent of variation within the DAT gene, we have identified a number of single nucleotide polymorphisms (SNPs) suitable for LD studies, 14 of which have been analyzed, along with a 3′ repeat polymorphism, in a sample of 120 parent-proband triads. Calculations of pairwise LD between the SNPs in the parental haplotypes revealed a high degree of LD (P < 0.00001) in the 5′ (distal promoter through intron 6) and 3′ (exon 9 through exon 15) regions of DAT. This segmental LD pattern is maintained over approximately 27 kb and 20 kb in these two regions, respectively, with very little significant LD between them, possibly due to the presence of a recombination hotspot located near the middle of the gene. These analyses of the DAT gene thus reveal a complex structure resulting from both recombination and mutation, knowledge of which may be invaluable to the design of future studies.
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Acknowledgements
We would like to thank the family members who participated in this study, without whom this work would not be possible. This work was supported by Novartis Pharma AG and grants to JRK from the Department of Veterans Affairs and the NIMH (MH47612, MH59567). Support was also provided by the UCSD Mental Health Clinical Research Center (MH30914) and the UCSD General Clinical Research Center (M01 RR00827). TAG was supported by training grants to the UCSD Biomedical Sciences and Genetics graduate programs (5T32CA67754, 1T32GM08666). Data and biomaterials were collected in four projects that participated in the National Institute of Mental Health (NIMH) Bipolar Disorder Genetics Initiative. From 1991–98, 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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Greenwood, T., Alexander, M., Keck, P. et al. Segmental linkage disequilibrium within the dopamine transporter gene. Mol Psychiatry 7, 165–173 (2002). https://doi.org/10.1038/sj.mp.4000958
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DOI: https://doi.org/10.1038/sj.mp.4000958
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