American Journal of Medical Genetics (Neuropsychiatric Genetics) 105:145±151 (2001) Evidence for Linkage Disequilibrium Between the Dopamine Transporter and Bipolar Disorder Tiffany A. Greenwood, 1 Meghan Alexander, 1 Paul E. Keck, 2 Susan McElroy, 2 A. Dessa Sadovnick, 3 Ronald A. Remick, 4 and John R. Kelsoe 1 * 1 Departments of Psychiatry, University of California, San Diego and San Diego VA Medical Center, San Diego, California 2 Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio 3 Department of Medical Genetics, University of British Columbia, Vancouver, Canada 4 Department of Psychiatry, St. Paul's Hospital, Vancouver, Canada A role for the dopamine transporter (DAT) in bipolar disorder is implicated by several lines of pharmacological evidence, as well as suggestive evidence of linkage at this locus, which we have reported previously. In an attempt to identify functional mutations within DAT contributing a susceptibility to bipolar disorder, we have screened the entire coding region, as well as signi®cant portions of the adjacent non-coding sequence. Though we have not found a de®nitive functional mutation, we have identi®ed a number of single nucleotide polymorphisms (SNPs) that span the gene from the distal promoter through exon 15. Of the 39 SNPs that are suitable for linkage disequilibrium (LD) studies, 14 have been analyzed by allele-speci®c PCR in a sample of 50 parent-proband triads with bipolar disorder. A haplotyped marker comprised of ®ve SNPs, spanning the region between exon 9 and exon 15, was constructed for each individual, and transmission/disequi- librium test (TDT) analysis revealed this haplotype to be in linkage disequilibrium with bipolar disorder (allele-wise TDT p  0.001, genotype-wise TDT p  0.0004). These data replicate our previous ®nding of linkage to markers within and near DAT in a largely different family set, and provide further evidence for a role of DAT in bipolar disorder. Published 2001 Wiley-Liss, Inc. y KEY WORDS: dopamine transporter; bipo- lar disorder; single nucleo- tide polymorphism; linkage disequilibrium; transmis- sion/disequilibrium test INTRODUCTION The dopamine transporter (DAT) has been implicated as a candidate gene in several disorders, including bipolar disorder and attention-de®cit hyperactivity disorder (ADHD) [Kelsoe et al., 1996; Cook et al., 1995; Waldman et al., 1998]. DAT plays a critical role in the regulation of dopaminergic transmission by mediating the active reuptake of dopamine from the synapse into the presynaptic terminal [Giros and Caron, 1993]. Several lines of pharmacological evidence suggest a possible role for dopamine in bipolar disorder, particularly in mania. Cocaine and amphetamine have been shown to increase synaptic dopamine concentra- tions by acting at DAT to inhibit dopamine reuptake [Giros et al., 1992]. The acute effects of such psychos- timulants closely resemble mania, and chronic ad- ministration can provoke a manic episode in bipolar patients and trigger psychosis in nonbipolar patients [Angrist, 1994]. In addition, L-dihydroxyphenylalanine (L-DOPA), which also increases synaptic dopamine, has been observed to precipitate mania, and antipsychotic drugs, which block dopamine receptors, are an effective treatment for mania [Murphy et al., 1971; Goodwin and Jameson, 1990]. Finally, the antidepressant bupropion acts at least in part at DAT and has been reported to be of particular ef®cacy in bipolar depression [Sachs et al., 1994]. Grant sponsor: Novartis Pharma AG; Grant sponsor: Depart- ment of Veterans Affairs and NIMH; Grant numbers: MH47612, MH59567; Grant sponsor: UCSD Mental Health Clinical Research Center; Grant number: MH30914; Grant sponsor: UCSD General Clinical Research Center; Grant number: M01 RR00827; Grant sponsor: UCSD Biomedical Sciences and Genet- ics graduate programs; Grant numbers: 5T32CA67754, 1T32GM08666. *Correspondence to: John R. Kelsoe, Department of Psychiatry, 0603, UCSD, La Jolla, CA 92093. E-mail: jkelsoe@ucsd.edu Received 5 May 2000; Accepted 12 October 2000 Published online 13 February 2001 Published 2001 Wiley-Liss, Inc. y This article is a US Government work and, as such, is in the public domain in the United States of America.