Segmental linkage disequilibrium within the dopamine transporter gene

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 3Ј 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 Ͻ 0.00001) in the 5Ј (distal promoter through intron 6) and 3Ј (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.

Investigation of Epistasis Between the Serotonin Transporter and Norepinephrine Transporter Genes in Anorexia Nervosa

“…There may be other functional polymorphisms in the SERT gene involved in AN that are not in linkage disequilibrium with 5-HTTLPR. A lack of linkage disequilibrium between the ends of a gene is demonstrated in the dopamine transporter gene (Greenwood et al, 2002) and dopamine 2 receptor (DRD2) gene (Gelernter et al, 1998). Recently, Kim et al (2002) also reported that autistic disorder may have stronger association at locations other than at 5-HTTLPR.…”

Replication of an association of a promoter polymorphism of the dopamine transporter gene and Attention Deficit Hyperactivity Disorder

“…An alternative explanation, is that the 10-repeat allele is not the causative allele itself, but rather 'tags' a nearby functional variant that is only partially correlated with the 10-repeat allele. Evidence for this comes from the observation in several studies that specific DAT1 haplotypes containing the 10-repeat allele confer risk for ADHD [3,4,6,13,16,17]. A c c e p t e d M a n u s c r i p t signal fell into two distinct groups of markers at the 3'and 5' ends of the gene.…”

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

“…', which differ by the first 6 SNPs, and 12 rare haplotypes define the haplotype structure of block 1, as we have previously suggested (data not presented; see Figure 2b for haplotypes). 11,19 The haplotypes of block 2 belong to two ancestral groups, 'CCC' and 'GG? ', which are differentiated by the first two SNPs and encompass the majority of haplotypes (data not presented; see Figure 2b for haplotypes).…”

“…6,11 An additional eight SNPs of those newly identified were chosen for genotyping based on location and genotyping feasibility. Genotyping of these SNPs in the combined sample of 120 trios was performed by Qiagen Genomics with the Masscode System, which uses cleavable mass spectrometry tags in multiplex reactions.…”

“…9 Those 33 sibpair families that showed linkage to this locus, including six UCSD/UBC/UC trios and 27 NIMH trios, were selected for further association studies of bipolar disorder. Introns 8,11,12,13, and 14 were exhaustively screened in overlapping segments of approximately 500 bp each using methods and samples that have previously been described. 6 Sequence for use as a reference was compiled from the complete DAT1 genomic sequence 10 and previously obtained sequence from a bacterial artificial chromosome (BAC) containing DAT1.…”