Associations have been reported of the seven-repeat (7R) allele of the human dopamine receptor D4 (DRD4) gene with both attentiondeficit͞hyperactivity disorder and the personality trait of novelty seeking. This polymorphism occurs in a 48-bp tandem repeat in the coding region of DRD4, with the most common allele containing four repeats (4R) and rarer variants containing 2-11. Here we show by DNA resequencing͞haplotyping of 600 DRD4 alleles, representing a worldwide population sample, that the origin of 2R-6R alleles can be explained by simple one-step recombination͞mutation events. In contrast, the 7R allele is not simply related to the other common alleles, differing by greater than six recombinations͞mutations. Strong linkage disequilibrium was found between the 7R allele and surrounding DRD4 polymorphisms, suggesting that this allele is at least 5-10-fold ''younger'' than the common 4R allele. Based on an observed bias toward nonsynonymous amino acid changes, the unusual DNA sequence organization, and the strong linkage disequilibrium surrounding the DRD4 7R allele, we propose that this allele originated as a rare mutational event that nevertheless increased to high frequency in human populations by positive selection.

Associations of the seven-repeat (7R) allele of the human dopamine receptor D4 (DRD4) gene with both the personality trait of novelty seeking and attention deficit/hyperactivity disorder have been reported. Recently, on the basis of the unusual DNA sequence organization of the DRD4 7R 48-bp tandem repeat (VNTR), we proposed that the 7R allele originated as a rare mutational event that increased to high frequency by positive selection. We now have resequenced the entire DRD4 locus from 103 individuals homozygous for 2R, 4R, or 7R variants of the VNTR, a method developed to directly estimate haplotype diversity. DNA from individuals of African, European, Asian, North and South American, and Pacific Island ancestry were used. 4R/4R homozygotes exhibit little linkage disequilibrium (LD) over the region examined, with more polymorphisms observed in DNA samples from African individuals. In contrast, the evidence for strong LD surrounding the 7R allele is dramatic, with all 7R/7R individuals (including those from Africa) exhibiting the same alleles at most polymorphic sites. By intra-allelic comparison at 18 high-heterozygosity sites spanning the locus, we estimate that the 7R allele arose prior to the upper Paleolithic era (approximately 40000-50000 years ago). Further, the pattern of recombination at these polymorphic sites is the pattern expected for selection acting at the 7R VNTR itself, rather than at an adjacent site. We propose a model for selection at the DRD4 locus consistent with these observed LD patterns and with the known biochemical and physiological differences between receptor variants.

An association of the dopamine receptor D4 (DRD4) gene located on chromosome 11p15.5 and attention deficit͞hyperactivity disorder (ADHD) has been demonstrated and replicated by multiple investigators. A specific allele [the 7-repeat of a 48-bp variable number of tandem repeats (VNTR) in exon 3] has been proposed as an etiological factor in attentional deficits manifested in some children diagnosed with this disorder. In the current study, we evaluated ADHD subgroups defined by the presence or absence of the 7-repeat allele of the DRD4 gene, using neuropsychological tests with reaction time measures designed to probe attentional networks with neuroanatomical foci in D4-rich brain regions. Despite the same severity of symptoms on parent and teacher ratings for the ADHD subgroups, the average reaction times of the 7-present subgroup showed normal speed and variability of response whereas the average reaction times of the 7-absent subgroup showed the expected abnormalities (slow and variable responses). This was opposite the primary prediction of the study. The 7-present subgroup seemed to be free of some of the neuropsychological abnormalities thought to characterize ADHD. Dopamine plays an important role in normal attention (1) and disorders of attention (2, 3). Recently, this role of dopamine has stimulated molecular genetic studies (4) of attention deficit͞ hyperactivity disorder (ADHD), the most prevalent psychiatric disorder of childhood recognized in the United States. The dopamine receptor genes (5) have been investigated in other psychiatric disorders (e.g., schizophrenia; see refs. 6 and 7), and the background from this work set the stage for our molecular genetic investigations of ADHD.In our program of research, we adopted a candidate gene approach, focusing on the dopamine receptor D4 (DRD4) gene on chromosome 11p15.5. This gene has a polymorphism in a coding region-a variable number of tandem repeats of a 48-base pair sequence in exon 3 (8) that codes for variation in the third intracellular loop of the D4 receptor, which may have functional significance. In vitro studies suggest that the receptor encoded by the DRD4 7-repeat allele may be subsensitive to endogenous dopamine compared with the receptor encoded by the 2-repeat allele (9), although this apparently is not due merely to the length of the third intracellular loop (10). Initially, in our clinical studies we used population-based (11) and family-based (12) association designs, which suggested that the DRD4 7-repeat allele is associated with ADHD, but with a small relative risk (about 1.5). A review of the recent literature (4) revealed that two independent groups have confirmed this association in children (13,14), but one group did not (15). The pattern of replication has held up in several other case studies not yet published.The presence of the DRD4, 7-repeat allele is not a necessary condition (about half of the ADHD cases did not have a 7-repeat allele) (11, 12) or a sufficient condition (about 20% of ethnically matched control subjects d...

Variable number tandem repeats (VNTRs) account for significant genetic variation in many organisms. In humans, VNTRs have been implicated in both Mendelian and complex disorders, but are largely ignored by genomic pipelines due to the complexity of genotyping and the computational expense. We describe adVNTR-NN, a method that uses shallow neural networks to genotype a VNTR in 18 seconds on 55X whole genome data, while maintaining high accuracy. We use adVNTR-NN to genotype 10,264 VNTRs in 652 GTEx individuals. Associating VNTR length with gene expression in 46 tissues, we identify 163 “eVNTRs”. Of the 22 eVNTRs in blood where independent data is available, 21 (95%) are replicated in terms of significance and direction of association. 49% of the eVNTR loci show a strong and likely causal impact on the expression of genes and 80% have maximum effect size at least 0.3. The impacted genes are involved in diseases including Alzheimer’s, obesity and familial cancers, highlighting the importance of VNTRs for understanding the genetic basis of complex diseases.