Associations have been reported of the 7-repeat (7R) allele of the human dopamine receptor D4 (DRD4) gene with both the personality trait of novelty seeking and attention-deficit/ hyperactivity disorder (ADHD). The increased prevalence of the 7R allele in ADHD probands is consistent with the common variant-common disorder hypothesis, which proposes that the high frequency of many complex genetic disorders is related to common DNA variants. Recently, based on the unusual DNA sequence organization and strong linkage disequilibrium surrounding the DRD4 7R allele, we proposed that this allele originated as a rare mutational event, which nevertheless increased to high prevalence in human populations by positive selection. We have now determined, by DNA resequencing of 250 DRD4 alleles obtained from 132 ADHD probands, that most ADHD 7R alleles are of the conserved haplotype found in our previous 600 allele worldwide DNA sample. Interestingly, however, half of the 24 haplotypes uncovered in ADHD probands were novel (not one of the 56 haplotypes found in our prior population studies). Over 10 percent of the ADHD probands had these novel haplotypes, most of which were 7R allele derived. The probability that this high incidence of novel alleles occurred by chance in our ADHD sample is much less than 0.0001. These results suggest that allelic heterogeneity at the DRD4 locus may also contribute to the observed association with ADHD.

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A large body of family data was analyzed to explain the genetics of hypodontia. Two multiple threshold models that were developed for quasicontinuous traits were used. The data fit the polygenic model much better than they fit the single major gene model.

Autism is a significant childhood disorder. Studies are underway to define more clearly the disorder and its various manifestations and to correlate this information with an etiology. Genes are known to play an important role in autism, and a vigorous search is underway to define those genes. The Human Genome Project provides the basis that allows us to move beyond single gene disorders and to contemplate progress for complex disorders, such as autism. Genome screens of affected siblings and detailed molecular analyses of chromosome abnormalities identified in autistic subjects has led in the past year to the identification of several candidate genes. However, the problem of determining which are the real genes remains. This is complicated because the presentation of the disorder is so variable, and milder manifestations in relatives are not yet understood. But the fact that we can now name possible genes for this disorder reflects how quickly our understanding is progressing.