Darier's disease is a rare autosomal dominant skin disorder in which there is abnormal adhesion between keratinocytes. It appears to be associated with an increased prevalence of neuropsychiatric disorders including mental retardation and epilepsy. In addition we have previously reported a family in which major affective disorder cosegregates with Darier's disease. In the present study we have localized the gene for Darier's disease to chromosome 12q23-q24.1 by linkage analysis in five British pedigrees. We obtained a maximum two point lod score of 4.29 with marker D12S84 at zero recombination fraction. All five families showed evidence of linkage between the disease gene and markers in this region. Subsequent identification of the Darier's disease gene will provide insights into normal mechanisms of cell adhesion and may be of importance in the genetic investigation of neuropsychiatric disorders as well as elucidating the pathogenesis of Darier's disease itself.

Allelic association studies provide the most powerful method for locating genes of small effect contributing to complex diseases and traits. However, in outbred populations, allelic association is usually maintained only over distances of <=1 cM. Therefore, systematic searches over large regions are costly. Here we present a method involving DNA pooling that can be used as a rapid preliminary screen for allelic association with the most common class of polymorphic markers, single-sequence repeats. Patient and control samples are pooled separately, and markers are typed in the two pools. By use of primers with fluorescent 5' ends, PCR products can be analyzed on an automated sequencing apparatus. Allele image patterns (AIPs) produced for the two groups are overlaid and differences in pattern area between pools computed. From this, a DeltaAIP statistic is calculated from the difference in areas between the two AIPs expressed as a fraction of the total shared and nonshared area. AIPs of a range of different-sized pools were generated by computer simulation for markers with a range of allele sizes and frequencies. DeltaAIPs from pools and chi2 values for individual genotypings were compared, with both simulated and real data from microsatellite markers. The results demonstrated a high correlation between DeltaAIP and chi2 values. DeltaAIP analysis of real microsatellite data indicated the feasibility of using this method in systematic searches for allelic association and generated a small number of false positives but few false negatives. We conclude that DeltaAIP analysis of DNA pools can be used effectively and efficiently as a rapid screen for allelic association in case-control studies.

We have recently described a family in which there is cosegregation of major affective disorder with Darier's disease and have mapped this autosomal dominant skin disorder to 12q23-q24.1. This has provided an interesting candidate region for genetic studies of bipolar disorder. We have studied the segregation of seven markers spanning the Darier's disease locus in 45 bipolar disorder pedigrees and found modest evidence in support of linkage under heterogeneity for 5 of these markers. Nonparametric analyses were suggestive of linkage with a marker at the gene encoding a secretory form of phospholipase A2. Our sample has relatively low power to detect linkage under heterogeneity and independent researchers should examine markers from this region in further samples of bipolar pedigrees.

Quantitative trait loci (QTLs) associated with general cognitive ability ( g) were investigated for several groups of children selected for very high or for average cognitive functioning. A DNA marker in the gene for insulin-like growth factor-2 receptor (IGF2R) on Chromosome 6 yielded a significantly greater frequency of a particular form of the gene (allele) in a high- g group (.303; average IQ = 136, N = 51) than in a control group (.156; average IQ = 103, N = 51). This association was replicated in an extremely-high- g group (all estimated IQs > 160, N = 52) as compared with an independent control group (average IQ = 101, N = 50), with allelic frequencies of .340 and .169, respectively. Moreover, a high-mathematics-ability group ( N = 62) and a high-verbal-ability group ( N = 51) yielded results that were in the same direction but only marginally significant ( p = .06 and .08, respectively).

We have tested the hypothesis that DNA markers in the MAOA gene show allelic association with bipolar affective disorder. Eighty-four unrelated Caucasian patients with DSM III-R bipolar disorder and 84 Caucasian controls were typed for three markers in MAOA: a dinucleotide repeat in intron 2, a VNTR in intron 1, and an Fnu4HI RFLP in exon 8. No evidence for allelic association was observed between any of the markers and bipolar disorder.