An integrated physical map of 18p11.2: a susceptibility region for bipolar disorder.

The reported linkage between bipolar disorder and a large pericentric portion of chromosome 18 has been replicated in an independent study. Further examination of this region showed that 18p11.2 had the greatest allele sharing in our pedigrees and increased sharing in other independently ascertained pedigree series permitting refinement of the region of significance. To facilitate positional cloning of a susceptibility gene, we used a combination of mapping reagents, including a subchromosomal somatic cell hybrid panel, a contig of clones in yeast artificial chromosomes (YAC), and a radiation hybrid (RH) panel, to construct a high resolution physical map of the region including sequence tag sites (STSs) and expressed sequence tags (ESTs). This approach generated the interlocus distance and order of 15 STSs and 16 ESTs including four novel transcripts, with an average of approximately 200 kb between loci, over a approximately 6-Mb region. This high resolution integrated map will be an important tool in providing loci for contig construction, and positional candidates for mutation screening.

No evidence for significant linkage between bipolar affective disorder and chromosome 18 pericentromeric markers in a large series of multiplex extended pedigrees.

Bipolar affective disorder (BP) is a major neuropsychiatric disorder with high heritability and complex inheritance. Previously reported linkage between BP and DNA markers in the pericentromeric region of chromosome 18, with a parent-of-origin effect (linkage was present in pedigrees with paternal transmission and absent in pedigrees with exclusive maternal inheritance), has been a focus of interest in human genetics. We reexamined the evidence in one of the largest samples reported to date (1,013 genotyped individuals in 53 unilineal multiplex pedigrees), using 10 highly polymorphic markers and a range of parametric and nonparametric analyses. There was no evidence for significant linkage between BP and chromosome 18 pericentromeric markers in the sample as a whole, nor was there evidence for significant parent-of-origin effect (pedigrees with paternal transmission were not differentially linked to the implicated chromosomal region). Two-point LOD scores and single-locus sib-pair results gave some support for suggestive linkage, but this was not substantiated by multilocus analysis, and the results were further tempered by multiple test effects. We conclude that there is no compelling evidence for linkage between BP and chromosome 18 pericentromeric markers in this sample.