A GENOME-WIDE SEARCH FOR GENES PREDISPOSING TO MANIC-DEPRESSION, ASSUMING AUTOSOMAL-DOMINANT INHERITANCE

Manic-depressive illness (MDI), also known as ''bipolar affective diso rder,'' is a common and devastating neuropsychiatric illness. Although pivotal biochemical alterations underlying the disease are unknown, r esults of family, twin, and adoption studies consistently implicate ge netic transmission in the pathogenesis of MDI. In order to carry out l inkage analysis, we ascertained eight moderately sized pedigrees conta ining multiple cases of the disease. For a four-allele marker mapping 5 cM from the disease gene, the pedigree sample has >97% power to dete ct a dominant allele under genetic homogeneity and has >73% power unde r 20% heterogeneity. To date, the eight pedigrees have been genotyped with 328 polymorphic DNA loci throughout the genome. When autosomal do minant inheritance was assumed, 273 DNA markers gave lod scores <-2.0 at recombination fraction (theta) = .0, 174 DNA loci produced lod scor es <-2.0 at theta = .05, and 4 DNA marker loci yielded lod scores >1 ( chromosome 5-D5S39, D5S43, and D5S62; chromosome 11-D11S85). Of the ma rkers giving lod scores >1, only D5S62 continued to show evidence for linkage when the affected-pedigree-member method was used. The D5S62 l ocus maps to distal 5q, a region containing neurotransmitter-receptor genes for dopamine, norepinephrine, glutamate, and gamma-aminobutyric acid. Although additional work in this region may be warranted, our li nkage results should be interpreted as preliminary data, as 68 unaffec ted individuals are not past the age of risk.