GENETIC-LINKAGE MAPPING FOR A SUSCEPTIBILITY LOCUS TO BIPOLAR ILLNESS- CHROMOSOME-2, CHROMOSOME-3, CHROMOSOME-4, CHROMOSOME-7, CHROMOSOME-9, CHROMOSOME-10P, CHROMOSOME-11P, CHROMOSOME-22, AND CHROMOSOME-XPTER

We are conducting a genome search for a predisposing locus to bipolar (manic-depressive) illness by genotyping 21 moderate-sized pedigrees. We report linkage data derived from screening marker loci on chromosom es 2, 3, 4, 7, 9, 10p, 11p, 22, and the pseudoautosomal region at Xpte r. To analyze for linkage, two-point marker to illness lod scores were calculated under a dominant model with either 85% or 50% maximum pene trance and a recessive model with 85% maximum penetrance, and two affe ction status models. Under the dominant high penetrance model the cumu lative lod scores in the pedigree series were less than -2 at Theta = 0.01 in 134 of 142 loci examined, indicating that if the disease is ge netically homogeneous linkage could be excluded in these marker region s. Similar results were obtained using the other genetic models. Heter ogeneity analysis was conducted when indicated, but no evidence for li nkage was found. In the course of mapping we found a positive total lo d score greater than +3 at the D7S78 locus at Theta = 0.01 under a dom inant, 50% penetrance model. The lod scores for additional markers wit hin the D7S78 region failed to support the initial finding, implying t hat this was a spurious positive. Analysis with affected pedigree memb er method for COL1A2 and D7S78 showed no significance for linkage but for PLANH1, at the weighting functions f(p)=1 and f(p)=1/sqrt(p) borde rline P values of 0.036 and 0.047 were obtained. We also detected new polymorphisms at the mineralocorticoid receptor (MLR) and calmodulin I I (CALMII) genes. These genes were genetically mapped and under affect ion status model 2 and a dominant, high penetrance mode of transmissio n the lod scores of <-2 at Theta = 0.01 were found. (C) 1994 Wiley-Lis s, Inc.