EVIDENCE FOR LINKAGE OF BIPOLAR DISORDER TO CHROMOSOME-18 WITH A PARENT-OF-ORIGIN EFFECT

A susceptibility gene on chromosome 18 and a parent-of-origin effect h ave been suggested for bipolar affective disorder (BPAD). We have stud ied 28 nuclear families selected for apparent unilineal transmission o f the BPAD phenotype, by using 31 polymorphic markers spanning chromos ome 18. Evidence for linkage was tested with affected-sib-pair and LOD score methods under two definitions of the affected phenotype. The af fected-sib-pair analyses indicated excess allele sharing for markers o n 18p within the region reported previously. The greatest sharing was at D18S37: 64% in bipolar and recurrent unipolar (RUP) sib pairs (P = .0006). In addition, excess sharing of the paternally, but not materna lly, transmitted alleles was observed at three markers on 18q: at D18S 41, 51 bipolar and RUP sib pairs were concordant for paternally transm itted alleles, and 21 pairs were discordant (P = .0004). The evidence for linkage to loci on both 18p and 18q was strongest in the 11 patern al pedigrees, i.e., those in which the father or one of the father's s ibs is affected. In these pedigrees, the greatest allele sharing (81%; P = .00002) and the highest LOD score (3.51; theta = 0.0) were observ ed at D18S41. Our results provide further support for linkage of BPAD to chromosome 18 and the first molecular evidence for a parent-of-orig in effect operating in this disorder. The number of loci involved, and their precise location, require further study.