55 However, this hypothesis (that a BP susceptibility gene exists on the tip of the short arm of chromosome 11) remains viable and interesting. The LOD score in the original Old Order Amish pedigree

110 is ≈2.0, and similar weakly positive LOD scores are reported for this region by other investigators.56,57 Furthermore, several reports have described evidence for association of tyrosine hydroxylase (located in llpl5) with BP disorder,58-64 although other groups have not confirmed this observation.65-74 Inhibitors,research,lifescience,medical The existence of an 11p15 locus of small effect on risk for BP illness remains a tenable hypothesis. Xq28 was reported linked to BP illness in studies employing clinically-assessed color blindness and glucose-6-phosphate dehydrogenase (G6PD) deficiency.75-81 Molecular studies have not confirmed these “pre-molecular reports.” 54,82-85 The linkage to color blindness and G6PD deficiency in the most recent positive Inhibitors,research,lifescience,medical report78 was not confirmed in those same pedigrees by molecular methods employing relevant Xq28 DNA

markers.86 There is no published molecular linkage study consistent with an Xq28 BP susceptibility locus. The complex inheritance of BP illness and the failure of multiple genome-wide scans to detect major gene effects indicate that BP susceptibility loci represent Inhibitors,research,lifescience,medical small to moderate effects. Novel statistical methods to detect loci of small effect38,39,87 and development of dense highly polymorphic marker maps88,89 have provided the necessary tools to conduct the large-scale,

definitive studies. Suarez et al90 simulated initial detection of linkage, and subsequent independent confirmation of the originally detected locus, in a complex disease caused in part by six equally frequent independent (unlinked) disease loci. A larger sample Inhibitors,research,lifescience,medical size is necessary and an extended waiting period is likely for confirmation of a previously detected Inhibitors,research,lifescience,medical locus. Ihis is intuitively reasonable, because of sampling variation. Independent pedigree samples might detect one of the other five loci, as opposed to the one locus initially detected. This simulation study90 suggests that universal agreement regarding BP linkage studies will not occur. If two or more independent investigators find significant evidence for linkage in independent series of pedigrees, it is reasonable to assume validity.36,91 It is reassuring to note that several groups have reported putative BP susceptibility loci that have been confirmed independently. This suggests that genetic Sitaxentan dissection of BP disorders will proceed from established GSK343 in vitro linkages, as has been the case with Alzheimer’s disease.44 Berrettini et al92,93 reported significant evidence for a BP susceptibility locus on chromosome 18 using affected sibling pair (ASP) and affected pedigree member (APM) methods (P=10-4-10-5), obtained in 22 Caucasian kindreds of European ancestry. Independent confirmation of this finding was reported by Stine et al94 and others as noted in Table II.