Linkage of bipolar disorder to chromosome 18q and the validity of bipolar II disorder

Background: An analysis of the relationship between clinical features and a llele sharing could clarify the issue of genetic linkage between bipolar af fective disorder (BPAD) and chromosome 18q, contributing to the definition of genetically valid clinical subtypes. Methods: Relatives ascertained through a proband who had bipolar I disorder (BPI) were interviewed by a psychiatrist, assigned an all-sources diagnosi s, and genotyped with 32 markers on 18q21-23. Exploratory findings from the first 28 families (n = 247) were tested prospectively in an additional 30 families (n = 259), and the effect of confirmed findings on the linkage evi dence was assessed. Results: In exploratory analyses, paternal allele sharing on 18q21 was sign ificantly (P=.03)associated with a diagnostic subtype, and was greatest in pairs where both siblings had bipolar II disorder (BPII). Prospective analy sis confirmed the finding that BPII-BPII sibling pairs showed significantly (P=.016) greater paternal allele sharing. Paternal allele sharing across 1 8q21-23 was also significantly greater in families with at least one BPII-B PII sibling pair. In these families, multipoint affected sibling-pair linka ge analysis produced a peak paternal lod score of 4.67 (1-lod confidence in terval, 12 centimorgans [cM]) vs 1.53 (1-lod confidence interval, 44 cM) in all families. Conclusions: Affected sibling pairs with BPII discriminated between familie s who showed evidence of linkage to 18q, and families who did not. Families with a BPII sibling pair produced an increased lod score and improved link age resolution, These findings, limited by the small number of BPII-BPII si bling pairs, strengthen the evidence of genetic linkage between BPAD and ch romosome 18q, and provide preliminary support for BPII as a genetically val id subtype of BPAD.