title: Linkage of bipolar disorder to chromosome 18q and the validity of bipolar II disorder.
abstract: BACKGROUND
  An analysis of the relationship between clinical features and allele sharing could clarify the issue of genetic linkage between bipolar affective 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 diagnosis, 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 evidence was assessed.
  
  
  RESULTS
  In exploratory analyses, paternal allele sharing on 18q21 was significantly (P =.03) associated with a diagnostic subtype, and was greatest in pairs where both siblings had bipolar II disorder (BPII). Prospective analysis confirmed the finding that BPII-BPII sibling pairs showed significantly (P =.016) greater paternal allele sharing. Paternal allele sharing across 18q21-23 was also significantly greater in families with at least one BPII-BPII sibling pair. In these families, multipoint affected sibling-pair linkage analysis produced a peak paternal lod score of 4.67 (1-lod confidence interval, 12 centimorgans [cM]) vs 1.53 (1-lod confidence interval, 44 cM) in all families.
  
  
  CONCLUSIONS
  Affected sibling pairs with BPII discriminated between families 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 linkage resolution. These findings, limited by the small number of BPII-BPII sibling pairs, strengthen the evidence of genetic linkage between BPAD and chromosome 18q, and provide preliminary support for BPII as a genetically valid subtype of BPAD.
authors.affiliation: Department of Psychiatry, University of Chicago, 924 E 57th St, R012, Chicago, IL 60637, USA. fmcmahon@uchicago.edu
authors.forename: F J
authors.initials: FJ
authors.lastname: McMahon
authors.forename: S G
authors.initials: SG
authors.lastname: Simpson
authors.forename: M G
authors.initials: MG
authors.lastname: McInnis
authors.forename: J A
authors.initials: JA
authors.lastname: Badner
authors.forename: D F
authors.initials: DF
authors.lastname: MacKinnon
authors.forename: J R
authors.initials: JR
authors.lastname: DePaulo
mesh_terms: D017668:Age of Onset; D000483:Alleles; D001714:Bipolar Disorder / Q000453:epidemiology / Q000235:genetics*; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics*; D005260:Female; D008040:Genetic Linkage; D005819:Genetic Markers; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D010375:Pedigree; D011446:Prospective Studies; D015203:Reproducibility of Results; D017678:Sex Distribution
chemical_list: D005819:Genetic Markers