title: Genome-wide scan and conditional analysis in bipolar disorder: evidence for genomic interaction in the National Institute of Mental Health genetics initiative bipolar pedigrees.
abstract: BACKGROUND
  In 1989 the National Institute of Mental Health began a collaborative effort to identify genes for bipolar disorder. The first 97 pedigrees showed evidence of linkage to chromosomes 1, 6, 7, 10, 16, and 22 (Nurnberger et al 1997). An additional 56 bipolar families have been genotyped, and the combined sample of 153 pedigrees studied.
  
  
  METHODS
  Three hierarchical affection status models were analyzed with 513 simple sequence repeat markers; 298 were common across all pedigrees. The primary analysis was a nonparametric genome-wide scan. We performed conditional analyses based on epistasis or heterogeneity for five regions.
  
  
  RESULTS
  One region, on 16p13, was significant at the genome-wide p <.05 level. Four additional chromosomal regions (20p12, 11p15, 6q24, and 10p12) showed nominally significant linkage findings (p </=.01). Conditional analysis assuming epistasis identified a significant increase in linkage at four regions. Families linked to 6q24 showed a significant increase in nonparametric logarithms of the odds (NPL) scores at 5q11 and 7q21. Epistasis also was observed between 20p12 and 13q21, and 16p13 and 9q21.
  
  
  CONCLUSIONS
  The findings are presented in rank order of nominal significance. Several of these regions have been previously implicated in independent studies of either bipolar disorder or schizophrenia. The strongest finding is at 16p13 at D16S748 with an NPL of 3.3, there is evidence of epistasis between this locus and 9q21. Application of conditional analyses is potentially useful in larger sample collections to identify susceptibility genes of modest influence that may not be identified in a genome-wide scan aimed to identify single gene effects.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21287-7463, USA.
authors.forename: Melvin G
authors.initials: MG
authors.lastname: McInnis
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Dick
authors.forename: Virginia L
authors.initials: VL
authors.lastname: Willour
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Avramopoulos
authors.forename: Dean F
authors.initials: DF
authors.lastname: MacKinnon
authors.forename: Sylvia G
authors.initials: SG
authors.lastname: Simpson
authors.forename: James B
authors.initials: JB
authors.lastname: Potash
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Edenberg
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Bowman
authors.forename: Francis J
authors.initials: FJ
authors.lastname: McMahon
authors.forename: Carrie
authors.initials: C
authors.lastname: Smiley
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Chellis
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Huo
authors.forename: Tyra
authors.initials: T
authors.lastname: Diggs
authors.forename: Eric T
authors.initials: ET
authors.lastname: Meyer
authors.forename: Marvin
authors.initials: M
authors.lastname: Miller
authors.forename: Amy T
authors.initials: AT
authors.lastname: Matteini
authors.forename: N Leela
authors.initials: NL
authors.lastname: Rau
authors.forename: J Raymond
authors.initials: JR
authors.lastname: DePaulo
authors.forename: Elliot S
authors.initials: ES
authors.lastname: Gershon
authors.forename: Judith A
authors.initials: JA
authors.lastname: Badner
authors.forename: John P
authors.initials: JP
authors.lastname: Rice
authors.forename: Alison M
authors.initials: AM
authors.lastname: Goate
authors.forename: Sevilla D
authors.initials: SD
authors.lastname: Detera-Wadleigh
authors.forename: John I
authors.initials: JI
authors.lastname: Nurnberger
authors.forename: Theodore
authors.initials: T
authors.lastname: Reich
authors.forename: Peter P
authors.initials: PP
authors.lastname: Zandi
authors.forename: Tatiana M
authors.initials: TM
authors.lastname: Foroud
mesh_terms: D001714:Bipolar Disorder / Q000235:genetics*; D002877:Chromosomes, Human; D005192:Family Health; D005260:Female; D008040:Genetic Linkage; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D008297:Male; D009315:National Institute of Mental Health (U.S.); D010375:Pedigree; D014481:United States