Genome-wide scan and conditional analysis in bipolar disorder: evidence for genomic interaction in the National Institute of Mental Health genetics initiative bipolar pedigrees.
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.
McInnis
Melvin G
MG
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21287-7463, USA.
Dick
Danielle M
DM
Willour
Virginia L
VL
Avramopoulos
Dimitrios
D
MacKinnon
Dean F
DF
Simpson
Sylvia G
SG
Potash
James B
JB
Edenberg
Howard J
HJ
Bowman
Elizabeth S
ES
McMahon
Francis J
FJ
Smiley
Carrie
C
Chellis
Jennifer L
JL
Huo
Yuqing
Y
Diggs
Tyra
T
Meyer
Eric T
ET
Miller
Marvin
M
Matteini
Amy T
AT
Rau
N Leela
NL
DePaulo
J Raymond
JR
Gershon
Elliot S
ES
Badner
Judith A
JA
Rice
John P
JP
Goate
Alison M
AM
Detera-Wadleigh
Sevilla D
SD
Nurnberger
John I
JI
Reich
Theodore
T
Zandi
Peter P
PP
Foroud
Tatiana M
TM
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