Sequence variation in DOCK9 and heterogeneity in bipolar disorder.
BACKGROUND
Linkage of bipolar disorder to a broad region on chromosome 13q has been supported in several studies including a meta-analysis on genome scans. Subsequent reports have shown that variations in the DAOA (G72) locus on 13q33 display association with bipolar disorder but these may not account for all of the linkage evidence in the region.


OBJECTIVE
To identify additional susceptibility loci on 13q32-q33 by linkage disequilibrium mapping and explore the impact of phenotypic heterogeneity on association.


METHODS
In the initial phase, 98 single nucleotide polymorphism (SNPs) located on 13q32-q33 were genotyped on 285 probands with bipolar disorder and their parents were drawn from families in the NIMH Genetics Initiative consortium for bipolar disorder (NIMH1-4) and two other series. Fine scale mapping using one family series (NIMH1-2) as the test sample was targeted on a gene that displayed the highest evidence of association. A secondary analysis of familial component phenotypes of bipolar disorder was conducted.


RESULTS
Three of seven SNPs in DOCK9, a gene that encodes an activator of the Rho-GTPase Cdc42, showed significant excess allelic transmission (P=0.0477-0.00067). Fine scale mapping on DOCK9 yielded evidence of association at nine SNPs in the gene (P=0.02-0.006). Follow-up tests detected excess transmission of the same allele of rs1340 in two out of three other sets of families. The association signals were largely attributable to maternally transmitted alleles (rs1927568: P=0.000083; odds ratio=3.778). A secondary analysis of familial component phenotypes of bipolar disorder detected significant association across multiple DOCK9 markers for racing thoughts, psychosis, delusion during mania and course of illness indicators.


CONCLUSIONS
These results suggest that DOCK9 contributes to both risk and increased illness severity in bipolar disorder. We found evidence for the effect of phenotypic heterogeneity on association. To our knowledge this is the first report to implicate DOCK9 or the Rho-GTPase pathway in the etiology of bipolar disorder.
Detera-Wadleigh
Sevilla D
SD
Genetic Basis of Mood and Anxiety Disorders, Mood and Anxiety Program, National Institute of Mental Health Intramural Research Program, National Institutes of Health/U.S. DHHS, 35 Convent Drive, Bethesda, MD 20892, USA. deteras@mail.nih.gov
Liu
Chun-yu
CY
Maheshwari
Manjula
M
Cardona
Imer
I
Corona
Winston
W
Akula
Nirmala
N
Steele
C J M
CJ
Badner
Judith A
JA
Kundu
Mukta
M
Kassem
Layla
L
Potash
James B
JB
Gibbs
Richard
R
Gershon
Elliot S
ES
McMahon
Francis J
FJ
D001714:Bipolar Disorder / Q000235:genetics* / Q000503:physiopathology; D005190:Family; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012720:Severity of Illness Index
C466321:DOCK9 protein, human; D020662:Guanine Nucleotide Exchange Factors