Sequence variation in DOCK9 and heterogeneity in bipolar disorder

Abstract

a 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.Conclusion 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.

A Cross-National Tool for Assessing and Studying Suicidal Behaviors

“…Lastly, we used data mining to examine the factors associated with suicide repetition in two neighboring countries (Spain and France) . Currently, no international consortium studies cultural and environmental contributors to suicide attempts prospectively and there are no consortia to support biological research as has been possible in other areas of psychiatric research (Detera-Wadleigh et al, 2007;Gur et al, 2007).…”

Dock protein family in brain development and neurological disease

“…Moreover, the PH domain and the DHR1 domain of Dock9 are important for its membrane targeting and activation of Cdc42. It is noteworthy that sequence variations have been found in the gene encoding Dock9 in bipolar disorder patients, and mutations of Dock9 gene are associated with several typical symptoms of the disease 59 . This suggests that Dock9 may contribute to both risk and increased illness severity in bipolar disorder.…”

The Atypical Guanine Nucleotide Exchange Factor Dock4 Regulates Neurite Differentiation through Modulation of Rac1 GTPase and Actin Dynamics

“…For instance, Dock1 (Dock180) regulates axon pathfinding and spine morphogenesis (6,7), Dock3 is important for axonal growth and survival (8), and Dock7 regulates neuronal polarization and cortical neurogenesis (9,10). Moreover, members of Dock, including Dock3, Dock8, and Dock9, have been found to be associated with neurodegenerative and neuropsychiatric diseases (11)(12)(13)(14)(15). These lines of evidence highlight a pivotal role of the Dock family during normal neuronal development and brain functioning.…”