Genome-Wide Association Study in Bipolar Patients Stratified by Co-Morbidity

Abstract

BackgroundBipolar disorder is a severe psychiatric disorder with high heritability. Co-morbid conditions are common and might define latent subgroups of patients that are more homogeneous with respect to genetic risk factors.MethodologyIn the Caucasian GAIN bipolar disorder sample of 1000 cases and 1034 controls, we tested the association of single nucleotide polymorphisms with patient subgroups defined by co-morbidity.ResultsBipolar disorder with psychosis and/or substance abuse in the absence of alcohol dependence was associated with the rare variant rs1039002 in the vicinity of the gene phosphodiesterase 10A (PDE10A) on chromosome 6q27 (p = 1.7×10−8). PDE10A has been implicated in the pathophysiology of psychosis. Antagonists to the encoded protein are currently in clinical testing. Another rare variant, rs12563333 (p = 5.9×10−8) on chromosome 1q41 close to the MAP/microtubule affinity-regulating kinase 1 (MARK1) gene, approached the genome-wide level of significance in this subgroup. Homozygotes for the minor allele were present in cases and absent in controls. Bipolar disorder with alcohol dependence and other co-morbidities was associated with SNP rs2727943 (p = 3.3×10−8) on chromosome 3p26.3 located between the genes contactin-4 precursor (BIG-2) and contactin 6 (CNTN6). All three associations were found under the recessive genetic model. Bipolar disorder with low probability of co-morbid conditions did not show significant associations.ConclusionConceptualizing bipolar disorder as a heterogeneous disorder with regard to co-morbid conditions might facilitate the identification of genetic risk alleles. Rare variants might contribute to the susceptibility to bipolar disorder.

Transcriptome sequencing implicates dorsal striatum-specific gene network, immune response and energy metabolism pathways in bipolar disorder

“…62 Finally, although not considered hubs by our criteria, M11 also included two phosphodiesterases (PDE7B and PDE10A) that have been implicated in BD. [63][64][65] Our finding of a molecular link between BD and the striatum complements studies that implicate the same brain region in BD at the anatomical level, including two recent functional imaging studies showing reduced activity in the dorsal striatum of BD subjects during tasks that involve prospect of a reward. 66,67 BD is categorized as a mood disorder, but the impulsive and risk-taking behavior of BD patients during mania is often as salient as changes in the emotional domain.…”

Association of Cell Adhesion Molecules Contactin-6 and Latrophilin-1 Regulates Neuronal Apoptosis

“…Furthermore, point mutations and shared CNVs between the CNTN4 and CNTN6 genes have also been implicated in the pathogenesis of bipolar disorder and anorexia nervosa (Pinto et al, 2010; Kerner et al, 2011; van Daalen et al, 2011; Wang et al, 2011). Finally, deletion of the tip of the short arm of chromosome 3, that harbors the CNTN6, CNTN4 and CHL1 genes, causes a mental retardation syndrome with ASD comorbidity, called 3p-deletion syndrome (Shuib et al, 2009).…”

Combined Whole Methylome and Genomewide Association Study ImplicatesCNTN4in Alcohol Use

“…An early GWAS reported an association of a pathway containing CNTN4 and level of response to alcohol, a measure inversely correlated with problem drinking behavior (Joslyn et al, 2010). A later GWAS found SNPs in close proximity to CNTN4 to be associated with co-morbid alcohol dependence in bipolar patients (Kerner et al, 2011). Studies have linked CNTN4 to olfaction and development of olfactory neurons (Mimmack et al, 1997).…”