Convergent genome wide association results for bipolar disorder and substance dependence

Abstract

Twin studies document substantial heritability for substance dependence and bipolar disorder [Shih et al. (2004); Uhl et al. (2008a)]. Individuals with bipolar disorder display substance use disorders at rates that are much higher than those in the general population [Krishnan (2005)]. We would thus predict: 1) substantial overlap between different genome wide association (GWA) studies of bipolar disorder 2) significant overlap between results from bipolar disorder and substance dependence. Recent GWA studies [Baum et al. (2007); Sklar et al. (2008); Uhl et al. (2008a); Wellcome Trust Consortium (2007)] allow us to test these ideas, although 1) these datasets display difficult features that include use of differing sets of SNPs, likely polygenic genetics, likely differences in linkage disequilibrium between samples, heterogeneity both between and within loci and 2) several, though not all, reports have failed to identify any allele of any single nucleotide polymorphism (SNP) ("same SNP same allele") that is reproducibly associated with bipolar disorder with "genome wide" significance. We now report analyses that identify clustered, P < 0.05 SNPs within genes that overlap between the bipolar samples (Monte Carlo P < 0.00001). Overlapping data from at least three of these studies identify 69 genes. 23 of these genes also contain overlapping clusters of nominally-positive SNPs for substance dependence. Variants in these "addiction/bipolar" genes are candidates to influence the brain in ways that manifest as enhanced vulnerabilites to both substance dependence and bipolar disorder.

Rare missense neuronal cadherin gene (CDH2) variants in specific obsessive-compulsive disorder and Tourette disorder phenotypes

“…[18][19][20]44,45 Protocadherins and other cadherins have also been studied as candidate risk genes, but generally in small samples (o100 patients) of schizophrenia, bipolar disorder and OCD patients. [46][47][48][49][50][51][52][53][54][55] In addition, some cadherins have been specifically identified in genome-wide association scans of ADHD, addiction and neuroticism personality features. [56][57][58] Of related interest, variants in CDH2 and other cadherins have been widely found to CDH2 variants in OCD and TD PR Moya et al be associated with various cancers 16,59,60 and, specifically, upregulated CDH2 has been associated with transepithelial spreading of melanoma and pancreatic cancer together with rapid recurrence of cancer.…”

Coming to grips with complex disorders: Genetic risk prediction in bipolar disorder using panels of genes identified through convergent functional genomics

“…BP WalssBass et al, 2006;Thomson et al, 2007;Georgieva et al, 2008] (assoc) D (unipolar depression) [Bertram et al, 2007] BP [Cichon et al, 2001;Park et al, 2004] 6096 RORB (RAR-related orphan receptor beta) BP [Baum et al, 2008;Johnson et al, 2009] (assoc)…”

Prospective progression from high-prevalence disorders to bipolar disorder: Exploring characteristics of pre-illness stages

“…One is that there could be shared genetic and environmental vulnerabilities among people with SUDs and BD. The presence of BD among probands was associated with a higher prevalence of SUDs among family members in an association study (Biederman et al, 2000) while a genome-wide association study has identified shared genes of risk between BD and SUD (Johnson et al, 2009). Such shared risk factors may include impulsivity and a propensity for risk-taking, which have been associated specifically with persons with bipolar disorder, especially when not taking antipsychotic medication (Reddy et al, 2014).…”