Genome-wide association study reveals two new risk loci for bipolar disorder

Abstract

Bipolar disorder (BD) is a common and highly heritable mental illness and genome-wide association studies (GWAS) have robustly identified the first common genetic variants involved in disease aetiology. The data also provide strong evidence for the presence of multiple additional risk loci, each contributing a relatively small effect to BD susceptibility. Large samples are necessary to detect these risk loci. Here we present results from the largest BD GWAS to date by investigating 2.3 million single-nucleotide polymorphisms (SNPs) in a sample of 24,025 patients and controls. We detect 56 genome-wide significant SNPs in five chromosomal regions including previously reported risk loci ANK3, ODZ4 and TRANK1, as well as the risk locus ADCY2 (5p15.31) and a region between MIR2113 and POU3F2 (6q16.1). ADCY2 is a key enzyme in cAMP signalling and our finding provides new insights into the biological mechanisms involved in the development of BD.

Genetic disruption of ankyrin-G in adult mouse forebrain causes cortical synapse alteration and behavior reminiscent of bipolar disorder

“…This finding has been replicated in many (if not all) GWASs of bipolar disorder (3)(4)(5). The ANK3 locus is also found to be associated, to a lesser extent, with schizophrenia (6,7).…”

Assessment of first and second degree relatives of individuals with bipolar disorder shows increased genetic risk scores in both affected relatives and young At‐Risk Individuals

“…Large scale collaborative genome‐wide association studies (GWAS) have identified a number of risk loci significantly associated with bipolar disorder (BP), including ODZ4 [Sklar et al, 2011; Muhleisen et al, 2014], CACNA1C [Ferreira et al, 2008; Sklar et al, 2008], ANK3 [Ferreira et al, 2008; Schulze et al, 2009; Muhleisen et al, 2014], NCAN [Cichon et al, 2011], C15ORF53 [Ferreira et al, 2008], and DGKH [Baum et al, 2008a,2008b]. Individually, each of those genes/loci contributes only a small fraction toward overall disease risk, typically <1% of the phenotypic variance [Ferreira et al, 2008].…”

Pharmacogenomics in the treatment of mood disorders: Strategies and Opportunities for personalized psychiatry

“…To date, GWAS approaches have identified 18 loci contributing to the risk of MDD [20,24,59] and over 8 loci associated with BPD [55,63,84,92,106], including shared genetic loci located in the CACNA1C, CACNB2, AS3MT, ITIH3, and CCDC68 genes [22]. An extension of the GWAS approaches such as polygenic score analysis [87], bivariate restricted maximum likelihood (REML) in genome-wide complex trait analysis (GCTA) [21] and linkage disequilibrium (LD) score regression have strongly suggested that mood disorders are polygenic in nature, in that multiple genetic variants interacting with environmental factors contribute to the development of the diseases [87].…”

“…Candidate gene and genome-wide association studies (GWASs) have identified a list of candidate genes for MDD [20,24,35,59] and BPD [55,84,92,106]. To date, GWAS approaches have identified 18 loci contributing to the risk of MDD [20,24,59] and over 8 loci associated with BPD [55,63,84,92,106], including shared genetic loci located in the CACNA1C, CACNB2, AS3MT, ITIH3, and CCDC68 genes [22].…”