Genome-wide association study of bipolar disorder in Canadian and UK populations corroborates disease loci including SYNE1 and CSMD1

Abstract

BackgroundRecently, genome-wide association studies (GWAS) for cases versus controls using single nucleotide polymorphism microarray data have shown promising findings for complex neuropsychiatric disorders, including bipolar disorder (BD).MethodsHere we describe a comprehensive genome-wide study of bipolar disorder (BD), cross-referencing analysis from a family-based study of 229 small families with association analysis from over 950 cases and 950 ethnicity-matched controls from the UK and Canada. Further, loci identified in these analyses were supported by pathways identified through pathway analysis on the samples.ResultsAlthough no genome-wide significant markers were identified, the combined GWAS findings have pointed to several genes of interest that support GWAS findings for BD from other groups or consortia, such as at SYNE1 on 6q25, PPP2R2C on 4p16.1, ZNF659 on 3p24.3, CNTNAP5 (2q14.3), and CDH13 (16q23.3). This apparent corroboration across multiple sites gives much confidence to the likelihood of genetic involvement in BD at these loci. In particular, our two-stage strategy found association in both our combined case/control analysis and the family-based analysis on 1q21.2 (closest gene: sphingosine-1-phosphate receptor 1 gene, S1PR1) and on 1q24.1 near the gene TMCO1, and at CSMD1 on 8p23.2, supporting several previous GWAS reports for BD and for schizophrenia. Pathway analysis suggests association of pathways involved in calcium signalling, neuropathic pain signalling, CREB signalling in neurons, glutamate receptor signalling and axonal guidance signalling.ConclusionsThe findings presented here show support for a number of genes previously implicated genes in the etiology of BD, including CSMD1 and SYNE1, as well as evidence for previously unreported genes such as the brain-expressed genes ADCY2, NCALD, WDR60, SCN7A and SPAG16.

Genetic background of extreme violent behavior

“…Thus far, more than 20 studies have found associations between CDH13 and attention deficit/hyperactivity disorder (ADHD), autism, schizophrenia, substance abuse or bipolar disorder. 23–33 CDH13 was identified as a ADHD-related gene in 2008, and it is one of the most important genes associated with ADHD, 26 which is a disorder strongly associated with violent criminality. 34,35 Our best hit, the rs11649622 genotype, has been observed to be linked to CDH13 expression especially in amygdala, 36 and other CDH13 variants have been observed to be associated with working memory 24 and cortical thickness in dorsolateral prefrontal cortex of patients with ADHD.…”

Dynein and intraflagellar transport

“…Lack of one allele of WDR60 is also asymptomatic (Perche et al, 2013). Genomewide association studies for bipolar disease cases versus controls using single nucleotide polymorphism microarray data implied that WDR60 is one of the associated genes (Xu et al, 2014). WDR60 also was identified as one of the many genes associated with autism spectrum disorders based on exome sequencing (Cukier et al, 2014).…”

Stressful life events and catechol-O-methyl-transferase (COMT ) gene in bipolar disorder

“…were considered under quality control tests including sample contaminations, duplications, and mis-identification using the genonme-wide identity-by-descent estimation. Inconsistent samples were removed (see Xu et al, 2014;Zai et al, 2015) for more details. The COMT Val 158 Met genotypic distribution (see Table 1) was in Hardy Weinberg Equilibrium (χ 2 (1)=1.61, p=0.21) and did not differ between the bipolar cases and controls (χ 2 (2)=2.08, p=0.35).…”