Exonic DNA sequencing of ERBB4 in bipolar disorder

Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America.
PLoS ONE (Impact Factor: 3.23). 05/2011; 6(5):e20242. DOI: 10.1371/journal.pone.0020242
Source: PubMed


The Neuregulin-ErbB4 pathway plays a crucial role in brain development and constitutes one of the most biologically plausible signaling pathways implicated in schizophrenia and, to a lesser extent, in bipolar disorder (BP). However, recent genome-wide association analyses have not provided evidence for common variation in NRG1 or ERBB4 influencing schizophrenia or bipolar disorder susceptibility. In this study, we investigate the role of rare coding variants in ERBB4 in BP cases with mood-incongruent psychotic features, a form of BP with arguably the greatest phenotypic overlap with schizophrenia. We performed Sanger sequencing of all 28 exons in ERBB4, as well as part of the promoter and part of the 3'UTR sequence, hypothesizing that rare deleterious variants would be found in 188 cases with mood-incongruent psychosis from the GAIN BP study. We found 42 variants, of which 16 were novel, although none were non-synonymous or clearly deleterious. One of the novel variants, present in 11.2% of cases, is located next to an alternative stop codon, which is associated with a shortened transcript of ERBB4 that is not translated. We genotyped this variant in the GAIN BP case-control samples and found a marginally significant association with mood-incongruent psychotic BP compared with controls (additive model: OR = 1.64, P-value = 0.055; dominant model: OR = 1.73. P-value = 0.039). In conclusion, we found no rare variants of clear deleterious effect, but did uncover a modestly associated novel variant that could affect alternative splicing of ERBB4. However, the modest sample size in this study cannot definitively rule out a role for rare variants in bipolar disorder and studies with larger sample sizes are needed to confirm the observed association.

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    • "The latter is currently the least expensive and a highly reliable alternative to WGS in uncovering genetic defects associated with various complex traits, particularly when combined with sequencing exome flanking non-coding regions [8,9]. Sanger sequencing of these additional regions has also shown their significance [10]. Some genetic variants will be absent or underrepresented using this approach, since approximately 15% of patients with a genetically predisposed condition do not have coding sequence mutations [5]. "
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