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Exonic DNA sequencing of ERBB4 in bipolar disorder.

Goes FS, Rongione M, Chen YC, Karchin R, Elhaik E, Bipolar Genome StudyPotash JB - PLoS ONE (2011)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America. fgoes1@jhmi.edu

ABSTRACT
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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Related in: MedlinePlus

ERBB4 gene structure with a focus on a novel variant                        within a “bleeding” exon 20.
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pone-0020242-g002: ERBB4 gene structure with a focus on a novel variant within a “bleeding” exon 20.

Mentions: Among the 16 novel variants, our power analyses indicated that only two variants (SNVs 7 and 8) had allele frequencies sufficiently high enough (MAF>0.03) to warrant additional genotyping in our available 999 independent controls. Of these, the potentially most interesting finding was SNV 7 (G>A), which was absent in dbSNP 132, but was present in 21 out of 188 cases (11.2% prevalence, MAF of 5.6%). As shown in Fig. 2, this SNV is 40 bp downstream of exon 20 and is located next to an alternate “bleeding” form of exon 20 that is associated with a prematurely truncated transcript of ERBB4, with no evidence of being translated (http://genome.ucsc.edu/).


Exonic DNA sequencing of ERBB4 in bipolar disorder.

Goes FS, Rongione M, Chen YC, Karchin R, Elhaik E, Bipolar Genome StudyPotash JB - PLoS ONE (2011)

ERBB4 gene structure with a focus on a novel variant                        within a “bleeding” exon 20.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3102700&req=5

pone-0020242-g002: ERBB4 gene structure with a focus on a novel variant within a “bleeding” exon 20.
Mentions: Among the 16 novel variants, our power analyses indicated that only two variants (SNVs 7 and 8) had allele frequencies sufficiently high enough (MAF>0.03) to warrant additional genotyping in our available 999 independent controls. Of these, the potentially most interesting finding was SNV 7 (G>A), which was absent in dbSNP 132, but was present in 21 out of 188 cases (11.2% prevalence, MAF of 5.6%). As shown in Fig. 2, this SNV is 40 bp downstream of exon 20 and is located next to an alternate “bleeding” form of exon 20 that is associated with a prematurely truncated transcript of ERBB4, with no evidence of being translated (http://genome.ucsc.edu/).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America. fgoes1@jhmi.edu

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus