Exonic DNA sequencing of ERBB4 in bipolar disorder.
Exonic DNA sequencing of ERBB4 in bipolar disorder.
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DOI：
10.1371/journal.pone.0020242
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Potash JB
中科院分区：
文献类型：
--
作者：
Goes FS;Rongione M;Chen YC;Karchin R;Elhaik E;Bipolar Genome Study;Potash JB
神经调节蛋白-ErbB 4通路在大脑发育中起着至关重要的作用，并且构成了与精神分裂症以及在较小程度上与双相情感障碍（BP）有关的最具生物学合理性的信号通路之一。然而，最近的全基因组关联分析没有提供证据表明NRG 1或ERBB 4的共同变异影响精神分裂症或双相情感障碍的易感性。在这项研究中，我们研究了ERBB 4中罕见的编码变体在具有情绪不一致精神病特征的BP病例中的作用，这是一种可以说与精神分裂症具有最大表型重叠的BP形式。我们对ERBB 4的所有28个外显子以及部分启动子和部分3′UTR序列进行了桑格测序，假设在GAIN BP研究的188例情绪不一致性精神病患者中发现了罕见的有害变体。我们发现了42种变异，其中16种是新的，尽管没有一种是非同义的或明显有害的。11.2%的病例中存在一种新变体，位于替代终止密码子旁边，这与ERBB 4的缩短转录物不翻译有关。我们在GAIN BP病例对照样本中对该变异体进行了基因分型，发现与对照组相比，与情绪不一致的精神病性BP存在轻微显著相关性（加性模型：OR = 1.64，P值= 0.055;显性模型：OR = 1.73）。 P值= 0.039）。 总之，我们没有发现明显有害作用的罕见变体，但确实发现了一种可能影响ERBB 4选择性剪接的适度相关的新变体。然而，本研究中的适度样本量不能明确排除罕见变异在双相情感障碍中的作用，需要更大样本量的研究来证实观察到的相关性。
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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