Biological validation of increased schizophrenia risk with NRG1, ERBB4, and AKT1 epistasis via functional neuroimaging in healthy controls.
Biological validation of increased schizophrenia risk with NRG1, ERBB4, and AKT1 epistasis via functional neuroimaging in healthy controls.
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DOI：
10.1001/archgenpsychiatry.2010.117
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发表时间：
2010-10
影响因子：
--
通讯作者：
Weinberger, Daniel R.
中科院分区：
文献类型：
--
作者：
Nicodemus, Kristin K.;Law, Amanda J.;Radulescu, Eugenia;Luna, Augustin;Kolachana, Bhaskar;Vakkalanka, Radhakrishna;Rujescu, Dan;Giegling, Ina;Straub, Richard E.;McGee, Kate;Gold, Bert;Dean, Michael;Muglia, Pierandrea;Callicott, Joseph H.;Tan, Hao-Yang;Weinberger, Daniel R.
NRG1是一种精神分裂症候选基因，在大脑发育和神经功能中起重要作用。精神分裂症是一种复杂的疾病，其病因可能是上位性。我们试图研究NRG1与nmda -谷氨酸通路伙伴（包括ERBB4、AKT1、DLG4、NOS1、NOS1AP）之间的相互作用。使用机器学习算法和逻辑回归对精神分裂症病例-对照样本进行分析，并对健康对照的独立样本进行神经影像学随访。符合DSM-IV精神分裂症谱系障碍标准的精神分裂症患者的参考样本（N = 296）和用于病例对照比较的自愿对照样本（N = 365）以及用于神经影像学的单独自愿对照样本（N = 172）。snp与病例对照状态的上位性关联功能磁共振成像（fMRI）测量工作记忆中snp与BOLD生理反应之间的上位性关联。我们观察到NRG1 5 ‘和3 ’ snp: rs4560751-rs3802160（似然比检验（LRT） p=0.00020）与精神分裂症之间存在相互作用，并通过健康对照组工作记忆功能磁共振成像（fMRI）进行了验证；风险相关基因型携带者在背外侧前额皮质（DLPFC）的加工效率低下（p=0.015， FWE校正）。我们观察到NRG1 （rs10503929; Val1066Ile）与其受体ERBB4 （rs1026882; LRT p=0.035）之间的上位性；这两个snp与AKT1 （rs2494734）也存在三向相互作用（OR=27.13； 95%可信区间3.30,223.03;LRT p=0.042）。这些相同的双向和三方相互作用通过fMRI进一步得到生物学验证：携带NRG1和ERBB4风险基因型的健康个体，或这两个基因型与AKT1一起，在DLPFC加工中的效率不成比例地低。在关联或神经影像学中未观察到NRG1/ERBB4-AKT1之间的低水平相互作用，这与NRG1- erbb4相互作用调节下游AKT1信号传导的生物学证据一致。我们的数据表明，复杂的上位性效应暗示了NRG1分子通路在认知脑功能和精神分裂症发病机制中的作用。
NRG1 is a schizophrenia candidate gene and plays an important role in brain development and neural function. Schizophrenia is a complex disorder, with etiology likely due to epistasis. We sought to examine epistasis between NRG1 and selected NMDA-glutamate pathway partners implicated in its effects, including ERBB4, AKT1, DLG4, NOS1, NOS1AP. Schizophrenia case-control sample analyzed using machine learning algorithms and logistic regression with follow-up using neuroimaging on an independent sample of healthy controls. A referred sample of schizophrenic patients (N = 296) meeting DSM-IV criteria for schizophrenia-spectrum disorder and a volunteer sample of controls for case-control comparison (N = 365) and a separate volunteer sample of controls for neuroimaging (N = 172). Epistatic association between SNPs and case-control status; epistatic association between SNPs and the BOLD physiological response during working memory measured by functional magnetic resonance imaging (fMRI). We observed interaction between NRG1 5’ and 3’ SNPs: rs4560751-rs3802160 (likelihood ratio test (LRT) p=0.00020) and schizophrenia which was validated using fMRI of working memory in healthy controls; carriers of risk-associated genotypes showed inefficient processing in dorsolateral prefrontal cortex (DLPFC) (p=0.015, FWE corrected). We observed epistasis between NRG1 (rs10503929; Val1066Ile) and its receptor ERBB4 (rs1026882; LRT p=0.035); a three-way interaction with these two SNPs and AKT1 (rs2494734) was also observed (OR=27.13; 95% confidence interval 3.30, 223.03; LRT p=0.042). These same two- and three-way interactions were further biologically validated via fMRI: healthy individuals carrying risk genotypes for NRG1 and ERBB4, or these two together with AKT1, were disproportionately less efficient in DLPFC processing. Lower-level interactions were not observed between NRG1/ERBB4-AKT1 in association or neuroimaging, consistent with biological evidence that NRG1-ERBB4 interaction modulates downstream AKT1 signaling. Our data suggest complex epistatic effects implicating a NRG1 molecular pathway in cognitive brain function and the pathogenesis of schizophrenia.
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DOI：
10.1038/nrg2579
发表时间：
2009-06
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
Cordell HJ
通讯作者：
Cordell HJ
DOI：
10.1002/ajmg.b.30209
发表时间：
2006-04-05
影响因子：
2.8
作者：
Kim, JW;Lee, YS;Hong, KS
通讯作者：
Hong, KS
影响因子：
3.5
作者：
Li, Dawei;Collier, David A.;He, Lin
通讯作者：
He, Lin
影响因子：
30.8
作者：
Allen, Nicole C.;Bagade, Sachin;Bertram, Lars
通讯作者：
Bertram, Lars
影响因子：
25
作者：
Bao, JX;Lin, H;Ambron, RT
通讯作者：
Ambron, RT