Identification of gene ontologies linked to prefrontal-hippocampal functional coupling in the human brain (Retracted Article)
Identification of gene ontologies linked to prefrontal-hippocampal functional coupling in the human brain (Retracted Article)
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DOI：
10.1073/pnas.1404082111
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发表时间：
2014-07-01
影响因子：
11.1
通讯作者：
Meyer-Lindenberg, Andreas
中科院分区：
文献类型：
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作者：
Dixson, Luanna;Walter, Henrik;Meyer-Lindenberg, Andreas
在工作记忆中，背外侧前额叶皮质和海马体之间的功能相互作用作为精神分裂症的中间表型已被广泛研究。已经在患者、他们未受影响的兄弟姐妹和与精神分裂症相关的常见基因变异的携带者中发现了偶联异常，但这种成像表型的全球遗传结构尚不清楚。为了实现全基因组范围内与前额叶-海马区相互作用相关的基因和途径的无假设识别，我们将基因集浓缩分析与全基因组基因分型和来自269名健康德国志愿者的功能磁共振成像数据相结合。我们发现突触组织和生物发生基因集显著丰富。该基因集包括已知的精神分裂症危险基因，如神经细胞黏附分子(NrCAM)和钙通道，电压依赖，β2亚单位(CACNB2)，以及在神经发育和可塑性过程中具有明确作用的基因，这些过程在精神分裂症中功能失调，并与前额叶-海马体功能相互作用有机械联系。我们的结果证明了一种易于推广的方法，可以用来识别系统水平表型的神经遗传学基础。此外，我们的发现确定了基因组，其中基因变异可能通过改变前额叶-海马体功能相互作用而导致疾病风险，并表明与正在进行的和发育中的突触可塑性有关。
Functional interactions between the dorsolateral prefrontal cortex and hippocampus during working memory have been studied extensively as an intermediate phenotype for schizophrenia. Coupling abnormalities have been found in patients, their unaffected siblings, and carriers of common genetic variants associated with schizophrenia, but the global genetic architecture of this imaging phenotype is unclear. To achieve genome-wide hypothesis-free identification of genes and pathways associated with prefrontal-hippocampal interactions, we combined gene set enrichment analysis with whole-genome genotyping and functional magnetic resonance imaging data from 269 healthy German volunteers. We found significant enrichment of the synapse organization and biogenesis gene set. This gene set included known schizophrenia risk genes, such as neural cell adhesion molecule (NRCAM) and calcium channel, voltage-dependent, beta 2 subunit (CACNB2), as well as genes with well-defined roles in neurodevelopmental and plasticity processes that are dysfunctional in schizophrenia and have mechanistic links to prefrontal-hippocampal functional interactions. Our results demonstrate a readily generalizable approach that can be used to identify the neurogenetic basis of systems-level phenotypes. Moreover, our findings identify gene sets in which genetic variation may contribute to disease risk through altered prefrontal-hippocampal functional interactions and suggest a link to both ongoing and developmental synaptic plasticity.