Altered functional connectivity in frontal lobe circuits is associated with variation in the autism risk gene CNTNAP2.
Altered functional connectivity in frontal lobe circuits is associated with variation in the autism risk gene CNTNAP2.
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DOI：
10.1126/scitranslmed.3001344
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发表时间：
2010-11-03
影响因子：
17.1
通讯作者：
Bookheimer SY
中科院分区：
文献类型：
--
作者：
Scott-Van Zeeland AA;Abrahams BS;Alvarez-Retuerto AI;Sonnenblick LI;Rudie JD;Ghahremani D;Mumford JA;Poldrack RA;Dapretto M;Geschwind DH;Bookheimer SY
遗传学研究正在迅速确定影响人类认知障碍风险的变异，但这些变异如何导致神经精神疾病的问题仍然存在。非侵入性人脑成像允许在体内评估大脑，遗传学和成像表型的组合仍然是探索人脑功能基因型-表型关联的唯一方法之一。接触素相关蛋白样2（CNTNAP 2）的常见变体，neurexin超家族成员，与几种相关的神经发育障碍有关，包括自闭症和特定的语言障碍，CNTNAP 2在发育中的人类大脑额叶回路中高度表达。使用功能性神经影像学，我们已经证明了额叶连接和CNTNAP 2中常见的遗传变异之间的关系。这些数据提供了神经发育障碍的特定遗传风险与自闭症额叶内长距离连接功能障碍的经验数据之间的机械联系。自闭症的基因发现和认知行为模型之间的趋同提供了证据，证明CNTNAP 2的遗传变异部分通过调节额叶连接而易患自闭症等疾病。
Genetic studies are rapidly identifying variants that shape risk for disorders of human cognition, but the question of how such variants predispose to neuropsychiatric disease remains. Noninvasive human brain imaging allows assessment of the brain in vivo, and the combination of genetics and imaging phenotypes remains one of the only ways to explore functional genotype-phenotype associations in human brain. Common variants in contactin-associated protein-like 2 (CNTNAP2), a neurexin superfamily member, have been associated with several allied neurodevelopmental disorders, including autism and specific language impairment, and CNTNAP2 is highly expressed in frontal lobe circuits in the developing human brain. Using functional neuroimaging, we have demonstrated a relationship between frontal lobar connectivity and common genetic variants in CNTNAP2. These data provide a mechanistic link between specific genetic risk for neurodevelopmental disorders and empirical data implicating dysfunction of long-range connections within the frontal lobe in autism. The convergence between genetic findings and cognitive-behavioral models of autism provides evidence that genetic variation at CNTNAP2 predisposes to diseases such asautism in part through modulation of frontal lobe connectivity.
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