Genetic variation in FGF20 modulates hippocampal biology.
Genetic variation in FGF20 modulates hippocampal biology.
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DOI：
10.1523/jneurosci.5773-09.2010
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发表时间：
2010-04-28
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影响因子：
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通讯作者：
Weinberger DR
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作者：
Lemaitre H;Mattay VS;Sambataro F;Verchinski B;Straub RE;Callicott JH;Kittappa R;Hyde TM;Lipska BK;Kleinman JE;McKay R;Weinberger DR
我们探索了与帕金森病（PD）风险相关的成纤维细胞生长因子20基因（FGF 20）中的单核苷酸多态性（SNP）对大样本健康成年人受试者和老年受试者脑结构和功能的影响，以观察遗传变异与年龄之间的相互作用（N = 237，116名男性，18-87岁）。我们分析了高分辨率解剖磁共振图像，使用基于体素的形态测量，定量神经解剖技术。我们还测量了死后人脑组织中FGF 20 mRNA的表达，以确定这些SNP的分子相关性（N = 108，72名男性，18-74岁）。我们发现，在3' UTR中rs 12720208的T等位基因携带者具有相对较大的海马体积（p = 0.0059），减少的言语情景记忆（p = 0.048），并且在正常老化时显示海马体积的急剧减少（p = 0.026）。在死后的大脑中，T等位基因携带者有更高的海马FGF 20 mRNA表达（p = 0.037），与先前表征的microRNA机制一致。C等位基因与预测的miR-433 microRNA结合结构域相匹配，而T等位基因破坏了它，导致更高的FGF 20蛋白翻译。海马中强的FGF 20遗传效应可能是通过FGF受体1（FGFR 1）的激活介导的，FGF受体1在哺乳动物脑中的海马中表达最丰富。这些关联，从mRNA表达到脑形态到认知以及与衰老的相互作用，证实了FGF 20在发育和衰老过程中在人脑结构和功能中的作用。
We explored the effect of Single Nucleotide Polymorphisms (SNPs) in the Fibroblast Growth Factor 20 gene (FGF20) associated with risk for Parkinson’s disease (PD) on brain structure and function in a large sample of healthy young-adult human subjects and also in elderly subjects to look at the interaction between genetic variations and age (N = 237, 116 men, 18–87 years). We analyzed high resolution anatomical magnetic resonance images using voxel-based morphometry, a quantitative neuroanatomical technique. We also measured FGF20 mRNA expression in post-mortem human brain tissue to determine the molecular correlates of these SNPs (N = 108, 72 men, 18–74 years). We found that the T allele carriers of rs12720208 in the 3’ UTR had relatively larger hippocampal volume (p = 0.0059), diminished verbal episodic memory (p = 0.048) and showed steeper decreases of hippocampal volume with normal ageing (p = 0.026). In post-mortem brain, T allele carriers had greater expression of hippocampal FGF20 mRNA (p = 0.037), consistent with a previously characterized microRNA mechanism. The C allele matches a predicted miR-433 microRNA binding domain, whereas the T allele disrupts it, resulting in higher FGF20 protein translation. The strong FGF20 genetic effects in hippocampus are presumably mediated by activation of the FGF receptor 1 (FGFR1), which is expressed in mammalian brain most abundantly in the hippocampus. These associations, from mRNA expression to brain morphology to cognition and an interaction with ageing, confirm a role of FGF20 in human brain structure and function during development and aging.