Enrichment of deleterious variants of mitochondrial DNA polymerase gene (POLG1) in bipolar disorder
Enrichment of deleterious variants of mitochondrial DNA polymerase gene (POLG1) in bipolar disorder
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DOI：
10.1111/pcn.12496
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发表时间：
2017-08-01
影响因子：
11.9
通讯作者：
Kato, Tadafumi
中科院分区：
文献类型：
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作者：
Kasahara, Takaoki;Ishiwata, Mizuho;Kato, Tadafumi
目的：罕见的错义变异可能占常见复杂疾病遗传“暗物质”的很大一部分，这是具有挑战性的，因为变异对疾病发展的影响难以证实。本研究的目的是检查在双相情感障碍中发现的POLG 1中的氨基酸取代变体的影响，作为一个例子和概念证明，在三种不同的评估模式中：计算机预测，体外生化测定和临床评价。然后，我们测试是否在POLG1有害的变异有助于双相情感障碍的遗传学。方法：我们寻找POLG1基因的变异在796例日本双相情感障碍患者和767名对照，并全面调查了所有23个确定的变异在三种评估方式。POLG1编码线粒体DNA聚合酶，是孟德尔遗传线粒体疾病的致病基因之一，偶尔伴有情绪障碍。结果：虽然有害变异携带者的频率因方法不同而不同，但每次评估都得出了相同的结论，即与对照组相比，双相情感障碍患者的有害POLG 1变异显著富集。结论：与双相情感障碍中的线粒体功能障碍一起，目前的结果表明有害的POLG1变体是多因素疾病的可信风险。
Aim: Rare missense variants, which likely account for a substantial portion of the genetic 'dark matter' for a common complex disease, are challenging because the impacts of variants on disease development are difficult to substantiate. This study aimed to examine the impacts of amino acid substitution variants in the POLG1 found in bipolar disorder, as an example and proof of concept, in three different modalities of assessment: in silico predictions, in vitro biochemical assays, and clinical evaluation. We then tested whether deleterious variants in POLG1 contributed to the genetics of bipolar disorder.Methods: We searched for variants in the POLG1 gene in 796 Japanese patients with bipolar disorder and 767 controls and comprehensively investigated all 23 identified variants in the three modalities of assessment. POLG1 encodes mitochondrial DNA polymerase and is one of the causative genes for a Mendelian-inheritance mitochondrial disease, which is occasionally accompanied by mood disorders. The healthy control data from the Tohoku Medical Megabank Organization were also employed.Results: Although the frequency of carriers of deleterious variants varied from one method to another, every assessment achieved the same conclusion that deleterious POLG1 variants were significantly enriched in the variants identified in patients with bipolar disorder compared to those in controls.Conclusion: Together with mitochondrial dysfunction in bipolar disorder, the present results suggested deleterious POLG1 variants as a credible risk for the multifactorial disease.