Rare variants in neuronal excitability genes influence risk for bipolar disorder
Rare variants in neuronal excitability genes influence risk for bipolar disorder
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DOI：
10.1073/pnas.1424958112
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发表时间：
2015-03-17
影响因子：
11.1
通讯作者：
Roach, Jared C.
中科院分区：
文献类型：
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作者：
Ament, Seth A.;Szelinger, Szabolcs;Roach, Jared C.
我们对来自41个受双相情感障碍（BD）多重影响的家庭的200个人的基因组进行了测序，以确定罕见变异对遗传风险的影响。我们最初关注的是3087个具有已知突触功能或来自全基因组关联研究的先前证据的候选基因。BD家系在编码神经元离子通道的基因中罕见变异的负担增加，包括γ-氨基丁酸A（GABA(A)）受体亚基和电压门控钙通道。四种不常见的编码和调控变异也显示出显著的关联，包括GABRA6中的一个错义变异。在另外3014例病例和1717例对照中对其中26个候选基因进行靶向测序，证实了ANK3、CACNA1B、CACNA1C、CACNA1D、C4CNG2、CAMK2A和NGF中的罕见变异关联。在家族系谱和病例 - 对照队列中，启动子以及5'和3'非翻译区（UTR）的变异对BD风险的影响比编码变异更强。本研究中确定的基因和通路调节神经元兴奋性的多个方面。我们得出结论，神经元兴奋性基因中的罕见变异导致了BD的风险。
We sequenced the genomes of 200 individuals from 41 families multiply affected with bipolar disorder (BD) to identify contributions of rare variants to genetic risk. We initially focused on 3,087 candidate genes with known synaptic functions or prior evidence from genome-wide association studies. BD pedigrees had an increased burden of rare variants in genes encoding neuronal ion channels, including subunits of GABA(A) receptors and voltage-gated calcium channels. Four uncommon coding and regulatory variants also showed significant association, including a missense variant in GABRA6. Targeted sequencing of 26 of these candidate genes in an additional 3,014 cases and 1,717 controls confirmed rare variant associations in ANK3, CACNA1B, CACNA1C, CACNA1D, C4CNG2, CAMK2A and NGF. Variants in promoters and 5' and 3' UTRs contributed more strongly than coding variants to risk for BD, both in pedigrees and in the case-control cohort. The genes and pathways identified in this study regulate diverse aspects of neuronal excitability. We conclude that rare variants in neuronal excitability genes contribute to risk for BD.