A population-based study of KCNH7 p.Arg394His and bipolar spectrum disorder.
A population-based study of KCNH7 p.Arg394His and bipolar spectrum disorder.
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DOI：
10.1093/hmg/ddu335
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发表时间：
2014-12-01
影响因子：
3.5
通讯作者：
Puffenberger EG
中科院分区：
文献类型：
--
作者：
Strauss KA;Markx S;Georgi B;Paul SM;Jinks RN;Hoshi T;McDonald A;First MB;Liu W;Benkert AR;Heaps AD;Tian Y;Chakravarti A;Bucan M;Puffenberger EG
我们对来自四个双相情感障碍家族的26名阿米什人（52 ± 11岁）进行了盲态精神病学评估，通过外显子组测序确定了10个潜在致病等位基因，在更大的阿米什人重大情感障碍研究（ASMAD）队列中测试了这些等位基因与临床诊断的相关性，并研究了神经元中的突变钾通道。26名阿米什人中有14人患有双相型谱系障碍。它们之间唯一共有的候选等位基因是rs78247304，这是KCNH 7的非同义变体（c.1181G>A，p.Arg394His）。KCNH 7 c.1181G>A和其他9种潜在致病性变体随后在ASMAD队列中进行了测试，该队列由340名受试者组成，这些受试者分为对照受试者和来自重叠临床类别（双相1型障碍、双相谱系障碍和任何严重情感障碍）的受影响受试者。KCNH 7 c.1181G>A在双相情感障碍患者中的富集度最高（χ2 = 7.3），与双相1型（P = 0.021）、双相情感障碍（P = 0.031）和任何严重情感障碍（P = 0.016）的家族基础关联性最强。在体外，p.Arg394His取代允许HERG 3/Kv11.3通道的正常表达、运输、组装和定位，但改变了神经元细胞中的稳态电压依赖性和激活动力学。尽管我们的全基因组统计结果并不能单独证明相关性，但来自多个独立来源（平行的全基因组研究队列、HERG型钾通道的药理学研究、电生理数据）的累积证据表明神经元HERG 3/Kv 11. 3钾通道与双相谱系障碍的病理生理学有关。这一发现，如果得到未来研究的证实，将对阿米什人的心理健康服务以及专门针对HERG 3/Kv11.3的药物开发产生影响。
We conducted blinded psychiatric assessments of 26 Amish subjects (52 ± 11 years) from four families with prevalent bipolar spectrum disorder, identified 10 potentially pathogenic alleles by exome sequencing, tested association of these alleles with clinical diagnoses in the larger Amish Study of Major Affective Disorder (ASMAD) cohort, and studied mutant potassium channels in neurons. Fourteen of 26 Amish had bipolar spectrum disorder. The only candidate allele shared among them was rs78247304, a non-synonymous variant of KCNH7 (c.1181G>A, p.Arg394His). KCNH7 c.1181G>A and nine other potentially pathogenic variants were subsequently tested within the ASMAD cohort, which consisted of 340 subjects grouped into controls subjects and affected subjects from overlapping clinical categories (bipolar 1 disorder, bipolar spectrum disorder and any major affective disorder). KCNH7 c.1181G>A had the highest enrichment among individuals with bipolar spectrum disorder (χ2 = 7.3) and the strongest family-based association with bipolar 1 (P = 0.021), bipolar spectrum (P = 0.031) and any major affective disorder (P = 0.016). In vitro, the p.Arg394His substitution allowed normal expression, trafficking, assembly and localization of HERG3/Kv11.3 channels, but altered the steady-state voltage dependence and kinetics of activation in neuronal cells. Although our genome-wide statistical results do not alone prove association, cumulative evidence from multiple independent sources (parallel genome-wide study cohorts, pharmacological studies of HERG-type potassium channels, electrophysiological data) implicates neuronal HERG3/Kv11.3 potassium channels in the pathophysiology of bipolar spectrum disorder. Such a finding, if corroborated by future studies, has implications for mental health services among the Amish, as well as development of drugs that specifically target HERG3/Kv11.3.
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影响因子：
5.2
作者：
Horvath, S;Xu, X;Laird, NM
通讯作者：
Laird, NM
精神分裂症，躁郁症和抑郁症的跨disor阶层基因组分析。
DOI：
10.1176/appi.ajp.2010.09091335
发表时间：
2010-10
期刊：
The American journal of psychiatry
影响因子：
--
作者：
Huang J;Perlis RH;Lee PH;Rush AJ;Fava M;Sachs GS;Lieberman J;Hamilton SP;Sullivan P;Sklar P;Purcell S;Smoller JW
通讯作者：
Smoller JW
影响因子：
17.7
作者：
Apud, Jose A.;Zhang, Fengyu;Weinberger, Daniel R.
通讯作者：
Weinberger, Daniel R.
DOI：
10.1006/bbrc.2001.5434
发表时间：
2001-08-24
影响因子：
3.1
作者：
Kang, JS;Chen, XL;Rampe, D
通讯作者：
Rampe, D
影响因子：
6
作者：
McNamara, Robert K.;Nandagopal, Jayasree J.;DelBello, Melissa P.
通讯作者：
DelBello, Melissa P.