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4个遗传标志物与5种精神疾病相关

Four genetic markers associated with five psychiatric disorders
来源:EGMN 2013-03-07 10:13点击次数:641发表评论

《柳叶刀》(Lancet)2月28日在线发表的一项研究显示,4个染色体位点的遗传变异与5种儿童和成人时期发生的精神疾病相关:精神分裂症、孤独谱系障碍、注意力缺陷/多动障碍、双相情感障碍和重度抑郁症。4个位点中的2个编码钙离子跨膜转运,可作为治疗靶点(2013 Feb. 28 [dx.doi.org/10.1016/S0140-6736(12)62129-1])。




Jordan Smoller博士


在这项目前为止同类研究中规模最大的全基因组关联研究中,麻省总医院的Jordan W. Smoller博士及其同事在33,332例患者和27,888例对照者中对上述5种疾病的单核苷酸多态性(SNP)进行了分析。所有这些研究对象均为欧洲血统。结果发现,4个独立位点含有的SNP与这些疾病显著相关。3个位点与所有5种疾病相关,1个位点仅与双相情感障碍和精神分裂症相关。


分析还发现,此前仅与精神分裂症相关的一些位点也与其他疾病相关,但这些关联不如在4个主要位点观察到的关联强烈。


4个位点中的2个与电压门控跨膜钙离子通道相关。其中1个位点此前被发现是精神分裂症、双相情感障碍和重度抑郁症的危险基因,该基因可促进钙离子进入质膜。


因此,研究结果表明,电压门控钙离子信号通路和钙离子通路活性(更广义上而言)是精神疾病的重要生物过程。钙离子通路的改变是精神病理学改变的基本机制。该通路可潜在作为精神疾病的治疗靶点。


该研究存在一些局限性。例如,诊断上对精神分裂症和双相情感障碍的错误分类可产生疾病之间遗传重叠的假证据。此外,由于该研究的分析对象仅限于欧洲血统人群,因此尚不清楚其结果是否适用于其他人群。但总体而言,研究结果有助于了解各种精神疾病的共同原因。


该研究获美国国立卫生研究院资助。Smoller博士及其同事是精神病基因组学联盟交叉疾病组成员,他们均声明无经济利益冲突。


随刊述评:研究观察到的生理关联具有临床意义


意大利博洛尼亚大学的神经精神病学家Alessandro Serretti博士表示,该研究的遗传结果有助于建立更合理的精神疾病分类系统,而其观察到的生理关联也具有临床转化价值,有助于未来建立病情学系统。钙离子信号是神经元生长和发育的关键调节因素。既往研究在小鼠中发现电压依赖性钙通道激动剂具有抗抑郁作用。如果此类通道被某一突变阻滞,则表明患者存在易于发生抑郁或其他疾病的遗传特征。上述研究发现电压门控钙通道信号通路参与一些精神疾病的发病机制。精神疾病的发生除了与上述这些遗传标志物相关之外,还涉及一些跨诊断的危险因素,因此并非所有存在这些遗传标志物的患者都会发生相关的疾病之一。不过,遗传标志物的存在增加了患者发生精神疾病的倾向,而且通过研究遗传标志物有助于了解精神疾病的发生和开发新一代的抗精神病药。


Serretti博士声明无经济利益冲突。


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By: MICHELE G. SULLIVAN, Internal Medicine News Digital Network


Genetic variants at four chromosomal positions have now been linked to five diverse childhood- and adult-onset psychiatric illnesses: schizophrenia, autism spectrum disorders, attention-deficit/hyperactivity disorder, bipolar disorder, and major depressive disorder.


Two of the four loci encode for transmembranal calcium ion transport, a physiologic finding that could become a treatment target, Dr. Jordan W. Smoller and his colleagues wrote in the Feb. 28 online issue of the Lancet (2013 Feb. 28 [dx.doi.org/10.1016/S0140-6736(12)62129-1]).
 
"The finding that genetic variants have cross-disorder effects is an empirical step toward helping clinicians understand the common co-occurrence of clinical phenotypes in individual patients," wrote Dr. Smoller of the Massachusetts General Hospital, Boston, and his coauthors. "Our results implicate a specific biological pathway – voltage-gated calcium-channel signaling – as a contributor to the pathogenesis of several psychiatric disorders, and support the potential of this pathway as a therapeutic target for psychiatric disease."


The findings also could further the goal of "moving beyond descriptive syndromes in psychiatry and towards a nosology informed by disease cause," the investigators noted.


The genome-wide association study – the largest yet of its kind – analyzed single nucleotide polymorphisms (SNPs) for the five disorders among 33,332 cases and 27,888 controls, all of European ancestry. Four independent regions contained SNPs that were significantly related to the disorders. Three were related to all five disorders, and one to only bipolar disorder and schizophrenia.


The analysis also identified additional cross-disorder associations with a number of loci previously identified only with schizophrenia, although these associations were not as strong as those seen with the four primary regions.


Two of the four loci are related to voltage-gated transmembranal calcium channels, the authors noted. One of these has been previously identified as a risk gene for schizophrenia, bipolar disorder, and major depressive disorder. The gene facilitates the passage of calcium ions into the plasma membrane.


"Thus, our results suggest that voltage-gated calcium signaling, and, more broadly, calcium channel activity, could be an important biological process in psychiatric disorders," Dr. Smoller and his colleagues wrote. "Alterations in calcium channel signaling could represent a fundamental mechanism contributing to a broad vulnerability to psychopathology."


The authors cited several possible limitations. For example, diagnostic misclassification in cases of schizophrenia and bipolar disorder could produce "spurious evidence of genetic overlap between disorders." In addition, because their analyses were restricted to people of European ancestry, it is unclear whether their findings would apply to other populations.


Nevertheless, they said these result could provide "insights into the shared causation of psychiatric disorders."


Dr. Smoller and his coauthors are members of the Cross-Disorder Group of the Psychiatric Genomics Consortium. Their work was sponsored by the National Institutes of Health; none of the authors had any financial disclosures.


View on the News
Associations offer clinical opportunities


While the genetic findings will contribute to a more logical classification system of psychotropic disorders, the physiologic associations hold out a tantalizing promise for the future, Dr. Alessandro Serretti, lead author, wrote in an accompanying editorial.


"In addition to methodological issues, which are pertinent to researchers, genetic studies should provide translational value for clinicians," wrote Dr. Serretti of the University of Bologna, Italy. "With this perspective, the present study might contribute to future nosographic systems, which could be based not only on statistically determined clinical categories, but also on biological pathogenic factors that are pivotal to the identification of suitable treatments."


Calcium signaling is a critical regulator of neuronal growth and development, he said. Prior studies have confirmed the antidepressant effects of voltage-dependent calcium channel agonists in mice; a mutation that blocks such channels would be a logical underpinning for an inherited prediction toward depression and, perhaps, other disorders.


"[Single nucleotide polymorphisms] associated previously with different psychiatric disorders identified convergence of pathways in synaptogenesis, axonal guidance, and synaptic plasticity, and now calcium signaling, which is pivotal in the mechanisms of all these biological processes."


Not all patients with these genetic markers will develop one of the associated disorders. "We agree about the presence of some transdiagnostic risk factors, but many genes and polymorphisms are expected to confer a liability to individual psychiatric diseases." Prenatal and postnatal environments – both their negative and positive environmental conditions – modulate the expression of any genetic predilection.


But genetic predilections present an invaluable look into both the development and treatment of disease. "We therefore believe that genetics, possibly thanks to more comprehensive phenotype and endophenotype assessments, can contribute to prediction and prevention of psychiatric diseases, along with the identification of molecular targets for new generations of psychotropic drugs."


Dr. Serretti is a neuropsychiatrist at the University of Bologna, Italy. He had no financial disclosures. 


学科代码:精神病学 医学遗传学   关键词:精神分裂症 孤独谱系障碍 注意力缺陷/多动障碍 双相情感障碍 重度抑郁症
来源: EGMN
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