李则亿 林名玉

Mental illness affects one in six U.S. adults， but scientists' sense of the underlying biology of most psychiatric disorders remains nebulous. That's frustrating for physicians treating the diseases， who must also make diagnoses based on symptoms that may only appear sporadically. No laboratory blood test or brain scan can yet distinguish whether someone has depression or bipolar disorder， for example.

精神疾病困擾着六分之一的美国成年人，至今，科学家对大多数精神疾病的潜在生物机理仍认识有限，只能基于偶发性症状来开展诊治，这让治疗精神疾病的内科医生们感到沮丧。例如，实验室里的血液检查或者脑部扫描尚无法区分出抑郁症与躁郁症。

Now， however， a large-scale analysis of postmortem brains is revealing distinctive molecular traces in people with mental illness. This week， an international team of researchers reports that five major psychiatric disorders have patterns of gene activity that often overlap but also vary in disease-specific—and sometimes counterintuitive—ways. The findings， they say， might someday lead to diagnostic tests and novel therapies， and one has already inspired a clinical trial of a new way to treat overactive brain cells in autism.

然而，如今，大量的死后脑分析正揭示出精神疾病患者脑部独特的分子运动痕迹。本周，一个国际研究团队报告说，五种重大精神疾病的基因活动模式虽常有重合，但也因病而异，有些时候还会出现有悖常识的情况。不过，也偶然会出现有悖常识的因病而异情况。该团队认为，此研究发现有朝一日或能促发诊断测试与全新疗法；而且，其中一项发现已经激发出一种新的临床方法，用以治疗自闭症患者脑细胞的过度活跃。

Outsiders say the data mark a milestone in psychiatry. "This [work] is changing fundamental views about the nature of psychiatric illness，" says Kenneth Kendler， a psychiatric geneticist at Virginia Commonwealth University in Richmond.

外界人士表示，这些数据标志着精神病治疗的里程碑。来自里士满弗吉尼亚联邦大学的精神病遗传学家肯内特·肯德勒称“这（项研究）正在改变人们对精神疾病性质的基本看法。”

Researchers have long known that genes influence mental illness. Five years ago， for example， the global Psychiatric Genomics Consortium found that people with autism， schizophrenia， bipolar disorder， depression， and attention-deficit hyperactivity disorder frequently share certain DNA variations. But that 2013 study did not say how those genetic alterations might lead to symptoms.

研究人员早已知道基因会影响精神疾病。例如，五年前，全球精神病学基因组学联盟就曾发现，自闭症、精神分裂症、躁郁症、抑郁症和注意力缺陷多动障碍患者频发特定DNA变异。但是，2013年进行的这项研究却未能说明这些基因变异如何引发病症。

Dan Geschwind， a neurologist and neuroscientist at the University of California， Los Angeles （UCLA）， who spearheaded the new work， wanted to know what happens at the molecular level in the brains of people with these disorders. He， his UCLA colleague Mike Gandal， and their team analyzed gene expression patterns from the cerebral cortex， the brain's outer layer， of 700 postmortem patients with autism， schizophrenia， bipolar disorder， depression， or alcoholism and compared the patterns with those from the brains of 293 matched healthy controls. For another control， they also looked at cortical gene expression in 197 patients with inflammatory bowel disease， which should help exclude general disease processes shared by non–central nervous system conditions.

加州大学洛杉矶分校的神经病学家与神经科学家丹·格什未温德领导了这项新研究，旨在了解精神病患者大脑在分子水平上的发展变化。他与同样来自加州大学洛杉矶分校的同事迈克·甘达尔带领团队分析了700名自闭症、精神分裂症、躁郁症、抑郁症或酗酒病人尸体大脑皮质（即大脑表层）的基因表现模式，并与293个健康对照组的情况做了对比。另一方面，他们还研究了197位炎症性肠病患者的皮质基因表现，以便排除非中枢神经系统疾病共有的普通病程。

The analysis revealed that certain psychiatric diseases are more similar biologically than their characteristic symptoms indicate. Bipolar disorder is commonly considered a mood disorder， like depression， so it stands to reason that the underlying biology of both ailments would be comparable. But the genomic data told a different story： Bipolar disorder overlapped the most in cortical gene activity with schizophrenia. "This is not what clinicians would've expected，" Kendler says. "It certainly suggests the idea that these are sharply different kinds of disorders is not valid."

该分析揭示出某些精神疾病在生物学上的相似度要高于它们在症状特点上的相似度。与抑郁症相似，躁郁症通常被认为是情感紊乱，抑郁症也是如此。，因此，这两种疾病的深层生物学原理具有可比性似乎不言而喻。然而，基因组数据却给出不同的答案：躁郁症的皮质基因活性与精神分裂症重合度最高。“这与之前临床医师的预想不同，”肯德勒说道，“很显然，那种把它们视为截然不同病症的观点并不可信。”

In another surprise， Geschwind， Gandal， and their colleagues found essentially zero correlation in gene activity patterns between alcoholism and the other four disorders. Many studies in identical twins， who have largely identical DNA， had suggested that the genetic risk factors for major depression and alcohol use disorder are similar， Kendler says. Yet the new work suggests that's not the case.

另一惊喜是格什未温德、甘达尔及其同事发现酗酒与其他四种精神疾病的基因活动模式本质上并无关联。肯德勒说，先前许多关于DNA大部分相同的同卵双胞胎研究曾表明，重度抑郁与酗酒的致患风险基因相似。然而，这项新研究显示情况并非如此。

Another series of tantalizing findings hinted at autism's molecular roots. The study showed， for example， that many genes in the cerebral cortex are active in both schizophrenia and autism—but they are far more active in autism. The finding suggests that gene overexpression might play a role in autism's symptoms. Meanwhile， genes linked to neuronal firing were turned down in autism， as well as in schizophrenia and bipolar disorder—suggesting that changes in brain cell communication play a role in all three conditions.

还有一系列令人兴奋的发现暗示了自闭症的分子根源。举例来说，该研究表明精神分裂症和孤独症患者的大脑皮质中许多基因都很活躍，但后者活跃度更高。这一发现表明基因过度活跃可能在自闭症症状中起到一定作用。同时，自闭症中的与神经元放电相关基因被抑制，精神分裂症和躁郁症也存在这种现象这说明脑细胞通讯机制的改变在上述三种疾病中均起作用。

Another cluster of gene activity that stood out in autism points to overactive microglia， a subset of brain immune cells that protect against inflammation. Based on that， Gandal is leading a small clinical trial that will test whether an antibiotic can keep these cells in a resting state in adults with autism.

自闭症引人注意的另一基因簇活动是小胶质细胞的过度活跃，这些保护大脑免受感染的细胞相聚成团。基于此，甘德尔正领导一场小规模临床试验来测试抗生素能否稳定成年自闭症患者体内的小胶质细胞活动。

Jordan Smoller， a psychiatric geneticist at Harvard Medical School in Boston who led the 2013 study of genetic variants in mental disorders， says the field needs to dive even deeper than the new work by focusing on gene expression from single cells， rather than the large brain area examined in the current analysis. That could help researchers zero in on specific cell types driving the disorders， he suggests.

波士顿哈佛医学院的精神病基因学家乔丹·斯默勒曾于2013年领导了有关精神病患基因变异的研究工作，他认为，在新研究聚焦单细胞基因表现的基础上，研究领域仍需深入，不能像当前分析那样局限于研究大脑区域，才能有助于研究者集中精力发现具体的致病细胞类型。

Nonetheless， Smoller applauds the trend in psychiatric genomics toward large consortia that can tackle big problems with masses of data. "The message [from the new study] is a broadly hopeful one，" Kendler adds. "We're beginning to see the bits of the puzzle starting to slowly get clearer."

盡管如此，斯默勒仍赞扬神经疾病基因组学的大范围合作趋势，认为大数据可以解决重大难题。“（新研究传递的）信息是大有希望的，”肯德勒补充道，“我们开始看到谜团正逐步解开。”