意外發(fā)現(xiàn)：重大精神疾病與大腦基因活動相關，更優(yōu)診療希望大增

李則億 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.

精神疾病困擾著六分之一的美國成年人，至今，科學家對大多數(shù)精神疾病的潛在生物機理仍認識有限，只能基于偶發(fā)性癥狀來開展診治，這讓治療精神疾病的內(nèi)科醫(yī)生們感到沮喪。例如，實驗室里的血液檢查或者腦部掃描尚無法區(qū)分出抑郁癥與躁郁癥。

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，大量的死后腦分析正揭示出精神疾病患者腦部獨特的分子運動痕跡。本周，一個國際研究團隊報告說，五種重大精神疾病的基因活動模式雖常有重合，但也因病而異，有些時候還會出現(xiàn)有悖常識的情況。不過，也偶然會出現(xiàn)有悖常識的因病而異情況。該團隊認為，此研究發(fā)現(xiàn)有朝一日或能促發(fā)診斷測試與全新療法；而且，其中一項發(fā)現(xiàn)已經(jīng)激發(fā)出一種新的臨床方法，用以治療自閉癥患者腦細胞的過度活躍。

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，這些數(shù)據(jù)標志著精神病治療的里程碑。來自里士滿弗吉尼亞聯(lián)邦大學的精神病遺傳學家肯內(nèi)特·肯德勒稱“這（項研究）正在改變?nèi)藗儗窦膊⌒再|(zhì)的基本看法?！?/p>

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.

研究人員早已知道基因會影響精神疾病。例如，五年前，全球精神病學基因組學聯(lián)盟就曾發(fā)現(xiàn)，自閉癥、精神分裂癥、躁郁癥、抑郁癥和注意力缺陷多動障礙患者頻發(fā)特定DNA變異。但是，2013年進行的這項研究卻未能說明這些基因變異如何引發(fā)病癥。

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.

加州大學洛杉磯分校的神經(jīng)病學家與神經(jīng)科學家丹·格什未溫德領導了這項新研究，旨在了解精神病患者大腦在分子水平上的發(fā)展變化。他與同樣來自加州大學洛杉磯分校的同事邁克·甘達爾帶領團隊分析了700名自閉癥、精神分裂癥、躁郁癥、抑郁癥或酗酒病人尸體大腦皮質(zhì)（即大腦表層）的基因表現(xiàn)模式，并與293個健康對照組的情況做了對比。另一方面，他們還研究了197位炎癥性腸病患者的皮質(zhì)基因表現(xiàn)，以便排除非中樞神經(jīng)系統(tǒng)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."

該分析揭示出某些精神疾病在生物學上的相似度要高于它們在癥狀特點上的相似度。與抑郁癥相似，躁郁癥通常被認為是情感紊亂，抑郁癥也是如此。，因此，這兩種疾病的深層生物學原理具有可比性似乎不言而喻。然而，基因組數(shù)據(jù)卻給出不同的答案：躁郁癥的皮質(zhì)基因活性與精神分裂癥重合度最高?！斑@與之前臨床醫(yī)師的預想不同，”肯德勒說道，“很顯然，那種把它們視為截然不同病癥的觀點并不可信?！?/p>

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.

另一驚喜是格什未溫德、甘達爾及其同事發(fā)現(xiàn)酗酒與其他四種精神疾病的基因活動模式本質(zhì)上并無關聯(lián)?？系吕照f，先前許多關于DNA大部分相同的同卵雙胞胎研究曾表明，重度抑郁與酗酒的致患風險基因相似。然而，這項新研究顯示情況并非如此。

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.

還有一系列令人興奮的發(fā)現(xiàn)暗示了自閉癥的分子根源。舉例來說，該研究表明精神分裂癥和孤獨癥患者的大腦皮質(zhì)中許多基因都很活躍，但后者活躍度更高。這一發(fā)現(xiàn)表明基因過度活躍可能在自閉癥癥狀中起到一定作用。同時，自閉癥中的與神經(jīng)元放電相關基因被抑制，精神分裂癥和躁郁癥也存在這種現(xiàn)象這說明腦細胞通訊機制的改變在上述三種疾病中均起作用。

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.

自閉癥引人注意的另一基因簇活動是小膠質(zhì)細胞的過度活躍，這些保護大腦免受感染的細胞相聚成團?；诖?，甘德爾正領導一場小規(guī)模臨床試驗來測試抗生素能否穩(wěn)定成年自閉癥患者體內(nèi)的小膠質(zhì)細胞活動。

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.

波士頓哈佛醫(yī)學院的精神病基因?qū)W家喬丹·斯默勒曾于2013年領導了有關精神病患基因變異的研究工作，他認為，在新研究聚焦單細胞基因表現(xiàn)的基礎上，研究領域仍需深入，不能像當前分析那樣局限于研究大腦區(qū)域，才能有助于研究者集中精力發(fā)現(xiàn)具體的致病細胞類型。

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，斯默勒仍贊揚神經(jīng)疾病基因組學的大范圍合作趨勢，認為大數(shù)據(jù)可以解決重大難題?！埃ㄐ卵芯總鬟f的）信息是大有希望的，”肯德勒補充道，“我們開始看到謎團正逐步解開?！?/p>