本帖最後由 yanjw2000 於 2009-7-28 21:53 編輯
作者：Janis Kelly
出處：WebMD醫學新聞
July 10, 2009 — 來自三個大陸的研究者完成了精神分裂症的基因圖研究，辨識出基因變化的排列，每個變化對於風險都有些微程度的影響，彙整後佔了30%以上的精神分裂症基因風險。這三篇線上發表於7月1日自然(Nature)期刊的報告，顯示這些變化也與躁鬱症風險增加有關。
此外，研究者在染色體6p22.1上辨識一個「熱點」，包括一個組織蛋白基因叢集，認為與控制DNA轉錄和修補及抗微生物防禦有關，在第二類HLA區域的一部份中，認為自體免疫與這些精神異常有關。
國家心智健康研究中心基因研究組主任Thomas Lehner博士向Medscape Psychiatry表示，這些研究整合成精神科基因學方面最重要的發現之一。
Lehner博士表示，這項研究在近期內無法運用到臨床，但是它可解釋超過30%的精神分裂症基因原因，以前只能解釋少部份病因。估計至少有70%的精神分裂症屬於遺傳。
Lehner博士對這些研究印象最深刻的有兩點。其一為，這所有的1,000個基因，每個都有小風險，整合後對精神分裂症風險有這麼大的解釋力。Lehner博士表示，這提醒我們，腦部是一個複雜的器官，很多小地方出錯將會造成腦部有重大傷害。現在，我們可以聚焦在其他基因變化並尋找更多的樣本。
Lehner博士印象最深刻的第二點為，納入的基因位於第二類HLA區域，這表示與產生傷害及免疫有關。
【清楚的基因過程】
這三篇精神分裂症基因研究的財團，均有接受NIMH的部分資助，全部都顯示與第6染色體(6p22.1)有關，已知該染色體與免疫有關，且控制基因如何以及何時啟動和關閉。
哈佛大學與Stanley精神研究中心的Pamela Sklar博士解釋，我們研究的獨特之處在於，運用一種新的方法辨識基因變化上有精神分裂症風險影響的分子特徵，Sklar博士同時也和哈佛的Shaun Purcell博士領導「國際精神分裂症財團(ISC)」這個研究團隊。
Purcell博士表示，個別看來，這些變化不會增加統計上的顯著效果，但累積起來之後，它們扮演重要角色，解釋將近至少三分之一、甚至更高的疾病風險。
顯示與精神分裂症有最強烈關聯的區域中，一個可疑區域為染色體22，這個區域比染色體6多出450種變化。統計類比確認，研究發現，不會只是與少數有大影響的一般基因變化有關，也不會只有少數變化。研究者表示，這包括了許多常見的基因變化，認為不同人的精神分裂症最後均可能追蹤到清楚的基因過程。
Sklar博士指出，精神分裂症與躁鬱症的基因風險有明顯的重疊，這是心智異常中很特別的。研究者發現，這些基因變化與常見的非精神異常，如冠狀動脈疾病、克隆氏症、高血壓、類風濕性關節炎與第1或第2型糖尿病之間沒有關聯。
【對少數已知DNA序列的重要性】
精神分裂症分子基因(MGS)財團的研究，準確指出精神分裂症與染色體6調節之基因表現如組織蛋白區域之間的關係。細胞調節的基因根本變化，或許有助於解釋環境因素在精神分裂症上的影響。
MGS的研究也發現，精神分裂症與染色體1的一個基因變化(1p22.1)有關，該變化對多發性硬化症有影響。
領導MGS的北岸大學健康體系研究中心Pablo Gejman醫師表示，其研究結果強調，不只基因，還有少數已知的DNA序列都與基因表現有關的重要性。生物科技、統計、人類基因、精神科學等各方面的進步，加上可以招募更多樣本的能力，使我們得以有可能找到新發現。
由Kari Stefansson醫師領銜、來自冰島雷克亞維克deCODE Genetics公司的研究團隊所進行的SGENE財團的研究，準確指出染色體6區域的變化位置，顯示與免疫和感染有關的過程。
研究也發現在染色體11和18之變化有關的顯著證據，與精神分裂症的思考和記憶缺損有關。根據該公司的新聞稿，單一字母變化(即單核苷酸變異[SNPs])之一，位於染色體11上、靠近神經顆粒素基因(NRGN)。NRGN是可能的藥物標靶之一，它在調節記憶和認知上扮演重要角色，這兩項是精神分裂症患者倍感困擾的問題。
Nature.線上發表於2009年7月1日。
Schizophrenia, Bipolar Disorder Share Genetic Roots
By Janis Kelly
Medscape Medical News
July 10, 2009 — Researchers from 3 continents have completed genomewide studies of schizophrenia that identify an array of gene variants, each contributing a very small degree of risk but together accounting for over 30% of the genetic risk for schizophrenia. The 3 papers, published online July 1 in Nature, show that these variants are also associated with an increased risk for bipolar disorder.
Further, the researchers identified a "hot spot" on chromosome 6p22.1 that includes a histone gene cluster, suggesting involvement in control of DNA transcription and repair and in antimicrobial defense, and in part of the class II HLA region, suggesting that autoimmunity is involved in these psychiatric disorders.
Thomas Lehner, PhD, chief of the genomics research branch at the National Institute of Mental Health (NIMH), in Bethesda, Maryland, told Medscape Psychiatry that together these studies are 1 of the most important findings ever in psychiatric genomics.
"This work won't be applicable to clinical medicine in the near future, but it does explain more than 30% of the genetic contribution to schizophrenia, while before we could explain only a small percentage of this effect," Dr. Lehner said. Schizophrenia is estimated to be at least 70% heritable.
Dr. Lehner was most impressed by 2 points in these studies. The first is that 1000 genes, each with low risk, together explain so much of the variation in schizophrenia risk.
"This reminds us that the brain is a complex organ, and many things can go wrong in very small ways and make the brain go bad," Dr. Lehner said. "Now we can focus on the rest of the genetic variance and look for larger effect sizes."
The second point Dr. Lehner stressed was the involvement of genes in the class II HLA region. "This indicates that some insult is required and that immunity plays a role," he said.
Distinct Gene Processes
Studies from the 3 schizophrenia genetics research consortia, each funded in part by NIMH, all implicate an area of chromosome 6 (6p22.1), which is known to harbor genes involved in immunity and controlling how and when genes turn on and off.
"Our study was unique in employing a new way of detecting the molecular signatures of genetic variations with very small effects on potential schizophrenia risk," explained Pamela Sklar, MD, PhD, from Harvard University and the Stanley Center for Psychiatric Research, in Boston, Massachusetts, who co-led the International Schizophrenia Consortium (ISC) team with Harvard's Shaun Purcell, PhD.
"Individually, these common variants' effects do not all rise to statistical significance, but cumulatively they play a major role, accounting for at least one-third — and probably much more — of disease risk," said Dr. Purcell.
Among the sites showing the strongest associations with schizophrenia was a suspect area on chromosome 22 and more than 450 variations in the suspect area on chromosome 6. Statistical simulations confirmed that the findings could not have been accounted for by a handful of common gene variants with large effect or just rare variants. This involvement of many common gene variants suggests that schizophrenia in different people might ultimately be traceable to distinct disease processes, say the researchers.
"There was substantial overlap in the genetic risk for schizophrenia and bipolar disorder that was specific to mental disorders," added Dr. Sklar. The researchers found no association between the suspect gene variants and common nonpsychiatric disorders such as coronary artery disease, Crohn's disease, hypertension, rheumatoid arthritis, and type 1 or type 2 diabetes.?
Importance of Little-Known DNA Sequences
The Molecular Genetics of Schizophrenia (MGS) consortium pinpointed an association between schizophrenia and genes in the chromosome-6 region that mediate gene expression, such as histones. Genetically rooted variation in cell regulation might help explain the role of environmental factors in schizophrenia.
The MGS study also found an association between schizophrenia and a genetic variation on chromosome 1 (1p22.1), which has been implicated in multiple sclerosis.
"Our study results spotlight the importance not only of genes but also the little-known DNA sequences between genes that control their expression," said Pablo Gejman, MD, from the North Shore University Health System Research Institute, in Evanston, Illinois, who led the MGS consortium team. "Advances in biotechnology, statistics, population genetics, and psychiatry, in combination with the ability to recruit large samples,?made the new findings possible."
The SGENE consortium, led by Kari Stefansson, MD, and a team of researchers from deCODE Genetics, in Reykjavik, Iceland, pinpointed a site of variation in the suspect chromosome-6 region that could implicate processes related to immunity and infection.
It also found significant evidence of association with variation on chromosomes 11 and 18 that could help account for the thinking and memory deficits of schizophrenia. According to a press release from the company, "one of the single-letter variants (SNPs) is located near the neurogranin gene (NRGN) on chromosome 11. NRGN may be a candidate drug target, as it appears to play an important role in regulating both memory and cognition, processes that are often perturbed in schizophrenics."
Nature. Published online July 1, 2009. |
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