Integration of DNA sequence and DNA methylation changes in monozygotic twin pairs discordant for schizophrenia
Integration of DNA sequence and DNA methylation changes in monozygotic twin pairs discordant for schizophrenia
复制标题
DOI：
10.1016/j.schres.2015.09.021
复制
发表时间：
2015-12-01
影响因子：
4.5
通讯作者：
Singh, S. M.
中科院分区：
文献类型：
--
作者：
Castellani, C. A.;Melka, M. G.;Singh, S. M.
精神分裂症是一种复杂的精神障碍，具有高遗传率（80%），广泛的遗传异质性，环境因素和只有50%的一致性，在不和谐的单卵（MZ）双胞胎。不一致的同卵双胞胎提供了一个特殊的机会，以评估患者特定的全基因组遗传和表观遗传的变化，可能占疾病的表型。基于两个原因，对同一对双胞胎的遗传和表观遗传变化进行综合分析有望提供一种更有效的方法。首先，现在可以在个体水平上产生相对可靠的完整基因组序列以及启动子甲基化状态，其次，来自同一受精卵的未受影响的双胞胎提供了近乎完美的遗传匹配用于对比和比较。本报告涉及两对临床随访超过20年的不一致同卵双胞胎的DNA序列数据和甲基化数据的综合分析。家庭1的结果显示，58个基因的DNA序列不同，以及在精神分裂症影响的双胞胎启动子甲基化相比，她的健康双胞胎。家庭2的相应数字是13。这两个列表都是由神经元基因代表的，包括许多已知的精神分裂症候选基因和药物靶点。结果表明，通过共定位遗传和表观遗传改变的多个基因的变化有助于精神分裂症发展所必需的责任阈值。这一新的假设虽然合乎逻辑，但仍有待验证。皇冠版权所有（C）2015由Elsevier B.V.出版。保留所有权利。
Schizophrenia is a complex mental disorder with high heritability (80%), extensive genetic heterogeneity, environmental contributions and only 50% concordance in discordant monozygotic (MZ) twins. Discordant MZ twins provide an exceptional opportunity to assess patient specific genome-wide genetic and epigenetic changes that may account for the disease phenotype. A combined analysis of genetic and epigenetic changes on the same twin pairs is expected to provide a more effective approach for two reasons. First, it is now possible to generate relatively reliable complete genome sequences as well as promoter methylation states on an individual level and second, the unaffected twin that originated from the same zygote provides a near perfect genetic match for contrast and comparison. This report deals with the combined analysis of DNA sequence data and methylation data on two pairs of discordant MZ twins that have been clinically followed for over 20 years. Results on Family 1 show that 58 genes differ in DNA sequence as well as promoter methylation in a schizophrenia-affected twin as compared to her healthy co-twin. The corresponding number for family 2 was 13. The two lists are over represented by neuronal genes and include a number of known schizophrenia candidate genes and drug targets. The results argue that changes in multiple genes via co-localized genetic and epigenetic alteration contribute to a liability threshold that is necessary for development of schizophrenia. This novel hypothesis, although logical, remains to be validated. Crown Copyright (C) 2015 Published by Elsevier B.V. All rights reserved.