孤独症的遗传学和神经生物学研究进展

Progress of Autism Spectrum Disorder on Genetics and Neurobiology

孤独症是一种遗传度高达90%的多基因复杂疾病,具有典型的遗传和表型异质性,并受到环境因素的影响.本文对近年来孤独症遗传学、表观遗传学和神经生物学3方面的进展进行了简要综述.细胞遗传学法、全基因组扫描及候选基因法是孤独症分子遗传学研究中较为常见的3种方法.虽然应用上述方法发现了一些孤独症易感基因集中的染色体区域,但确切的致病或易感基因仍未被检出.因而,越来越多的关注被集中于如何提高样本同质性、如何将遗传学机制与环境作用相联系、如何提高微效基因的检出率上.在提高样本同质性方面,功能核磁共振及交叉表型的研究正在进行.同时,表观遗传学的研究可以联系遗传与环境因素,从而更好地解释孤独症的发病机制.目前,对染色体上表观遗传与遗传共同调控的区域,如7号和15号染色体长臂,进行了大量研究.在神经生物学方面,神经递质、神经发育及神经免疫学假说均有一定的进展.其中,针对神经递质的研究主要集中于5-羟色胺、?-氨基丁酸及谷氨酸.在神经发育假说方面,神经发育相关蛋白,如肝细胞生长因子、神经生长因子及Reelin,研究得较为深入.

Autism is a group of complex genetic diseases. The genetic contribution or heritability may be as high as 90%, presenting as a group of clinically heterogeneous spectrum disorders involving multiple genes and environmental factors. This article focuses on recent progress in autism research in the area of genetics, epigenetics and neurobiology. First, extensive studies using cytogenetics, genome-wide association and candidate gene approaches have led to the identification of several chromosomal regions and loci associated with autism susceptibility. However, major causal genes for autism remain to be defined. Increasing effort is being made to improve the homogeneity of samples and detection of genes with small effects as well as how to study genetic-environmental interactions. Functional brain imaging approaches, such as magnetic resonances and behavioral correlation, are being developed and employed. Second, epigenetic studies, which integrate genetic factors with environment influences, may provide more comprehensive explanations for the pathogenesis of autism. A number of studies have been carried out in the chromosomal regions co-regulated by epigenetic and genetic mechanisms, including 7q and 15 q. Third, several hypotheses based on changes in neurotransmitters, neural development and neural immunity have been proposed to explain neurobiological basis of autism. For example, neurotransmitters have been implicated, including serotonin, ？-aminobutyric acid and glutamate. Several proteins important for neural development such as hepatocyte growth factor, nerve growth factor and reelin have been associated with pathogenesis of autism.