Kim Young Shin, Leventhal Bennett L
Department of Psychiatry, University of California, San Francisco, San Francisco, California..
Department of Psychiatry, Yonsei University College of Medicine, Seoul, South Korea.
Biol Psychiatry. 2015 Jan 1;77(1):66-74. doi: 10.1016/j.biopsych.2014.11.001. Epub 2014 Nov 5.
Understanding the pathogenesis of neurodevelopmental disorders has proven to be challenging. Using autism spectrum disorder (ASD) as a paradigmatic neurodevelopmental disorder, this article reviews the existing literature on the etiological substrates of ASD and explores how genetic epidemiology approaches including gene-environment interactions (G×E) can play a role in identifying factors associated with ASD etiology. New genetic and bioinformatics strategies have yielded important clues to ASD genetic substrates. The next steps for understanding ASD pathogenesis require significant effort to focus on how genes and environment interact with one another in typical development and its perturbations. Along with larger sample sizes, future study designs should include sample ascertainment that is epidemiologic and population-based to capture the entire ASD spectrum with both categorical and dimensional phenotypic characterization; environmental measurements with accuracy, validity, and biomarkers; statistical methods to address population stratification, multiple comparisons, and G×E of rare variants; animal models to test hypotheses; and new methods to broaden the capacity to search for G×E, including genome-wide and environment-wide association studies, precise estimation of heritability using dense genetic markers, and consideration of G×E both as the disease cause and a disease course modifier. Although examination of G×E appears to be a daunting task, tremendous recent progress in gene discovery has opened new horizons for advancing our understanding of the role of G×E in the pathogenesis of ASD and ultimately identifying the causes, treatments, and even preventive measures for ASD and other neurodevelopmental disorders.
事实证明，了解神经发育障碍的发病机制具有挑战性。本文以自闭症谱系障碍（ASD）作为典型的神经发育障碍为例，回顾了关于ASD病因基础的现有文献，并探讨了包括基因-环境相互作用（G×E）在内的遗传流行病学方法如何在识别与ASD病因相关的因素中发挥作用。新的遗传和生物信息学策略为ASD的遗传基础提供了重要线索。了解ASD发病机制的下一步需要付出巨大努力，重点关注基因和环境在正常发育及其扰动过程中如何相互作用。除了更大的样本量外，未来的研究设计应包括基于人群的流行病学样本确定，以通过分类和维度表型特征来捕捉整个ASD谱系；进行具有准确性、有效性和生物标志物的环境测量；采用统计方法来解决人群分层、多重比较以及罕见变异的G×E问题；利用动物模型来检验假设；以及采用新方法来扩大搜索G×E的能力，包括全基因组和全环境关联研究、使用密集遗传标记精确估计遗传力，以及将G×E既视为疾病病因又视为疾病病程修饰因素。尽管研究G×E似乎是一项艰巨的任务，但最近在基因发现方面取得的巨大进展为增进我们对G×E在ASD发病机制中的作用的理解，最终确定ASD和其他神经发育障碍的病因、治疗方法甚至预防措施开辟了新的视野。
