Braff David L, Freedman Robert, Schork Nicholas J, Gottesman Irving I
Department of Psychiatry, University of California San Diego, 9500 Gilman Drive, Mail Code 0804, La Jolla, CA 92093, USA.
Schizophr Bull. 2007 Jan;33(1):21-32. doi: 10.1093/schbul/sbl049. Epub 2006 Nov 6.
The genetics of schizophrenia has been approached utilizing a variety of methods. One emerging strategy is the use of endophenotypes in order to understand and identify the functional importance of genetically transmitted, brain-based deficits across schizophrenia kindreds. The endophenotype strategy is a topic of this issue of Schizophrenia Bulletin. Endophenotypes are quantitative, heritable, trait-related deficits typically assessed by laboratory-based methods rather than clinical observation. Endophenotypes are seen as closer to genetic variation than are clinical symptoms of schizophrenia, and are therefore closely linked to heritable risk factors. There has been a broad expansion of opportunities available to psychiatric neuroscientists who use the endophenotype strategy to understand the genetic basis of schizophrenia. In this context, genetic variation such as single nucleotide polymorphisms (SNPs) induces abnormalities in endophenotypic domains such as neurocognition, neurodevelopment, metabolism, and neurophysiology. This article discusses the challenges that abound in genetic research of schizophrenia, including issues in ascertainment, epistasis, ethnic diversity, and the potentially normalizing effects of second-generation antipsychotic medications on neurocognitive and neurophysiological measures. Robust strategies for meeting these challenges are discussed in this review and the subsequent articles in this issue. This article summarizes conceptual advances and progress in the measurement and use of endophenotypes in schizophrenia that form the basis of the multisite National Institute of Mental Health Consortium on the Genetics of Schizophrenia. The endophenotype strategy offers powerful and exciting opportunities to understand the genetically conferred neurobiological vulnerabilities and possible new strong inference and molecularly based treatments for schizophrenia.
精神分裂症的遗传学研究已采用了多种方法。一种新兴策略是利用内表型来理解和识别精神分裂症家族中遗传的、基于大脑的缺陷的功能重要性。内表型策略是本期《精神分裂症通报》的一个主题。内表型是定量的、可遗传的、与特质相关的缺陷，通常通过基于实验室的方法而非临床观察来评估。与精神分裂症的临床症状相比，内表型被认为更接近遗传变异，因此与遗传风险因素密切相关。对于使用内表型策略来理解精神分裂症遗传基础的精神科神经科学家来说，可用的机会有了广泛扩展。在这种背景下，诸如单核苷酸多态性（SNP）等遗传变异会在内表型领域如神经认知、神经发育、代谢和神经生理学中诱发异常。本文讨论了精神分裂症遗传研究中存在的诸多挑战，包括确定问题、上位性、种族多样性以及第二代抗精神病药物对神经认知和神经生理学测量可能产生的正常化影响。本综述以及本期后续文章讨论了应对这些挑战的有力策略。本文总结了精神分裂症内表型测量和使用方面的概念进展和成果，这些构成了国立精神卫生研究所精神分裂症遗传学多中心联盟的基础。内表型策略为理解遗传赋予的神经生物学易感性以及可能为精神分裂症提供新的有力推断和基于分子的治疗方法提供了强大且令人兴奋的机会。
