Virginia Institute of Psychiatric and Behavioral Genetics, and Departments of Psychiatry, and Human and Molecular Genetics, School of Medicine/Virginia Commonwealth University, Richmond, VA, USA.
Mol Psychiatry. 2013 Oct;18(10):1058-66. doi: 10.1038/mp.2013.50. Epub 2013 Apr 30.
Psychiatric genetics has taught us a great deal about the nature of psychiatric disorders. Traditional family, twin and adoption studies have demonstrated the substantial role of genetic factors in their etiology, clarified the role of genetic factors in comorbidity, elucidated development pathways, and documented the importance of gene-environment correlation and interaction. We have also received some hard lessons when we were unable to detect replicable genes of large effect size and found that our much-valued candidate genes did not live up to their expected promise. With more mature molecular and statistical methods, we are entering now a different era. Statistical analyses of aggregate molecular signals are validating earlier heritability estimates. Replicated findings from genome-wide association studies are beginning to emerge, as are discoveries of large-effect size rare genomic variants. The number of such findings is likely to soon grow dramatically. The most pressing question facing the field is what biological picture these results will reveal. I articulate four possible scenarios that reflect (i) no, (ii) minimal, (iii) moderate and (iv) high biological coherence in the replicated molecular variant findings, which are soon likely to emerge. I discuss the factors that will likely influence these patterns, including the problems of etiological heterogeneity and multiple realizability. These findings could provide critical insights into the underlying biology of our psychiatric syndromes and potentially permit us to perceive, 'through a glass darkly,' the levels of the mind-brain system that are disordered.
精神病遗传学为我们了解精神障碍的性质提供了很多知识。传统的家族、双胞胎和收养研究表明，遗传因素在其发病机制中起着重要作用，阐明了遗传因素在共病中的作用，阐明了发展途径，并证明了基因-环境相关性和相互作用的重要性。当我们无法检测到具有较大效应大小的可复制基因时，我们也得到了一些惨痛的教训，并且发现我们非常重视的候选基因并没有达到预期的效果。随着更成熟的分子和统计方法的出现，我们现在进入了一个不同的时代。对聚合分子信号的统计分析验证了早期的遗传估计。全基因组关联研究的重复发现开始出现，大效应大小的罕见基因组变异的发现也开始出现。此类发现的数量可能很快会大幅增加。该领域面临的最紧迫问题是这些结果将揭示什么样的生物学图景。我详细说明了四种可能的情况，这些情况反映了（i）没有、（ii）最小、（iii）中度和（iv）在重复分子变异发现中具有高度生物学一致性，这些情况很可能很快就会出现。我讨论了可能影响这些模式的因素，包括病因异质性和多重实现性的问题。这些发现可以为我们的精神障碍的基础生物学提供关键的见解，并有可能使我们能够“透过黑暗的玻璃”，感知到大脑系统紊乱的水平。
