Hess Jonathan L, Tylee Daniel S, Mattheisen Manuel, Børglum Anders D, Als Thomas D, Grove Jakob, Werge Thomas, Mortensen Preben Bo, Mors Ole, Nordentoft Merete, Hougaard David M, Byberg-Grauholm Jonas, Bækvad-Hansen Marie, Greenwood Tiffany A, Tsuang Ming T, Curtis David, Steinberg Stacy, Sigurdsson Engilbert, Stefánsson Hreinn, Stefánsson Kári, Edenberg Howard J, Holmans Peter, Faraone Stephen V, Glatt Stephen J
Psychiatric Genetic Epidemiology & Neurobiology Laboratory (PsychGENe Lab), Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Syracuse, NY, USA.
Department of Psychiatry, Yale New Haven Hospital, New Haven, CT, USA.
Mol Psychiatry. 2021 Mar;26(3):800-815. doi: 10.1038/s41380-019-0463-8. Epub 2019 Sep 6.
Based on the discovery by the Resilience Project (Chen R. et al. Nat Biotechnol 34:531-538, 2016) of rare variants that confer resistance to Mendelian disease, and protective alleles for some complex diseases, we posited the existence of genetic variants that promote resilience to highly heritable polygenic disorders1,0 such as schizophrenia. Resilience has been traditionally viewed as a psychological construct, although our use of the term resilience refers to a different construct that directly relates to the Resilience Project, namely: heritable variation that promotes resistance to disease by reducing the penetrance of risk loci, wherein resilience and risk loci operate orthogonal to one another. In this study, we established a procedure to identify unaffected individuals with relatively high polygenic risk for schizophrenia, and contrasted them with risk-matched schizophrenia cases to generate the first known "polygenic resilience score" that represents the additive contributions to SZ resistance by variants that are distinct from risk loci. The resilience score was derived from data compiled by the Psychiatric Genomics Consortium, and replicated in three independent samples. This work establishes a generalizable framework for finding resilience variants for any complex, heritable disorder.
基于复原力项目（Chen R.等人，《自然生物技术》34:531 - 538，2016年）发现的赋予对孟德尔疾病抗性的罕见变异以及一些复杂疾病的保护性等位基因，我们推测存在促进对高度遗传的多基因疾病（如精神分裂症）具有复原力的遗传变异。传统上，复原力被视为一种心理概念，尽管我们对“复原力”一词的使用指的是一种与复原力项目直接相关的不同概念，即：通过降低风险位点的外显率来促进对疾病抗性的可遗传变异，其中复原力和风险位点彼此正交运作。在本研究中，我们建立了一种程序来识别精神分裂症多基因风险相对较高的未患病个体，并将他们与风险匹配的精神分裂症病例进行对比，以生成第一个已知的“多基因复原力评分”，该评分代表了与风险位点不同的变异对精神分裂症抗性的累加贡献。复原力评分源自精神基因组学联盟汇编的数据，并在三个独立样本中得到复制。这项工作为寻找任何复杂的、可遗传疾病的复原力变异建立了一个可推广的框架。
