Genomic findings in schizophrenia and their implications.
Genomic findings in schizophrenia and their implications.
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DOI：
10.1038/s41380-023-02293-8
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发表时间：
2023-09
影响因子：
11
通讯作者：
O'Donovan, Michael C.
中科院分区：
文献类型：
--
作者：
Owen, Michael J.;Legge, Sophie E.;Rees, Elliott;Walters, James T. R.;O'Donovan, Michael C.
在过去的15年里，对精神分裂症遗传学的理解有了实质性的进展。这揭示了一种高度多基因的条件，目前解释的遗传性大多来自常见的等位基因的影响小，但与罕见的拷贝数和编码变异的额外贡献。许多特定的基因和基因座已经牵连，提供了一个坚实的基础上，机制的研究可以进行。这表明神经元，特别是突触功能的紊乱并不局限于少数大脑区域和回路。遗传学研究结果还揭示了精神分裂症与其他疾病的密切关系，特别是双相情感障碍和儿童神经发育障碍，并解释了常见的风险等位基因如何在生育力下降的人群中持续存在。目前的基因组学方法只能解释大约40%的遗传率，但其中只有一小部分可归因于可靠的基因座。极端的多基因性对理解生物学机制提出了挑战。高度的多效性表明需要更多的转诊断研究和目前的诊断标准的缺点，作为划定生物学上不同的阶层。它也对在人类和模型系统的观察和实验研究中推断因果关系提出了挑战。最后，基因组研究的欧洲中心偏见需要得到纠正，以最大限度地提高利益，并确保这些利益在不同的社区都能感受到。通过将全基因组测序和长读段测序等新兴技术应用于大规模和多样化的样本，可能会取得进一步的进展。生物学理解的实质性进展将需要在功能基因组学和蛋白质组学方面取得平行进展，这些进展适用于大脑的各个发育阶段。为了使这些努力成功地确定疾病机制和定义新的分层，它们将需要与足够细粒度的表型数据相结合。
There has been substantial progress in understanding the genetics of schizophrenia over the past 15 years. This has revealed a highly polygenic condition with the majority of the currently explained heritability coming from common alleles of small effect but with additional contributions from rare copy number and coding variants. Many specific genes and loci have been implicated that provide a firm basis upon which mechanistic research can proceed. These point to disturbances in neuronal, and particularly synaptic, functions that are not confined to a small number of brain regions and circuits. Genetic findings have also revealed the nature of schizophrenia’s close relationship to other conditions, particularly bipolar disorder and childhood neurodevelopmental disorders, and provided an explanation for how common risk alleles persist in the population in the face of reduced fecundity. Current genomic approaches only potentially explain around 40% of heritability, but only a small proportion of this is attributable to robustly identified loci. The extreme polygenicity poses challenges for understanding biological mechanisms. The high degree of pleiotropy points to the need for more transdiagnostic research and the shortcomings of current diagnostic criteria as means of delineating biologically distinct strata. It also poses challenges for inferring causality in observational and experimental studies in both humans and model systems. Finally, the Eurocentric bias of genomic studies needs to be rectified to maximise benefits and ensure these are felt across diverse communities. Further advances are likely to come through the application of new and emerging technologies, such as whole-genome and long-read sequencing, to large and diverse samples. Substantive progress in biological understanding will require parallel advances in functional genomics and proteomics applied to the brain across developmental stages. For these efforts to succeed in identifying disease mechanisms and defining novel strata they will need to be combined with sufficiently granular phenotypic data.
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影响因子：
64.8
作者：
Bycroft C;Freeman C;Petkova D;Band G;Elliott LT;Sharp K;Motyer A;Vukcevic D;Delaneau O;O'Connell J;Cortes A;Welsh S;Young A;Effingham M;McVean G;Leslie S;Allen N;Donnelly P;Marchini J
通讯作者：
Marchini J
影响因子：
25.8
作者：
Allardyce J;Leonenko G;Hamshere M;Pardiñas AF;Forty L;Knott S;Gordon-Smith K;Porteous DJ;Haywood C;Di Florio A;Jones L;McIntosh AM;Owen MJ;Holmans P;Walters JTR;Craddock N;Jones I;O'Donovan MC;Escott-Price V
通讯作者：
Escott-Price V
影响因子：
6.6
作者：
Farrell, Martilias;Dietterich, Tyler E.;Josiassen, Richard C.
通讯作者：
Josiassen, Richard C.
影响因子：
17.7
作者：
Escott-Price, Valentina;Pardinas, Antonio F.;ODonovan, Michael C.
通讯作者：
ODonovan, Michael C.
影响因子：
30.8
作者：
Bulik-Sullivan B;Finucane HK;Anttila V;Gusev A;Day FR;Loh PR;ReproGen Consortium;Psychiatric Genomics Consortium;Genetic Consortium for Anorexia Nervosa of the Wellcome Trust Case Control Consortium 3;Duncan L;Perry JR;Patterson N;Robinson EB;Daly MJ;Price AL;Neale BM
通讯作者：
Neale BM