Department of Psychiatry, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, Institute for Genomics and Multiscale Biology, One Gustave L. Levy Place, New York, NY, 10029, USA.
Transl Psychiatry. 2019 Jan 17;9(1):21. doi: 10.1038/s41398-018-0342-0.
The genetic architecture of schizophrenia (SCZ) includes numerous risk loci across a range of frequencies and sizes, including common and rare single-nucleotide variants and insertions/deletions (indels), as well as rare copy number variants (CNVs). Despite the clear heritability of the disease, monozygotic twins are discordant for SCZ at a significant rate. Somatic variants-genetic changes that arise after fertilization rather than through germline inheritance-are widespread in the human brain and known to contribute to risk for both rare and common neuropsychiatric conditions. The contribution of somatic variants in the brain to risk of SCZ remains to be determined. In this study, we surveyed somatic single-nucleotide variants (sSNVs) in the brains of controls and individuals with SCZ (n = 10 and n = 9, respectively). From each individual, whole-exome sequencing (WES) was performed on DNA from neuronal and non-neuronal nuclei isolated by fluorescence activated nuclear sorting (FANS) from frozen postmortem prefrontal cortex (PFC) samples, as well as DNA extracted from temporal muscle as a reference. We identified an increased burden of sSNVs in cases compared to controls (SCZ rate = 2.78, control rate = 0.70; P = 0.0092, linear mixed effects model), that included a higher rate of non-synonymous and loss-of-function variants (SCZ rate = 1.33, control rate = 0.50; P = 0.047, linear mixed effects model). Our findings suggest sSNVs in the brain may constitute an additional component of the complex genetic architecture of SCZ. This perspective argues for the need to further investigate somatic variation in the brain as an explanation of the discordance in monozygotic twins and a potential guide to the identification of novel therapeutic targets.
精神分裂症（SCZ）的遗传结构包括许多不同频率和大小的风险位点，包括常见和罕见的单核苷酸变体和插入/缺失（indels），以及罕见的拷贝数变异（CNVs）。尽管该疾病具有明显的遗传性，但同卵双胞胎患 SCZ 的不一致率仍然很高。体细胞变异——受精后而非通过种系遗传产生的遗传变化——在人类大脑中广泛存在，已知会导致罕见和常见神经精神疾病的风险。体细胞变异在大脑中对 SCZ 风险的贡献仍有待确定。在这项研究中，我们调查了对照组和 SCZ 患者大脑中的体细胞单核苷酸变体（sSNVs）（分别为 n = 10 和 n = 9）。从每个个体中，通过荧光激活核分选（FANS）从冷冻死后前额叶皮质（PFC）样本中分离的神经元和非神经元核中进行全外显子组测序（WES），以及从颞肌中提取的 DNA 作为参考。我们发现病例组的 sSNVs 负担高于对照组（SCZ 发生率=2.78，对照组发生率=0.70；P=0.0092，线性混合效应模型），包括更高的非同义突变和失活突变率（SCZ 发生率=1.33，对照组发生率=0.50；P=0.047，线性混合效应模型）。我们的研究结果表明，大脑中的 sSNVs 可能构成 SCZ 复杂遗传结构的另一个组成部分。这种观点认为需要进一步研究大脑中的体细胞变异，作为解释同卵双胞胎不一致的原因，并为鉴定新的治疗靶点提供潜在的指导。
