The Mind Research Network Albuquerque, NM, USA.
The Mind Research Network Albuquerque, NM, USA ; Department of Electrical and Computer Engineering, University of New Mexico Albuquerque, NM, USA.
Front Hum Neurosci. 2015 Mar 3;9:100. doi: 10.3389/fnhum.2015.00100. eCollection 2015.
It is becoming a consensus that white matter integrity is compromised in schizophrenia (SZ), however the underlying genetics remains elusive. Evidence suggests a polygenic basis of the disorder, which involves various genetic variants with modest individual effect sizes. In this work, we used a multivariate approach, parallel independent component analysis (P-ICA), to explore the genetic underpinnings of white matter abnormalities in SZ. A pre-filtering step was first applied to locate 6527 single nucleotide polymorphisms (SNPs) discriminating patients from controls with a nominal uncorrected p-value of 0.01. These potential susceptibility loci were then investigated for associations with fractional anisotropy (FA) images in a cohort consisting of 73 SZ patients and 87 healthy controls (HC). A significant correlation (r = -0.37, p = 1.25 × 10(-6)) was identified between one genetic factor and one FA component after controlling for scanning site, ethnicity, age, and sex. The identified FA-SNP association remained stable in a 10-fold validation. A 5000-run permutation test yielded a p-value of 2.00 × 10(-4). The FA component reflected decreased white matter integrity in the forceps major for SZ patients. The SNP component was overrepresented in genes whose products are involved in corpus callosum morphology (e.g., CNTNAP2, NPAS3, and NFIB) as well as canonical pathways of synaptic long term depression and protein kinase A signaling. Taken together, our finding delineates a part of genetic architecture underlying SZ-related FA reduction, emphasizing the important role of genetic variants involved in neural development.
越来越多的证据表明精神分裂症（SZ）患者的脑白质完整性受损，但潜在的遗传机制仍难以捉摸。有证据表明，这种疾病具有多基因基础，涉及到各种具有适度个体效应大小的遗传变异体。在这项工作中，我们使用多元方法，即平行独立成分分析（P-ICA），来探索 SZ 患者脑白质异常的遗传基础。首先应用了一个预过滤步骤，定位了 6527 个单核苷酸多态性（SNP），这些 SNP 可以区分患者和对照，其未校正的名义 p 值为 0.01。然后，在一个由 73 名 SZ 患者和 87 名健康对照（HC）组成的队列中，对这些潜在的易感基因座与各向异性分数（FA）图像之间的相关性进行了研究。在控制扫描部位、种族、年龄和性别后，发现一个遗传因素与一个 FA 成分之间存在显著相关性（r = -0.37，p = 1.25×10(-6)）。在 10 倍验证中，FA-SNP 相关性仍然稳定。5000 次随机置换检验的 p 值为 2.00×10(-4)。FA 成分反映了 SZ 患者内囊前肢的白质完整性降低。该 SNP 成分在涉及胼胝体形态的基因（如 CNTNAP2、NPAS3 和 NFIB）以及突触长时程抑制和蛋白激酶 A 信号通路的经典途径中过度表达。总之，我们的发现描绘了 SZ 相关 FA 减少的遗传结构的一部分，强调了涉及神经发育的遗传变异体的重要作用。
