Department of Psychosomatic Medicine, People's Hospital of Deyang City, Deyang, 618000, Sichuan, China.
Laboratory of Radiation Oncology and Radiobiology, Fujian Provincial Cancer Hospital, the Teaching Hospital of Fujian Medical University, Fuzhou, 350014, Fujian, China.
Sci Rep. 2023 Mar 8;13(1):3890. doi: 10.1038/s41598-023-27448-z.
Cortical and subcortical structural alteration has been extensively reported in schizophrenia, including the unusual expansion of gray matter volumes (GMVs) of basal ganglia (BG), especially putamen. Previous genome-wide association studies pinpointed kinectin 1 gene (KTN1) as the most significant gene regulating the GMV of putamen. In this study, the role of KTN1 variants in risk and pathogenesis of schizophrenia was explored. A dense set of SNPs (n = 849) covering entire KTN1 was analyzed in three independent European- or African-American samples (n = 6704) and one mixed European and Asian Psychiatric Genomics Consortium sample (n = 56,418 cases vs. 78,818 controls), to identify replicable SNP-schizophrenia associations. The regulatory effects of schizophrenia-associated variants on the KTN1 mRNA expression in 16 cortical or subcortical regions in two European cohorts (n = 138 and 210, respectively), the total intracranial volume (ICV) in 46 European cohorts (n = 18,713), the GMVs of seven subcortical structures in 50 European cohorts (n = 38,258), and the surface areas (SA) and thickness (TH) of whole cortex and 34 cortical regions in 50 European cohorts (n = 33,992) and eight non-European cohorts (n = 2944) were carefully explored. We found that across entire KTN1, only 26 SNPs within the same block (r > 0.85) were associated with schizophrenia across ≥ 2 independent samples (7.5 × 10 ≤ p ≤ 0.048). The schizophrenia-risk alleles, which increased significantly risk for schizophrenia in Europeans (q < 0.05), were all minor alleles (f < 0.5), consistently increased (1) the KTN1 mRNA expression in 12 brain regions significantly (5.9 × 10 ≤ p ≤ 0.050; q < 0.05), (2) the ICV significantly (6.1 × 10 ≤ p ≤ 0.008; q < 0.05), (3) the SA of whole (9.6 × 10 ≤ p ≤ 0.047) and two regional cortices potentially (2.5 × 10 ≤ p ≤ 0.042; q > 0.05), and (4) the TH of eight regional cortices potentially (0.006 ≤ p ≤ 0.050; q > 0.05), and consistently decreased (1) the BG GMVs significantly (1.8 × 10 ≤ p ≤ 0.050; q < 0.05), especially putamen GMV (1.8 × 10 ≤ p ≤ 1.0 × 10; q < 0.05, (2) the SA of four regional cortices potentially (0.010 ≤ p ≤ 0.048), and (3) the TH of four regional cortices potentially (0.015 ≤ p ≤ 0.049) in Europeans. We concluded that we identified a significant, functional, and robust risk variant block covering entire KTN1 that might play a critical role in the risk and pathogenesis of schizophrenia.
皮质和皮质下结构改变在精神分裂症中得到了广泛的报道，包括基底节（BG），尤其是壳核的灰质体积（GMV）的异常扩大。先前的全基因组关联研究指出驱动蛋白 1 基因（KTN1）是调节壳核 GMV 的最重要基因。在这项研究中，探讨了 KTN1 变体在精神分裂症风险和发病机制中的作用。在三个独立的欧洲或非裔美国人样本（n=6704）和一个混合的欧洲和亚洲精神科基因组联盟样本（n=56418 例与 78818 例对照）中分析了覆盖整个 KTN1 的一组密集的 SNP（n=849），以确定可复制的 SNP-精神分裂症关联。在两个欧洲队列（n=138 和 210）的 16 个皮质或皮质下区域中，对与精神分裂症相关的变异对 KTN1 mRNA 表达的调节作用，在 46 个欧洲队列中的总颅内体积（ICV）（n=18713），在 50 个欧洲队列中的 7 个皮质下结构的 GMV（n=38258），以及在 50 个欧洲队列中的整个皮质和 34 个皮质区域的表面积（SA）和厚度（TH）（n=33992）和 8 个非欧洲队列（n=2944）进行了仔细研究。我们发现，在整个 KTN1 中，只有 26 个 SNP 在同一块内（r>0.85）在≥2 个独立样本中与精神分裂症相关（7.5×10≤p≤0.048）。在欧洲人中显著增加精神分裂症风险的风险等位基因（q<0.05）均为次要等位基因（f<0.5），一致增加了（1）12 个大脑区域的 KTN1 mRNA 表达（5.9×10≤p≤0.050；q<0.05），（2）ICV 显著（6.1×10≤p≤0.008；q<0.05），（3）全脑的 SA（9.6×10≤p≤0.047）和两个区域皮质的潜在 SA（2.5×10≤p≤0.042；q>0.05），以及（4）8 个区域皮质的潜在 TH（0.006≤p≤0.050；q>0.05），并一致降低了（1）BG 的 GMV 显著（1.8×10≤p≤0.050；q<0.05），特别是壳核 GMV（1.8×10≤p≤1.0×10；q<0.05），（2）四个区域皮质的潜在 SA（0.010≤p≤0.048），和（3）四个区域皮质的潜在 TH（0.015≤p≤0.049）在欧洲人。我们得出结论，我们确定了一个覆盖整个 KTN1 的显著、功能和稳健的风险变异块，它可能在精神分裂症的风险和发病机制中发挥关键作用。
