■精神分裂症通常与皮质体积减少和基底神经节扩张有关,尤其是壳核。最近的全基因组关联研究强调了与kinectin1基因(KTN1)相邻的3'调节区变异在调节壳核灰质体积(GMV)中的重要性。本研究旨在全面调查该地区在精神分裂症中的参与情况。
■我们分析了4个独立的dbGaP样本中覆盖整个3个调控区的1136个单核苷酸多态性(SNPs)(4604例精神分裂症患者与4884名健康受试者)和3个独立的精神病学基因组学联盟样本(107240例与210203控件)以识别一致的关联。此外,我们在348名受试者中检测了精神分裂症相关等位基因对16个脑区KTN1mRNA表达的调节作用,以及38258名受试者中7个皮质下核的GMV,36936名受试者的整个皮质和34个皮质区域的表面积(SA)和厚度(TH)。
■25个变异的主要等位基因(f>0.5)在2至5个独立样本(8.4×10-4≤P≤.049)中增加(β>0)精神分裂症的风险。这些精神分裂症相关等位基因显着升高(β>0)基底神经节的GMV,包括壳核(6.0×10-11≤P≤1.1×10-4),尾状(8.7×10-4≤P≤9.4×10-3),苍白球(P=6.0×10-4),和伏隔核(P=2.7×10-5)。此外,它们可能会增加(β>0)后扣带和岛叶皮质的SA,以及额叶(三角部和内侧眶额)的TH,顶叶(上级,precuneus,和劣等),和时间(横向)皮质,但可能降低(β<0)整体的SA,额叶(内侧眶额),和时间(极点,上级,中间,和内嗅)皮质,以及中段额叶和上额叶皮质的TH(8.9×10-4≤P≤.050)。
■我们的发现确定了与KTN1相邻的3'调控区的显著和功能相关的风险等位基因,暗示了它们在精神分裂症发展中的关键作用。
UNASSIGNED: Schizophrenia is often associated with volumetric reductions in cortices and expansions in basal ganglia, particularly the putamen. Recent genome-wide association studies have highlighted the significance of variants in the 3\' regulatory region adjacent to the kinectin 1 gene (KTN1) in regulating gray matter volume (GMV) of the putamen. This study aimed to comprehensively investigate the involvement of this region in schizophrenia.
UNASSIGNED: We analyzed 1136 single-nucleotide polymorphisms (SNPs) covering the entire 3\' regulatory region in 4 independent dbGaP samples (4604 schizophrenia patients vs. 4884 healthy subjects) and 3 independent Psychiatric Genomics Consortium samples (107 240 cases vs. 210 203 controls) to identify consistent associations. Additionally, we examined the regulatory effects of schizophrenia-associated alleles on KTN1 mRNA expression in 16 brain areas among 348 subjects, as well as GMVs of 7 subcortical nuclei in 38 258 subjects, and surface areas (SA) and
thickness (TH) of the entire cortex and 34 cortical areas in 36 936 subjects.
UNASSIGNED: The major alleles (f > 0.5) of 25 variants increased (β > 0) the risk of schizophrenia across 2 to 5 independent samples (8.4 × 10-4 ≤ P ≤ .049). These schizophrenia-associated alleles significantly elevated (β > 0) GMVs of basal ganglia, including the putamen (6.0 × 10-11 ≤ P ≤ 1.1 × 10-4), caudate (8.7 × 10-4 ≤ P ≤ 9.4 × 10-3), pallidum (P = 6.0 × 10-4), and nucleus accumbens (P = 2.7 × 10-5). Moreover, they potentially augmented (β > 0) the SA of posterior cingulate and insular cortices, as well as the TH of frontal (pars triangularis and medial orbitofrontal), parietal (superior, precuneus, and inferior), and temporal (transverse) cortices, but potentially reduced (β < 0) the SA of the whole, frontal (medial orbitofrontal), and temporal (pole, superior, middle, and entorhinal) cortices, as well as the TH of rostral middle frontal and superior frontal cortices (8.9 × 10-4 ≤ P ≤ .050).
UNASSIGNED: Our findings identify significant and functionally relevant risk alleles in the 3\' regulatory region adjacent to KTN1, implicating their crucial roles in the development of schizophrenia.