Norwegian Centre for Mental Disorders Research (NORMENT), Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Norwegian Centre for Mental Disorders Research (NORMENT), Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Biol Psychiatry. 2024 Jan 1;95(1):62-71. doi: 10.1016/j.biopsych.2023.06.008. Epub 2023 Jun 20.
For many brain disorders, a subset of patients jointly exhibit alterations in cortical brain structure and elevated levels of circulating immune markers. This may be driven in part by shared genetic architecture. Therefore, we investigated the phenotypic and genetic associations linking global cortical surface area and thickness with blood immune markers (i.e., white blood cell counts and plasma C-reactive protein levels).
Linear regression was used to assess phenotypic associations in 30,823 UK Biobank participants. Genome-wide and local genetic correlations were assessed using linkage disequilibrium score regression and local analysis of covariance annotation. The number of shared trait-influencing genetic variants was estimated using MiXeR. Shared genetic architecture was assessed using a conjunctional false discovery rate framework, and mapped genes were included in gene-set enrichment analyses.
Cortical structure and blood immune markers exhibited predominantly inverse phenotypic associations. There were modest genome-wide genetic correlations, the strongest of which were for C-reactive protein levels (r = -0.13, false discovery rate-corrected p = 4.17 × 10; r = -0.13, false discovery rate-corrected p = 4.00 × 10). Meanwhile, local genetic correlations showed a mosaic of positive and negative associations. White blood cells shared on average 46.24% and 38.64% of trait-influencing genetic variants with surface area and thickness, respectively. Additionally, surface area shared 55 unique loci with the blood immune markers while thickness shared 15. Overall, monocyte count exhibited the largest genetic overlap with cortical brain structure. A series of gene enrichment analyses implicated neuronal-, astrocytic-, and schizophrenia-associated genes.
The findings indicate shared genetic underpinnings for cortical brain structure and blood immune markers, with implications for neurodevelopment and understanding the etiology of brain-related disorders.
对于许多脑部疾病，一部分患者同时表现出皮质脑结构的改变和循环免疫标志物水平的升高。这可能部分是由共同的遗传结构驱动的。因此，我们研究了将大脑皮质表面积和厚度与血液免疫标志物（即白细胞计数和血浆 C 反应蛋白水平）联系起来的表型和遗传关联。
使用线性回归在 30823 名英国生物库参与者中评估表型关联。使用连锁不平衡评分回归和局部协方差注释评估全基因组和局部遗传相关性。使用 MiXeR 估计共享性状影响遗传变异的数量。使用结合假发现率框架评估共享遗传结构，并将映射基因纳入基因集富集分析。
皮质结构和血液免疫标志物表现出主要的反相关联。存在适度的全基因组遗传相关性，其中最强的是 C 反应蛋白水平（r=-0.13，经假发现率校正的 p 值=4.17×10；r=-0.13，经假发现率校正的 p 值=4.00×10）。同时，局部遗传相关性显示出正相关和负相关的镶嵌图案。白细胞分别与表面积和厚度平均共享 46.24%和 38.64%的性状影响遗传变异。此外，表面积与血液免疫标志物共享 55 个独特的基因座，而厚度共享 15 个。总体而言，单核细胞计数与皮质脑结构的遗传重叠最大。一系列基因富集分析表明与神经元、星形胶质细胞和精神分裂症相关的基因。
这些发现表明皮质脑结构和血液免疫标志物具有共同的遗传基础，这对神经发育和理解与大脑相关的疾病的病因具有重要意义。
