Federmann Lydia M, David Friederike S, Jockwitz Christiane, Mühleisen Thomas W, Pelzer Dominique I, Nöthen Markus M, Caspers Svenja, Amunts Katrin, Goltermann Janik, Andlauer Till F M, Stein Frederike, Brosch Katharina, Kircher Tilo, Cichon Sven, Dannlowski Udo, Sindermann Lisa, Forstner Andreas J
Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich, Jülich, Germany.
Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.
Transl Psychiatry. 2024 Oct 2;14(1):406. doi: 10.1038/s41398-024-03098-1.
A previously published genome-wide association study (GWAS) meta-analysis across eight neuropsychiatric disorders identified antagonistic single-nucleotide polymorphisms (SNPs) at eleven genomic loci where the same allele was protective against one neuropsychiatric disorder and increased the risk for another. Until now, these antagonistic SNPs have not been further investigated regarding their link to brain structural phenotypes. Here, we explored their associations with cortical surface area and cortical thickness (in 34 brain regions and one global measure each) as well as the volumes of eight subcortical structures using summary statistics of large-scale GWAS of brain structural phenotypes. We assessed if significantly associated brain structural phenotypes were previously reported to be associated with major neuropsychiatric disorders in large-scale case-control imaging studies by the ENIGMA consortium. We further characterized the effects of the antagonistic SNPs on gene expression in brain tissue and their association with additional cognitive and behavioral phenotypes, and performed an exploratory voxel-based whole-brain analysis in the FOR2107 study (n = 754 patients with major depressive disorder and n = 847 controls). We found that eight antagonistic SNPs were significantly associated with brain structural phenotypes in regions such as anterior parts of the cingulate cortex, the insula, and the superior temporal gyrus. Case-control differences in implicated brain structural phenotypes have previously been reported for bipolar disorder, major depressive disorder, and schizophrenia. In addition, antagonistic SNPs were associated with gene expression changes in brain tissue and linked to several cognitive-behavioral traits. In our exploratory whole-brain analysis, we observed significant associations of gray matter volume in the left superior temporal pole and left superior parietal region with the variants rs301805 and rs1933802, respectively. Our results suggest that multiple antagonistic SNPs for neuropsychiatric disorders are linked to brain structural phenotypes. However, to further elucidate these findings, future case-control genomic imaging studies are required.
一项先前发表的针对八种神经精神疾病的全基因组关联研究（GWAS）荟萃分析，在11个基因组位点发现了拮抗单核苷酸多态性（SNP），其中相同的等位基因对一种神经精神疾病具有保护作用，却会增加另一种疾病的风险。到目前为止，尚未对这些拮抗SNP与脑结构表型的联系进行进一步研究。在此，我们利用脑结构表型大规模GWAS的汇总统计数据，探索了它们与皮质表面积和皮质厚度（分别在34个脑区和一项整体测量中）以及八个皮质下结构体积的关联。我们评估了在大规模病例对照成像研究中，由ENIGMA联盟先前报告的与主要神经精神疾病相关的脑结构表型是否存在显著关联。我们进一步表征了拮抗SNP对脑组织基因表达的影响及其与其他认知和行为表型的关联，并在FOR2107研究（n = 754例重度抑郁症患者和n = 847例对照）中进行了基于体素的全脑探索性分析。我们发现，八个拮抗SNP与扣带回前部、脑岛和颞上回等区域的脑结构表型显著相关。先前已报道双相情感障碍、重度抑郁症和精神分裂症在相关脑结构表型上存在病例对照差异。此外，拮抗SNP与脑组织中的基因表达变化相关，并与几种认知行为特征有关。在我们的探索性全脑分析中，我们分别观察到左侧颞上极和左侧顶上叶区域的灰质体积与变体rs301805和rs1933802存在显著关联。我们的结果表明，多种神经精神疾病的拮抗SNP与脑结构表型有关。然而，为了进一步阐明这些发现，未来需要进行病例对照基因组成像研究。
