Associations between antagonistic SNPs for neuropsychiatric disorders and human brain structure.

IF 5.8 1区 医学 Q1 PSYCHIATRY Translational Psychiatry Pub Date : 2024-10-02 DOI:10.1038/s41398-024-03098-1
Lydia M Federmann, Friederike S David, Christiane Jockwitz, Thomas W Mühleisen, Dominique I Pelzer, Markus M Nöthen, Svenja Caspers, Katrin Amunts, Janik Goltermann, Till F M Andlauer, Frederike Stein, Katharina Brosch, Tilo Kircher, Sven Cichon, Udo Dannlowski, Lisa Sindermann, Andreas J Forstner
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Abstract

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.

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神经精神疾病的拮抗 SNP 与人类大脑结构之间的关联。
此前发表的一项全基因组关联研究(GWAS)荟萃分析发现,在八个神经精神疾病的十一个基因组位点上存在拮抗性单核苷酸多态性(SNPs),其中相同的等位基因对一种神经精神疾病具有保护作用,而对另一种神经精神疾病则会增加患病风险。迄今为止,这些拮抗 SNPs 与大脑结构表型的联系尚未得到进一步研究。在此,我们利用大规模脑结构表型 GWAS 的汇总统计,探讨了它们与皮质表面积和皮质厚度(分别在 34 个脑区和一个总体测量中)以及 8 个皮质下结构体积的关联。我们评估了在 ENIGMA 联盟进行的大规模病例对照成像研究中,与大脑结构表型明显相关的疾病是否与主要神经精神疾病有关。我们进一步确定了拮抗 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 例重度抑郁障碍患者和 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,8 个拮抗 SNP 与扣带皮层前部、岛叶和颞上回等区域的大脑结构表型有显著关联。以前曾有报道称,在双相情感障碍、重度抑郁障碍和精神分裂症中,病例对照与大脑结构表型存在相关性差异。此外,拮抗 SNP 与脑组织中的基因表达变化有关,并与几种认知行为特征相关。在我们的探索性全脑分析中,我们观察到左上颞极和左上顶叶区的灰质体积分别与变异 rs301805 和 rs1933802 显著相关。我们的研究结果表明,神经精神疾病的多个拮抗 SNP 与大脑结构表型有关。然而,要进一步阐明这些发现,还需要未来的病例对照基因组成像研究。
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来源期刊
CiteScore
11.50
自引率
2.90%
发文量
484
审稿时长
23 weeks
期刊介绍: Psychiatry has suffered tremendously by the limited translational pipeline. Nobel laureate Julius Axelrod''s discovery in 1961 of monoamine reuptake by pre-synaptic neurons still forms the basis of contemporary antidepressant treatment. There is a grievous gap between the explosion of knowledge in neuroscience and conceptually novel treatments for our patients. Translational Psychiatry bridges this gap by fostering and highlighting the pathway from discovery to clinical applications, healthcare and global health. We view translation broadly as the full spectrum of work that marks the pathway from discovery to global health, inclusive. The steps of translation that are within the scope of Translational Psychiatry include (i) fundamental discovery, (ii) bench to bedside, (iii) bedside to clinical applications (clinical trials), (iv) translation to policy and health care guidelines, (v) assessment of health policy and usage, and (vi) global health. All areas of medical research, including — but not restricted to — molecular biology, genetics, pharmacology, imaging and epidemiology are welcome as they contribute to enhance the field of translational psychiatry.
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