多变量全基因组关联研究对组织敏感的扩散指标进行分析，突出了塑造人类大脑的途径。
Multivariate genome-wide association study on tissue-sensitive diffusion metrics highlights pathways that shape the human brain.
机构信息
Population Neuroscience and Genetics Lab, University of California, San Diego, La Jolla, CA, USA.
Center for Multimodal Imaging and Genetics, University of California, San Diego, La Jolla, CA, USA.
出版信息
Nat Commun. 2022 May 3;13(1):2423. doi: 10.1038/s41467-022-30110-3.
The molecular determinants of tissue composition of the human brain remain largely unknown. Recent genome-wide association studies (GWAS) on this topic have had limited success due to methodological constraints. Here, we apply advanced whole-brain analyses on multi-shell diffusion imaging data and multivariate GWAS to two large scale imaging genetic datasets (UK Biobank and the Adolescent Brain Cognitive Development study) to identify and validate genetic association signals. We discover 503 unique genetic loci that have impact on multiple regions of human brain. Among them, more than 79% are validated in either of two large-scale independent imaging datasets. Key molecular pathways involved in axonal growth, astrocyte-mediated neuroinflammation, and synaptogenesis during development are found to significantly impact the measured variations in tissue-specific imaging features. Our results shed new light on the biological determinants of brain tissue composition and their potential overlap with the genetic basis of neuropsychiatric disorders.
人类大脑组织成分的分子决定因素在很大程度上仍然未知。由于方法学上的限制，最近针对这一主题的全基因组关联研究（GWAS）取得的成果有限。在这里，我们应用多壳层扩散成像数据的先进全脑分析和多变量 GWAS 来对两个大型成像遗传数据集（英国生物银行和青少年大脑认知发展研究）进行分析，以确定和验证遗传关联信号。我们发现了 503 个独特的遗传位点，这些位点对人类大脑的多个区域有影响。其中，超过 79%的位点在两个大型独立成像数据集中得到了验证。在发育过程中，涉及轴突生长、星形胶质细胞介导的神经炎症和突触发生的关键分子途径被发现显著影响了组织特异性成像特征的可测量变化。我们的研究结果为大脑组织成分的生物学决定因素及其与神经精神疾病遗传基础的潜在重叠提供了新的认识。
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