Bian Beilei, Couvy-Duchesne Baptiste, Wray Naomi R, McRae Allan F
Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
Paris Brain Institute, CNRS, INRIA, Paris, France.
Brain Commun. 2022 Mar 31;4(2):fcac078. doi: 10.1093/braincomms/fcac078. eCollection 2022.
Genetic variants in the human leukocyte antigen and killer cell immunoglobulin-like receptor regions have been associated with many brain-related diseases, but how they shape brain structure and function remains unclear. To identify the genetic variants in and genes associated with human brain phenotypes, we performed a genetic association study of ∼30 000 European unrelated individuals using brain MRI phenotypes generated by the UK Biobank (UKB). We identified 15 alleles in class I and class II genes significantly associated with at least one brain MRI-based phenotypes ( < 5 × 10). These associations converged on several main haplotypes within the . In particular, the human leukocyte antigen alleles within an ancestral haplotype 8.1 were associated with multiple MRI measures, including grey matter volume, cortical thickness (TH) and diffusion MRI (dMRI) metrics. These alleles have been strongly associated with schizophrenia. Additionally, associations were identified between *04∼*03:01∼*03:02 and isotropic volume fraction of diffusion MRI in multiple white matter tracts. This haplotype has been reported to be associated with Parkinson's disease. These findings suggest shared genetic associations between brain MRI biomarkers and brain-related diseases. Additionally, we identified 169 associations between the complement component 4 () gene and imaging phenotypes. We found that gene copy number was associated with cortical TH and dMRI metrics. No gene copy numbers were associated with image-derived phenotypes at genome-wide threshold. To address the multiple testing burden in the phenome-wide association study, we performed a multi-trait association analysis using trait-based association test that uses extended Simes procedure and identified MRI image-specific associations. This study contributes to insight into how critical immune genes affect brain-related traits as well as the development of neurological and neuropsychiatric disorders.
人类白细胞抗原和杀伤细胞免疫球蛋白样受体区域的基因变异与许多脑相关疾病有关，但它们如何塑造脑结构和功能仍不清楚。为了确定与人类脑表型相关的基因和基因变异，我们利用英国生物银行（UKB）生成的脑MRI表型，对约30000名欧洲无关个体进行了基因关联研究。我们在I类和II类基因中鉴定出15个等位基因，它们与至少一种基于脑MRI的表型显著相关（P<5×10）。这些关联集中在该区域内的几个主要单倍型上。特别是，祖先单倍型8.1内的人类白细胞抗原等位基因与多种MRI测量指标相关，包括灰质体积、皮质厚度（CTH）和扩散MRI（dMRI）指标。这些等位基因与精神分裂症密切相关。此外，还发现*04∼*03:01∼*03:02与多个白质束扩散MRI的各向同性体积分数之间存在关联。据报道，这种单倍型与帕金森病有关。这些发现表明脑MRI生物标志物与脑相关疾病之间存在共同的基因关联。此外，我们还鉴定出补体成分4（C4）基因与成像表型之间的169种关联。我们发现C4基因拷贝数与皮质CTH和dMRI指标相关。在全基因组阈值下，没有C4基因拷贝数与图像衍生表型相关。为了解决全表型关联研究中的多重检验负担，我们使用基于性状的关联检验进行了多性状关联分析，该检验使用扩展的西姆斯程序并确定了MRI图像特异性关联。这项研究有助于深入了解关键免疫基因如何影响脑相关性状以及神经和神经精神疾病的发展。
