中国科学院心理健康重点实验室知识库

通过全基因组关联分析(genome-wide association study, GWAS)探索中国汉族人群疼痛诱发脑岛神经响应个体差异背后的遗传影响因素.研究共纳入333名经质控合格且同时采集了基因和脑影像数据的中国汉族健康被试,基因型数据经质控插补后包含5270947个单核苷酸多态性(single nucleotide polymorphism, SNP)位点,脑影像数据为痛觉刺激任务态功能磁共振成像(functional magnetic resonance imaging, fMRI)数据.首先基于f MRI数据利用一般线性模型(general linear model, GLM)获得痛觉刺激条件下每位被试左侧和右侧脑岛区域各自的平均激活值以及双侧脑岛的平均激活值,并将其作为GWAS表型数据分别对5270947个SNP逐一计算脑岛激活与SNP之间的关联.结果显示,在P<5×10-6阈值下, 10个独立SNP位点与左侧脑岛的激活水平存在显著关联, 7个独立SNP位点与右侧脑岛的激活水平存在显著关联, 12个独立SNP位点与双侧脑岛的平均激活水平存在显著关联.所有显著位点可注释到9个基因上,其中BACE1基因已被报道与疼痛相关,其他基因与脑影像表型或常见神经精神疾病相关.这些发现为深入理解疼痛诱发脑岛神经响应个体差异背后的遗传机制提供了有力证据.

The insula serves as one of the central hubs for the processing of pain. This cortical structure has been shown to be robustly activated by nociceptive stimuli but exhibits large inter-individual variability. One reason behind such inter-individual variability of pain-elicited insular activation may be attributed to genetic factors. Therefore, understanding its genetic underpinnings is essential to understanding the origin of the inter-individual variability of the insular activations and consequently the inter-individual differences in pain sensitivity and behaviors. Genome-wide association study (GWAS) has emerged as a powerful tool for uncovering the genetic basis of complex traits and diseases, providing a comprehensive analysis of single nucleotide polymorphisms (SNPs) across the entire genome. The objective of the present study is to uncover possible genetic factors underlying the inter-individual differences in pain-elicited neural responses within the insula using a GWAS approach in a cohort of healthy Chinese Han subjects. A total of 333 healthy Chinese Han participants with both genetic and brain imaging data after quality control were included in the present study. The genotype data contained 5270947 SNP loci after quality control and imputation. Brain imaging data were functional magnetic resonance imaging (fMRI) data of a nociceptive stimulation task. Based on these fMRI data, a voxel-wise general linear model (GLM) was used to obtain a group-level activation by nociceptive stimulation within a pre-defined bilateral insular area; then a mean activation value (i.e., the average β value across voxels within the group-level insular activation area) was obtained for each of the left, the right and the bilateral insular regions for each participant. After outliers removal and normal score transformation, the three mean insular activations were used as the phenotypes in the subsequent GWAS analyses. In the GWAS analyses, associations were tested between each of the three insular activation phenotypes and each of the 5270947 SNPs. The results demonstrated that, at the threshold of P<5×10 −6 , the activation amplitudes of the left insula, the right insula and the overall activation of the bilateral insula were significantly associated with 10, 7 and 12 independent SNP loci, respectively. All significant SNP loci were annotated to 9 specific genes, among which BACE1 has previously been reported to be associated with pain, and the remaining genes have been linked to brain imaging phenotypes or common neuropsychiatric disorders. In summary, the present study discovered 28 associations between pain-elicited insular activations and SNP loci in humans using fMRI and GWAS. These findings provide important evidence for the genetic underpinnings of the interindividual variability in pain-elicited neural responses within the human insula.

国家自然科学基金(81971694)资助