Mental Health Center and Psychiatric Laboratory, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan, China; West China Brain Research Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China; Sichuan Clinical Medical Research Center for Mental Disorders, Chengdu, Sichuan, China.
Center for Health Policy and Health Services Research, Henry Ford Health, Detroit, MI, USA.
Brain Behav Immun. 2023 Oct;113:389-400. doi: 10.1016/j.bbi.2023.08.003. Epub 2023 Aug 8.
The correlation between human gut microbiota and psychiatric diseases has long been recognized. Based on the heritability of the microbiome, genome-wide association studies on human genome and gut microbiome (mbGWAS) have revealed important host-microbiome interactions. However, establishing causal relationships between specific gut microbiome features and psychological conditions remains challenging due to insufficient sample sizes of previous studies of mbGWAS.
Cross-cohort meta-analysis (via METAL) and multi-trait analysis (via MTAG) were used to enhance the statistical power of mbGWAS for identifying genetic variants and genes. Using two large mbGWAS studies (7,738 and 5,959 participants respectively) and12 disease-specific studies from the Psychiatric Genomics Consortium (PGC), we performed bidirectional two-sample mendelian randomization (MR) analyses between microbial features and psychiatric diseases (up to 500,199 individuals). Additionally, we conducted downstream gene- and gene-set-based analyses to investigate the shared biology linking gut microbiota and psychiatric diseases.
METAL and MTAG conducted in mbGWAS could boost power for gene prioritization and MR analysis. Increases in the number of lead SNPs and mapped genes were witnessed in 13/15 species and 5/10 genera after using METAL, and MTAG analysis gained an increase in sample size equivalent to expanding the original samples from 7% to 63%. Following METAL use, we identified a positive association between Bacteroides faecis and ADHD (OR, 1.09; 95 %CI, 1.02-1.16; P = 0.008). Bacteroides eggerthii and Bacteroides thetaiotaomicron were observed to be positively associated with PTSD (OR, 1.11; 95 %CI, 1.03-1.20; P = 0.007; OR, 1.11; 95 %CI, 1.01-1.23; P = 0.03). These findings remained stable across statistical models and sensitivity analyses. No genetic liabilities to psychiatric diseases may alter the abundance of gut microorganisms.Using biological annotation, we identified that those genes contributing to microbiomes (e.g., GRIN2A and RBFOX1) are expressed and enriched in human brain tissues.
Our statistical genetics strategy helps to enhance the power of mbGWAS, and our genetic findings offer new insights into biological pleiotropy and causal relationship between microbiota and psychiatric diseases.
人类肠道微生物群与精神疾病之间的相关性早已得到认可。基于微生物组的遗传性，人类基因组和肠道微生物组的全基因组关联研究（mbGWAS）揭示了重要的宿主-微生物组相互作用。然而，由于先前 mbGWAS 研究的样本量不足，确定特定肠道微生物组特征与心理状况之间的因果关系仍然具有挑战性。
通过 METAL 进行跨队列荟萃分析（meta-analysis）和通过 MTAG 进行多性状分析（multi-trait analysis），以增强 mbGWAS 识别遗传变异和基因的统计能力。使用两项大型 mbGWAS 研究（分别有 7738 名和 5959 名参与者）和精神疾病基因组学联盟（PGC）的 12 项疾病特异性研究，我们在微生物特征和精神疾病之间进行了双向两样本孟德尔随机化（MR）分析（最多可达 500199 人）。此外，我们进行了下游基于基因和基因集的分析，以研究将肠道微生物群与精神疾病联系起来的共同生物学。
mbGWAS 中的 METAL 和 MTAG 可以提高基因优先级和 MR 分析的能力。在使用 METAL 后，在 15 个物种中的 13 个和 10 个属中的 5 个中观察到了 lead SNPs 和映射基因数量的增加，而 MTAG 分析则使样本量增加了相当于将原始样本从 7%扩大到 63%。使用 METAL 后，我们发现双歧杆菌（Bacteroides faecis）与 ADHD 呈正相关（OR，1.09；95%CI，1.02-1.16；P=0.008）。观察到脆弱拟杆菌（Bacteroides eggerthii）和普通拟杆菌（Bacteroides thetaiotaomicron）与 PTSD 呈正相关（OR，1.11；95%CI，1.03-1.20；P=0.007；OR，1.11；95%CI，1.01-1.23；P=0.03）。这些发现在统计模型和敏感性分析中均保持稳定。没有精神疾病的遗传易感性可能会改变肠道微生物的丰度。通过生物注释，我们发现那些对微生物组有贡献的基因（例如，GRIN2A 和 RBFOX1）在人类脑组织中表达并富集。
我们的统计遗传学策略有助于增强 mbGWAS 的能力，我们的遗传发现为微生物组和精神疾病之间的生物学多效性和因果关系提供了新的见解。
