Table_6_Evaluating the link between immune characteristics and attention deficit hyperactivity disorder through a bi-directional Mendelian randomization study.xls

ContextDespite the recognition of attention deficit hyperactivity disorder (ADHD) as a multifaceted neurodevelopmental disorder, its core causes are still ambiguous. The objective of this study was to explore if the traits of circulating immune cells contribute causally to susceptibility to ADHD.
MethodsBy employing a unified GWAS summary data covering 731 immune traits from the GWAS Catalog (accession numbers from GCST0001391 to GCST0002121), our analysis focused on the flow cytometry of lymphocyte clusters, encompassing 3,757 Sardinians, to identify genetically expected immune cells. Furthermore, we obtained summarized GWAS statistics from the Psychiatric Genomics Consortium to evaluate the genetic forecasting of ADHD. The studies employed ADHD2019 (20,183 cases and 35,191 controls from the 2019 GWAS ADHD dataset) and ADHD2022 (38,691 cases and 275,986 controls from the 2022 GWAS ADHD dataset). Through the examination of genome-wide association signals, we identified shared genetic variances between circulating immune cells and ADHD, employing the comprehensive ADHD2022 dataset. We primarily utilized inverse variance weighted (IVW) and weighted median methods in our Mendelian randomization research and sensitivity assessments to evaluate diversity and pleiotropy.
ResultsAfter adjusting for false discovery rate (FDR), three distinct immunophenotypes were identified as associated with the risk of ADHD: CD33 in Im MDSC (OR=1.03, CI: 1.01~1.04, P=3.04×10−5, PFDR=0.015), CD8br NKT %T cell (OR=1.08, 95%CI: 1.04~1.12, P=9.33×10−5, PFDR=0.023), and CD8br NKT %lymphocyte (OR=1.08, 95%CI: 1.03~1.12, P=3.59×10−4, PFDR=0.066). Furthermore, ADHD showed no statistical effects on immunophenotypes. It’s worth noting that 20 phenotypes exist where ADHD’s appearance could diminish 85% of immune cells, including FSC-A in myeloid DC (β= -0.278, 95% CI: 0.616~0.931, P=0.008), CD3 in CD45RA- CD4+ (β= -0.233, 95% CI: 0.654~0.960, P=0.017), CD62L- monocyte AC (β=0.227, 95% CI: 0.038~1.518, P=0.019), CD33 in CD33br HLA DR+ CD14dim (β= -0.331, 95% CI: 0.543~0.950, P=0.020), and CD25 in CD39+ resting Treg (β=0.226, 95% CI: 1.522, P=0.022), and FSC-A in monocytes (β= -0.255, 95% CI: 0.621~0.967, P=0.234), among others.
ConclusionStudies indicate that the immune system’s response influences the emergence of ADHD. The findings greatly improve our understanding of the interplay between immune responses and ADHD risk, aiding in the development of treatment strategies from an immunological perspective.

背景：尽管注意缺陷多动障碍（attention deficit hyperactivity disorder, ADHD）已被公认为一种多维度的神经发育障碍，但其核心致病机制仍未明确。本研究旨在探究循环免疫细胞的特征是否在因果层面上参与了ADHD的易感性。

方法：本研究采用来自全基因组关联研究（Genome-Wide Association Study, GWAS）目录的统一GWAS汇总数据，涵盖731种免疫性状（登录号范围为GCST0001391至GCST0002121），并聚焦于纳入3757名撒丁岛人群的淋巴细胞群流式细胞术分析，以鉴定具有遗传特征的免疫细胞。此外，我们从精神疾病基因组联盟（Psychiatric Genomics Consortium）获取了GWAS汇总统计数据，以评估ADHD的遗传预测效能。本研究使用了两套ADHD数据集：ADHD2019（2019年ADHD的GWAS数据集，包含20183例病例与35191例对照）以及ADHD2022（2022年ADHD的GWAS数据集，包含38691例病例与27598例对照）。通过分析全基因组关联信号，我们借助完整的ADHD2022数据集，鉴定了循环免疫细胞与ADHD之间的共享遗传变异。本研究的孟德尔随机化分析与敏感性评估主要采用逆方差加权（inverse variance weighted, IVW）法和加权中位数法，以评估遗传异质性与多效性。

结果：在校正错误发现率（false discovery rate, FDR）后，共鉴定出三种与ADHD风险显著相关的免疫表型：髓系来源抑制细胞中的CD33（CD33 in Im MDSC，比值比OR=1.03，95%置信区间CI：1.01~1.04，P=3.04×10−5，校正后P值PFDR=0.015）、CD8br NKT细胞占T细胞百分比（CD8br NKT %T cell，OR=1.08，95%CI：1.04~1.12，P=9.33×10−5，PFDR=0.023）以及CD8br NKT细胞占淋巴细胞百分比（CD8br NKT %lymphocyte，OR=1.08，95%CI：1.03~1.12，P=3.59×10−4，PFDR=0.066）。此外，ADHD对免疫表型未表现出统计学显著影响。值得注意的是，存在20种免疫性状，ADHD的发生可使对应免疫细胞丰度发生改变，包括髓系树突状细胞中的前向散射角A（FSC-A in myeloid DC，β=-0.278，95%CI：0.616~0.931，P=0.008）、CD45RA- CD4+ T细胞中的CD3表达（CD3 in CD45RA- CD4+，β=-0.233，95%CI：0.654~0.960，P=0.017）、CD62L-单核细胞活化细胞（CD62L- monocyte AC，β=0.227，95%CI：0.038~1.518，P=0.019）、CD33br HLA DR+ CD14dim细胞中的CD33表达（CD33 in CD33br HLA DR+ CD14dim，β=-0.331，95%CI：0.543~0.950，P=0.020）以及CD39+静息调节性T细胞（regulatory T cell, Treg）中的CD25表达（CD25 in CD39+ resting Treg，β=0.226，95%CI：1.522，P=0.022）、单核细胞中的前向散射角A（FSC-A in monocytes，β=-0.255，95%CI：0.621~0.967，P=0.234）等。

结论：本研究结果表明，免疫系统的应答参与了ADHD的发生与发展。本研究发现极大地增进了我们对免疫应答与ADHD风险之间相互作用的理解，有助于从免疫学视角开发ADHD的治疗策略。