Supplementary Material for: Mendelian randomization analyses reveal causal relationships between brain structural connectivity and risk of polycystic ovary syndrome

Background: It is well known that brain structure is affected by sex hormones, and polycystic ovary syndrome(PCOS) is often accompanied by abnormal hormone production. However, the relationship between brain structural connectivity and polycystic ovary syndrome is currently unknown.
Methods: Two-sample mendelian randomization (2SMR) was used by searching an appropriate European population genome-wide association studies (GWAS) database of the structural connections of the brain and polycystic ovary syndrome from the Ieu Open GWAS Project database. 206 related brain structural connectivity single-nucleotide polymorphisms (SNPs) were screened as instrumental variables (IVs). Subsequently, we employ various statistical methods including inverse variance weighting (IVW), weighted median method (WME), MR-Egger regression, Simple mode, and Weighted mode to investigate the causal link between the structural connections of the brain and polycystic ovary syndrome.
Results: According to the IVW results, it was confirmed that the white matter structural connections between the right hemisphere default mode network and the amygdala are associated with the occurrence of PCOS (odds ratio [OR] = 1.559; 95% confidence interval [CI] = 1.028–2.36; P = 0.037). The white matter structural connectivity between the right-hemisphere somatomotor network and the right-hemisphere limbic network was also linked to the development of PCOS (OR = 1.800; 95% CI = 1.077–3.009; P = 0.025). Additionally, the white matter structural connections from the left hemisphere limbic network to the right hemisphere control network, from the left hemisphere limbic network to the thalamus, from the left hemisphere somatomotor network to the left hemisphere control network, and from the right hemisphere limbic network to the thalamus are negatively correlated with the development of PCOS. Leave-one-out sensitivity analyses and heterogeneity tests were performed, and no horizontal pleiotropy was found.
Conclusion: Our results point to a causal relationship between the development of PCOS and the white matter structural connectivity from the right hemisphere default mode network to the amygdala, as well as from the right hemisphere somatomotor network to the right hemisphere limbic network.

背景：众所周知，大脑结构受性激素影响，而多囊卵巢综合征（polycystic ovary syndrome, PCOS）常伴随激素分泌异常。但目前大脑结构连接与多囊卵巢综合征之间的关联仍不明确。
方法：本研究采用双样本孟德尔随机化（two-sample mendelian randomization, 2SMR）方法，从Ieu开放GWAS项目数据库中检索适用于欧洲人群的大脑结构连接与多囊卵巢综合征的全基因组关联研究（genome-wide association studies, GWAS）数据集。共筛选出206个与大脑结构连接相关的单核苷酸多态性（single-nucleotide polymorphisms, SNPs）作为工具变量（instrumental variables, IVs）。随后，本研究采用多种统计方法探究大脑结构连接与多囊卵巢综合征之间的因果关联，包括逆方差加权（inverse variance weighting, IVW）、加权中位数法（weighted median method, WME）、MR-Egger回归（MR-Egger regression）、简单模式法（Simple mode）以及加权模式法（Weighted mode）。
结果：基于逆方差加权分析结果，证实右侧半球默认模式网络（default mode network）与杏仁核（amygdala）之间的白质结构连接与多囊卵巢综合征的发生存在关联（比值比[odds ratio, OR] = 1.559；95%置信区间[confidence interval, CI] = 1.028–2.36；P = 0.037）。右侧半球躯体运动网络（somatomotor network）与右侧半球边缘网络（limbic network）之间的白质结构连接同样与多囊卵巢综合征的发生发展相关（OR = 1.800；95% CI = 1.077–3.009；P = 0.025）。此外，左半球边缘网络至右半球控制网络（control network）、左半球边缘网络至丘脑（thalamus）、左半球躯体运动网络至左半球控制网络，以及右半球边缘网络至丘脑的白质结构连接与多囊卵巢综合征的发生发展呈负相关。本研究开展了留一法敏感性分析（leave-one-out sensitivity analyses）与异质性检验（heterogeneity tests），未发现水平多效性（horizontal pleiotropy）现象。
结论：本研究结果表明，多囊卵巢综合征的发生发展与右侧半球默认模式网络至杏仁核、右侧半球躯体运动网络至右侧半球边缘网络的白质结构连接存在因果关联。