Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands.
Transl Psychiatry. 2022 Feb 14;12(1):59. doi: 10.1038/s41398-022-01817-0.
The prevalence of somatic insulinopathies, like metabolic syndrome (MetS), obesity, and type 2 diabetes mellitus (T2DM), is higher in Alzheimer's disease (AD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD). Dysregulation of insulin signalling has been implicated in these neuropsychiatric disorders, and shared genetic factors might partly underlie this observed multimorbidity. We investigated the genetic overlap between AD, ASD, and OCD with MetS, obesity, and T2DM by estimating pairwise global genetic correlations using the summary statistics of the largest available genome-wide association studies for these phenotypes. Having tested these hypotheses, other potential brain "insulinopathies" were also explored by estimating the genetic relationship of six additional neuropsychiatric disorders with nine insulin-related diseases/traits. Stratified covariance analyses were then performed to investigate the contribution of insulin-related gene sets. Significant negative genetic correlations were found between OCD and MetS (r = -0.315, p = 3.9 × 10), OCD and obesity (r = -0.379, p = 3.4 × 10), and OCD and T2DM (r = -0.172, p = 3 × 10). Significant genetic correlations with insulin-related phenotypes were also found for anorexia nervosa (AN), attention-deficit/hyperactivity disorder (ADHD), major depressive disorder, and schizophrenia (p < 6.17 × 10). Stratified analyses showed negative genetic covariances between AD, ASD, OCD, ADHD, AN, bipolar disorder, schizophrenia and somatic insulinopathies through gene sets related to insulin signalling and insulin receptor recycling, and positive genetic covariances between AN and T2DM, as well as ADHD and MetS through gene sets related to insulin processing/secretion (p < 2.06 × 10). Overall, our findings suggest the existence of two clusters of neuropsychiatric disorders, in which the genetics of insulin-related diseases/traits may exert divergent pleiotropic effects. These results represent a starting point for a new research line on "insulinopathies" of the brain.
躯体胰岛素代谢病的患病率，如代谢综合征（MetS）、肥胖和 2 型糖尿病（T2DM），在阿尔茨海默病（AD）、自闭症谱系障碍（ASD）和强迫症（OCD）中更高。胰岛素信号的失调与这些神经精神疾病有关，共同的遗传因素可能部分解释了这种观察到的多种疾病并存现象。我们通过估计最大可用全基因组关联研究的汇总统计数据来计算 AD、ASD 和 OCD 与 MetS、肥胖和 T2DM 之间的成对全球遗传相关性，以研究 AD、ASD 和 OCD 与 MetS、肥胖和 T2DM 之间的遗传重叠。在测试了这些假设后，我们还通过估计另外六种神经精神疾病与九种与胰岛素相关的疾病/特征之间的遗传关系，探索了其他潜在的“脑胰岛素代谢病”。然后进行分层协方差分析，以研究与胰岛素相关的基因集的贡献。我们发现 OCD 与 MetS（r=-0.315，p=3.9×10）、OCD 与肥胖（r=-0.379，p=3.4×10）和 OCD 与 T2DM（r=-0.172，p=3×10）之间存在显著的负遗传相关性。厌食症（AN）、注意缺陷多动障碍（ADHD）、重度抑郁症和精神分裂症也与胰岛素相关表型存在显著的遗传相关性（p<6.17×10）。分层分析显示，AD、ASD、OCD、ADHD、AN、双相情感障碍、精神分裂症与躯体胰岛素代谢病之间存在负遗传协方差，通过与胰岛素信号和胰岛素受体回收相关的基因集；而 AN 与 T2DM 以及 ADHD 与 MetS 之间存在正遗传协方差，通过与胰岛素处理/分泌相关的基因集（p<2.06×10）。总的来说，我们的研究结果表明存在两个神经精神疾病簇，其中胰岛素相关疾病/特征的遗传可能产生不同的多效性影响。这些结果为“大脑胰岛素代谢病”的新研究线提供了一个起点。
