自闭症谱系障碍(ASD)是一种临床表现不均匀的神经发育障碍,变量严重性,和多种合并症。复杂的潜在遗传结构与临床异质性相匹配,证据表明,几种共同发生的脑部疾病与ASD具有遗传成分。在这项研究中,我们建立了一种遗传相似性疾病网络方法来探索ASD和常见共病脑疾病(和亚型)之间的共享遗传学,即智力残疾,注意缺陷/多动症,癫痫,以及精神分裂症和双相疾病谱中其他很少同时发生的神经精神疾病。使用由DisGeNET数据库管理的疾病相关基因集,根据疾病对之间的Jaccard系数估计疾病遗传相似性,Leiden检测算法用于识别网络疾病群落并定义共享的生物途径。我们发现了一个与ASD基因更相似的异质性脑疾病群落,包括癫痫,双相情感障碍,注意缺陷/多动障碍综合类型,和精神分裂症谱系中的一些疾病。为了确定疾病群落共同基因中的功能丧失罕见的从头变异,我们分析了一个大型ASD全基因组测序数据集,表明ASD与其他多种脑部疾病共享基因,基因相似度较低,社区。一些基因(例如,SHANK3,ASH1L,SCN2A,CHD2和MECP2)先前与ASD和这些疾病有关。这种方法能够进一步澄清ASD和脑部疾病之间的遗传共享,具有更精细的疾病分类粒度和来自DisGeNet的多层次证据。了解疾病之间的遗传共享对疾病的发病具有重要意义,病理生理学,个性化治疗。
Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder with heterogeneous clinical presentation, variable severity, and multiple comorbidities. A complex underlying genetic architecture matches the clinical heterogeneity, and evidence indicates that several co-occurring brain disorders share a genetic component with ASD. In this study, we established a genetic similarity disease network approach to explore the shared genetics between ASD and frequent comorbid brain diseases (and subtypes), namely Intellectual Disability, Attention-Deficit/Hyperactivity Disorder, and Epilepsy, as well as other rarely co-occurring neuropsychiatric conditions in the Schizophrenia and Bipolar Disease spectrum. Using sets of disease-associated genes curated by the DisGeNET database, disease genetic similarity was estimated from the Jaccard coefficient between disease pairs, and the Leiden detection algorithm was used to identify network disease communities and define shared biological pathways. We identified a heterogeneous brain disease community that is genetically more similar to ASD, and that includes Epilepsy, Bipolar Disorder, Attention-Deficit/Hyperactivity Disorder combined type, and some disorders in the Schizophrenia Spectrum. To identify loss-of-function rare de novo variants within shared genes underlying the disease communities, we analyzed a large ASD whole-genome sequencing dataset, showing that ASD shares genes with multiple brain disorders from other, less genetically similar, communities. Some genes (e.g., SHANK3, ASH1L, SCN2A, CHD2, and MECP2) were previously implicated in ASD and these disorders. This approach enabled further clarification of genetic sharing between ASD and brain disorders, with a finer granularity in disease classification and multi-level evidence from DisGeNET. Understanding genetic sharing across disorders has important implications for disease nosology, pathophysiology, and personalized treatment.