Ellegood Jacob, Beauchamp Antoine, Yee Yohan, Devenyi Gabe, Ziolkowski Justine, Qiu Lily, Askalan Rand, Ayub Muhammad, Suetterlin Philipp, Donovan Alex, Basson M Albert, Quesnel Katherine M, Berube Nathalie G, Woo Taeseon, Beversdorf David, Bjornsson Hans, Blakely Randy, Crawley Jacqueline, Crosbie Jennifer, Orr Brian O, Davis Graeme W, Genestine Matthew, DiCicco-Bloom Emanuel, Egan Sean, Fink Kyle D, Asbury Sarah, Lai Jonathan, Rilett Kelly, Foster Jane A, Vincent John B, Frankland Paul, Georgiades Stelios, Penagarikano Olga, Geschwind Daniel, Giger Roman J, Markx Sander, Gogos Joseph, Golzio Christelle, Pagani Marco, Gozzi Alessandro, Pacey Laura K, Hampson David, Huang Tzyy-Nan, Yen Tzu-Li, Hsueh Yi-Ping, Iaboni Alana, Amar Megha, Iakoucheva Lilia M, Jones Jessica K, Kelly Elizabeth, Kieffer Brigette, Bae Mihyun, Jung Hwajin, Kim Hyosang, Park Haram, Roh Junye Daniel, Kim Eunjoon, Konopka Genevieve, Laliberte Christine, Lefebvre Julie L, Eagleson Kathie, Levitt Pat, Bach Aurea Martins, Cunningham Thomas J, Fisher Elizabeth, Miller Karla, Mills Alea, Muotri Alyson, Nicolson Rob, Noakes Leigh Spencer, Nieman Brian J, Canales Cesar P, Nord Alex S, Nutter Lauryl Mj, Tam Elaine, Osborne Lucy R, Clipperton-Allen Amy, Page Damon, Babineau Brooke, Palmer Theo D, Yan Keqin, Picketts David, Xia Qiangqiang, Powell Craig M, Raznahan Armin, Robins Diane M, Rumbaugh Gavin, Sengar Ameet S, Salter Michael William, Schachar Russell James, D'Abate Lia, Bradley Clarissa A, Scherer Stephen W, Copping Nycole W, Petkova Stela P, Silverman Jill L, Singh Karun Kar, Kim Nam-Shik, Yoon Ki-Jun Kar, Ming Guo-Li, Song Hongjun, Spring Shoshana, Nakatani Jin, Nakai Nobuhiro, Nomura J, Takumi Toru, Taylor Margot, Tsai Peter, Bruce Matthew, Jones Karen L, Van de Water Judy, Van Eede Matthijs C, Kerr Travis M, Muller Christopher L, VanderWeele Jeremy Veenstra, Vandewouw Marlee, Weksberg Rosanna, Wevrick Rachel, Belinson Haim, Wynshaw-Boris Anthony, Zarbalis Konstantinos, Trost Brett, Mars Rogier B, Chakravarty Mallar, Kushki Azadek, Anagnostou Evdokia, Lerch Jason P
bioRxiv. 2025 Mar 8:2025.03.04.641443. doi: 10.1101/2025.03.04.641443.
Significant genetic, behavioural and neuroanatomic heterogeneity is common in autism spectrum- and related- neurodevelopmental disorders (NDDs). This heterogeneity constrains the development of effective therapies for diverse patients in precision medicine paradigms. This has led to the search for subgroups of individuals having common etiologic factors/biology (e.g., genetic pathways), thus creating potential uniformity in prognosis and/or treatment response. Despite NDDs having a strong genetic component, only ~15-20% of individuals will present with a specific rare genetic variant considered clinically pathogenic, and therefore, subtyping efforts tend to focus on using clinical, cognitive, and/or brain imaging phenotypes to group individuals. Here we delineated mechanisms via mouse to human translational neuroscience. Using MRI derived structural neuroanatomy and a spatial transcriptomic comparison, we linked subgroups of 135 NDD relevant mouse models (3,515 individual mice) separately to two human databases, with 1,234 and 1,015 human individuals with NDDs, composed of autism, attention-deficit/hyperactivity disorder (ADHD), obsessive compulsive disorder (OCD), other related NDDs, and typically developing controls. Subgroups were significantly linked by consistent neuroanatomy across all three datasets, mouse and human, indicating that direct cross-species subgrouping and translation is consistent and reproducible. Ultimately, four specific neuroanatomical clusters were found and linked to precise molecular mechanisms: two showing a chromatin/transcription motif, with one of those showing specific links to G-protein coupled receptors (GPCR) and Notch signalling, and another two being mainly synaptic in origin, with one off those showing specific connections to axon guidance and Wnt signaling. Assigning molecular pathways, and thus genetic information, from the mouse to individual participants provides an insight into undetected and/or related genetic variants that could be working in combination or interacting with an environmental influence. Moreover, the subgroups found are transdiagnostic, including participants with autism, ADHD, and OCD, which indicates that NDDs as a whole can be subdivided into consistent neuroanatomical clusters with cohesive underlying biological mechanisms. This work allows us to bridge the gap between preclinical models and human disorders, linking previously idiopathic human patients to pertinent genetics, molecular mechanisms, and pathways.
显著的遗传、行为和神经解剖学异质性在自闭症谱系及相关神经发育障碍（NDDs）中很常见。这种异质性限制了精准医学模式下针对不同患者的有效治疗方法的开发。这促使人们寻找具有共同病因因素/生物学特征（如遗传途径）的个体亚组，从而在预后和/或治疗反应方面创造潜在的一致性。尽管NDDs具有很强的遗传成分，但只有约15 - 20%的个体将表现出被认为具有临床致病性的特定罕见遗传变异，因此，亚型分类工作往往侧重于使用临床、认知和/或脑成像表型对个体进行分组。在这里，我们通过从小鼠到人类的转化神经科学描绘了相关机制。利用磁共振成像（MRI）得出的结构神经解剖学和空间转录组比较，我们将135个与NDD相关的小鼠模型（3515只个体小鼠）的亚组分别与两个人类数据库相联系，这两个人类数据库分别包含1234名和1015名患有NDDs的个体，这些个体包括自闭症、注意力缺陷多动障碍（ADHD）、强迫症（OCD）、其他相关NDDs患者以及典型发育的对照者。所有三个数据集（小鼠和人类）中一致的神经解剖学特征显著地将这些亚组联系起来，表明直接的跨物种亚组分类和转化是一致且可重复的。最终，发现了四个特定的神经解剖学集群，并将其与精确的分子机制联系起来：两个显示出染色质/转录基序，其中一个显示出与G蛋白偶联受体（GPCR）和Notch信号传导的特定联系，另外两个主要起源于突触，其中一个显示出与轴突导向和Wnt信号传导的特定联系。从小鼠到个体参与者确定分子途径以及由此确定遗传信息，能够深入了解可能共同起作用或与环境影响相互作用的未被检测到的和/或相关的遗传变异。此外，所发现的亚组具有跨诊断性，包括自闭症、ADHD和OCD患者，这表明整个NDDs可以细分为具有内在连贯生物学机制的一致神经解剖学集群。这项工作使我们能够弥合临床前模型与人类疾病之间的差距，将以前病因不明的人类患者与相关的遗传学、分子机制和途径联系起来。
