Engchuan Worrawat, Shanta Omar, Kumar Kuldeep, MacDonald Jeffrey R, Thiruvahindrapuram Bhooma, Hamdan Omar, Klein Marieke, Maihofer Adam, Guevara James, Hong Oanh, Huguet Guillaume, Sacks Molly, Ahangari Mohammad, Feitosa Rayssa M M W, Han Kara, Mendes Marla, Zhou Xiaopu, Bautista Nelson X, Pellecchia Giovanna, Wang Zhouzhi, Merico Daniele, Yuen Ryan K C, Trost Brett, Sønderby Ida, Adams Mark J, Adolfsson Rolf, Agartz Ingrid, Aiello Allison E, Alda Martin, Allardyce Judith, Amstadter Ananda B, Andlauer Till F M, Andreassen Ole A, Artigas María S, Austin S Bryn, Ayub Muhammad, Baker Dewleen G, Bass Nick, Baune Bernhard T, Bayas Maximilian, Berger Klaus, Biernacka Joanna M, Bigdeli Tim, Bisson Jonathan I, Blackwood Douglas, Boks Marco, Braff David, Bramon Elvira, Breen Gerome, Brueckl Tanja, Bryant Richard A, Bulik Cynthia M, Buxbaum Joseph, Cairns Murray J, Caldas-de-Almeida Jose M, Campbell Megan, Campion Dominique, Carr Vaughan J, Castelao Enrique, Chaumette Boris, Cichon Sven, Cohen David, Corvin Aiden, Craddock Nicholas, Crosbie Jennifer, Czamara Darrina, Dannlowski Udo, Degenhardt Franziska, Delahanty Douglas L, Dempfle Astrid, Desachy Guillaume, Di Florio Arianna, Dickerson Faith B, Djurovic Srdjan, Domschke Katharina, Douglas Lisa, Drange Ole K, Duncan Laramie E, Edenberg Howard J, Esko Tonu, Faraone Steve, Feeny Norah C, Forstner Andreas J, Franke Barbara, Frye Mark, Fu Dong-Jing, Fullerton Janice M, Gareeva Anna, Garvert Linda, Gatt Justine M, Gejman Pablo, Geschwind Daniel H, Giegling Ina, Glatt Stephen J, Glessner Joe, Goes Fernando S, Gordon-Smith Katherine, Grabe Hans, Green Melissa J, Green Michael F, Greenwood Tiffany, Grigoroiu-Serbanescu Maria, Gur Raquel E, Gur Ruben C, Guzman-Parra Jose, Haavik Jan, Hahn Tim, Hakonarson Hakon, Hallmayer Joachim, Hamshere Marian L, Hartmann Annette M, Hassan Arsalan, Hayward Caroline, Hebebrand Johannes, Hemmings Sian M J, Herms Stefan, Herrera-Rivero Marisol, Hinney Anke, Homuth Georg, Ingason Andrés, Ito Lucas T, Iwata Nakao, Jones Ian, Jones Lisa A, Jonsson Lina, Jönsson Erik G, Kahn René S, Karlsson Robert, Kaufman Milissa L, Kelsoe John R, Kennedy James L, King Anthony, Kircher Tilo, Kirov George, Knappskog Per, Knowles James A, Kobayashi Nene, Koenen Karestan C, Konte Bettina, Korgaonkar Mayuresh, Kowalec Kaarina, Krebs Marie-Odile, Landén Mikael, Laurent-Levinson Claudine, Lebois Lauren A, Levinson Doug, Lewis Cathryn, Li Qingqin, Liberzon Israel, Light Greg, Loo Sandra K, Lu Yi, Lucae Susanne, Marmar Charles, Martin Nicholas G, Mayoral Fermin, McIntosh Andrew M, McLaughlin Katie A, McLean Samuel A, McQuillin Andrew, Medland Sarah E, Meyer-Lindenberg Andreas, Milanova Vihra, Mitchell Philip B, Molina Esther, Mowry Bryan, Muller-Myhsok Bertram, Mullins Niamh, Murray Robin, Nöthen Markus M, Nurnberger John I, O'Connell Kevin S, Ophoff Roel A, Orcutt Holly K, Owen Michael J, Palotie Aarno, Pato Carlos, Pato Michele, Pawlak Joanna, Peters Triinu, Petryshen Tracey L, Pistis Giorgio, Potash James B, Powell John, Preisig Martin, Quested Digby, Ramos-Quiroga Josep A, Reif Andreas, Ressler Kerry J, Ribasés Marta, Rietschel Marcella, Risbrough Victoria B, Rivera Margarita, Rothbaum Alex O, Rothbaum Barbara O, Rujescu Dan, Saito Takeo, Sanders Alan R, Schachar Russell J, Schofield Peter R, Schulte Eva C, Schulze Thomas G, Scott Laura J, Seedat Soraya, Sheerin Christina, Shi Jianxin, Sklar Pamela, Smalley Susan, Smeland Olav B, Smoller Jordan W, Sonuga-Barke Edmund, Clair David St, Steen Nils Eiel, Stein Dan, Stein Frederike, Stein Murray B, Streit Fabian, Swerdlow Neal, Thibaut Florence, Thygesen Johan H, Timerbulatov Ilgiz, Toma Claudio, Trapido Edward, Tremblay Micheline, Tsuang Ming T, Uddin Monica, Vawter Marquis P, Vincent John B, Völzke Henry, Walters James T, Weickert Cynthia S, Weiss Lauren A, Weissman Myrna M, Werge Thomas, Witt Stephanie H, Xavier Miguel, Yolken Robert, Young Ross M, Zayats Tetyana, Zoellner Lori A, Kendall Kimberley, Riley Brien, Wray Naomi R, O'Donovan Michael C, Sullivan Patrick F, Sanchez-Roige Sandra, Nievergelt Caroline M, Jacquemont Sébastien, Scherer Stephen W, Sebat Jonathan
The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, Canada.
Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.
medRxiv. 2025 Jul 16:2025.07.11.25331381. doi: 10.1101/2025.07.11.25331381.
Psychiatric conditions share common genes, but mechanisms that differentiate diagnoses remain unclear. We present a multidimensional framework for functional analysis of rare copy number variants (CNVs) across 6 diagnostic categories, including schizophrenia (SCZ), autism (ASD), bipolar disorder (BD), depression (MDD), PTSD, and ADHD (N = 574,965). Using gene-set burden analysis (GSBA), we tested duplication (DUP) and deletion (DEL) burden across 2,645 functional gene sets defined by the intersections of pathways, cell types, and cortical regions. While diagnoses converge on shared pathways, mixed-effects modeling revealed divergence of pathway effects by cell type, brain region, and gene dosage. Factor analysis identified latent dimensions aligned with clinical axes. A primary factor (F1) captured reciprocal dose-dependent effects of DUP and DEL in SCZ reflecting positive and negative effects in excitatory versus inhibitory neurons and association versus sensory cortex. SCZ and ASD were both strongly aligned with F1 but with opposing directionalities. Orthogonal factors highlighted neuronal versus non-neuronal effects in mood disorders (F2) and differential spatial distributions of DEL effects in ADHD and MDD (F3). High-impact CNVs at 16p11.2 and 22q11.2 were enriched for combinations of cell-type-specific genes involved in pathways consistent with our broader findings. These results reveal molecular and cellular mechanisms that are broadly shared across psychiatric traits but differ between diagnostic categories in context and directionality.
精神疾病具有共同的基因，但区分诊断的机制仍不清楚。我们提出了一个多维框架，用于对6种诊断类别的罕见拷贝数变异（CNV）进行功能分析，包括精神分裂症（SCZ）、自闭症（ASD）、双相情感障碍（BD）、抑郁症（MDD）、创伤后应激障碍（PTSD）和注意力缺陷多动障碍（ADHD）（N = 574,965）。使用基因集负担分析（GSBA），我们测试了由通路、细胞类型和皮质区域的交集定义的2645个功能基因集的重复（DUP）和缺失（DEL）负担。虽然诊断集中在共享通路上，但混合效应模型显示通路效应在细胞类型、脑区和基因剂量方面存在差异。因子分析确定了与临床轴对齐的潜在维度。一个主要因子（F1）捕捉了SCZ中DUP和DEL的相互剂量依赖性效应，反映了兴奋性与抑制性神经元以及联合与感觉皮层中的正负效应。SCZ和ASD都与F1高度对齐，但方向相反。正交因子突出了情绪障碍中的神经元与非神经元效应（F2）以及ADHD和MDD中DEL效应的不同空间分布（F3）。16p11.2和22q11.2处的高影响CNV富集了与我们更广泛发现一致的通路中涉及的细胞类型特异性基因组合。这些结果揭示了在精神特质中广泛共享但在诊断类别之间在背景和方向性上存在差异的分子和细胞机制。
