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Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap
- Gandal, Michael J;
- Haney, Jillian R;
- Parikshak, Neelroop N;
- Leppa, Virpi;
- Ramaswami, Gokul;
- Hartl, Chris;
- Schork, Andrew J;
- Appadurai, Vivek;
- Buil, Alfonso;
- Werge, Thomas M;
- Liu, Chunyu;
- White, Kevin P;
- Horvath, Steve;
- Geschwind, Daniel H;
- Sestan, Nenad;
- Vaccarino, Flora;
- Gerstein, Mark;
- Weissman, Sherman;
- Pochareddy, Sirisha;
- State, Matthew;
- Knowles, James;
- Farnham, Peggy;
- Akbarian, Schahram;
- Pinto, Dalila;
- Van Baekl, Harm;
- Dracheva, Stella;
- Jaffe, Andrew;
- Hyde, Thomas;
- Zandi, Peter;
- Crawford, Gregory;
- Sullivan, Pat;
- Thompson, Wesley Kurt;
- Mortensen, Preben Bo;
- Agerbo, Esben;
- Pedersen, Marianne Giørtz;
- Pedersen, Carsten Bøcker;
- Mors, Ole;
- Børglum, Anders D;
- Nordentoft, Merete;
- Hougaard, David M;
- Bybjerg-Grauholm, Jonas;
- Bækvad-Hansen, Marie;
- Martin, Alicia R;
- Dumont, Ashley;
- Stevens, Christine;
- Churchhouse, Claire;
- Howrigan, Daniel P;
- Palmer, Duncan S;
- Robinson, Elise B;
- Satterstrom, Kyle F;
- Cerrato, Felecia;
- Huang, Hailiang;
- Goldstein, Jacqueline;
- Moran, Jennifer;
- Julian, Joanna Martin;
- Kimberly, Maller;
- Patrick, Chambert;
- Turley, Patrick;
- Walters, Raymond;
- Belliveau, Rich;
- Ripke, Stephan;
- Poterba, Timothy;
- Daly, Mark J;
- Neale, Benjamin;
- Fromer, Menachem;
- Roussos, Panos;
- Johnson, Jessica S;
- Shah, Hardik R;
- Mahajan, Milind C;
- Schadt, Eric;
- Haroutunian, Vahram;
- Ruderfer, Douglas M;
- Buxbaum, Joseph D;
- Sieberts, Solveig K;
- Dang, Kristen;
- Logsdon, Ben;
- Mangravite, Lara M;
- Peters, Mette;
- Gur, Raquel E;
- Hahn, Chang-Gyu;
- Devlin, Bernie;
- Klei, Lambertus L;
- Lewis, David;
- Lipska, Barbara;
- Hirai, Keisuke;
- Toyoshiba, Hiroyoshi;
- Domenici, Enrico
Published Web Location
https://doi.org/10.1126/science.aad6469Abstract
The predisposition to neuropsychiatric disease involves a complex, polygenic, and pleiotropic genetic architecture. However, little is known about how genetic variants impart brain dysfunction or pathology. We used transcriptomic profiling as a quantitative readout of molecular brain-based phenotypes across five major psychiatric disorders-autism, schizophrenia, bipolar disorder, depression, and alcoholism-compared with matched controls. We identified patterns of shared and distinct gene-expression perturbations across these conditions. The degree of sharing of transcriptional dysregulation is related to polygenic (single-nucleotide polymorphism-based) overlap across disorders, suggesting a substantial causal genetic component. This comprehensive systems-level view of the neurobiological architecture of major neuropsychiatric illness demonstrates pathways of molecular convergence and specificity.
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