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Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes

2019; Nature Portfolio; Volume: 4; Issue: 1 Linguagem: Inglês

10.1038/s41525-019-0093-8

2056-7944

Pamela Feliciano, Xueya Zhou, Irina Astrovskaya, Tychele N. Turner, Tianyun Wang, Leo Brueggeman, Rebecca Barnard, Alexander Hsieh, LeeAnne Green Snyder, Donna M. Muzny, Aniko Sabo, Leonard Abbeduto, John Acampado, J. Andrea, Charles F. Albright, Michael Alessandri, David G. Amaral, Alpha Amatya, Robert D. Annett, Ivette Arriaga, Ethan Bahl, Adithya Balasubramanian, Nicole Bardett, Asif Bashar, Arthur L. Beaudet, Landon Beeson, Raphael Bernier, Elizabeth Berry‐Kravis, Stephanie Booker, Stephanie Brewster, Elizabeth Brooks, Martin E. Butler, Eric Butter, Kristen Callahan, Alexies Camba, Laura A. Carpenter, Nicholas Carriero, Lindsey A. Cartner, Ahmad S. Chatha, Wubin Chin, Renee D. Clark, Cheryl Cohen, Eric Courchesne, Joseph F. Cubells, Mary Hannah Currin, Amy M. Daniels, Lindsey DeMarco, Megan Y. Dennis, Gabriel S. Dichter, Yan Ding, Huyen Dinh, Ryan N. Doan, HarshaVardhan Doddapaneni, Sara Eldred, Christine M. Eng, Craig A. Erickson, Amy Esler, Ali Fatemi, Gregory J. Fischer, I. Fisk, Éric Fombonne, Emily A. Fox, Sunday M. Francis, Sandra Friedman, Swami Ganesan, Michael R. Garrett, Vahid Gazestani, Madeleine R. Geisheker, Jennifer Gerdts, Daniel H. Geschwind, Robin P. Goin‐Kochel, Anthony J. Griswold, Luke P. Grosvenor, Angela Gruber, Amanda C. Gulsrud, Jaclyn Gunderson, Anibal Gutierrez, Melissa N. Hale, Monica Haley, Jacob B. Hall, Kira E. Hamer, Bing Han, Nathan Hanna, Christina Harkins, Nina Harris, Brenda Hauf, Caitlin Hayes, Susan Hepburn, Lynette M. Herbert, Michelle Heyman, Brittani A. Phillips, Susannah Horner, Taobo Hu, Lark Y. Huang-Storms, Hanna Hutter, Dalia Istephanous, Suma Jacob, William B. Jensen, Mark Jones, Michelle Jordy, Aline Juárez, Stephen M. Kanne, Hannah E. Kaplan, Matt Kent, Alex Kitaygorodsky, Tanner Koomar, Viktoriya Korchina, Anthony D. Krentz, Hoa Lam Schneider, Elena Lamarche, Rebecca Landa, Alex E. Lash, Kiely Law, Noah Lawson, Kevin Layman, Holly Lechniak, Charles Lee, Soo J. Lee, Daniel L. Coury, Alastair J. Martin, Deana Li, Hai Li, Natasha Lillie, Xiuping Liu, Catherine Lord, Malcolm D. Mallardi, Patricia Manning, Julie Manoharan, Richard P. Marini, Gabriela Marzano, Andrew L. Mason, Emily T. Matthews, James T. McCracken, Alexander P. McKenzie, Zeineen Momin, Michael J. Morrier, Shwetha C. Murali, Vincent J. Myers, Jason Neely, Caitlin Nessner, Amy Nicholson, Kaela O’Brien, Eirene O’Connor, Cesar Ochoa-Lubinoff, Jéssica Orobio, Opal Ousley, Lillian D. Pacheco, Juhi Pandey, Anna Marie Paolicelli, Katherine G. Pawlowski, Karen Pierce, Joseph Piven, Samantha Plate, Marc Popp, Tiziano Pramparo, Lisa M. Prock, Hongjian Qi, Shanping Qiu, Angela L. Rachubinski, Kshitij Rajbhandari, Rishiraj Rana, Rick Remington, Catherine E. Rice, Chris Rigby, B. E. Robertson, Katherine Roeder, Cordelia Robinson Rosenberg, Nicole M. Russo‐Ponsaran, Elizabeth K. Ruzzo, Mustafa Şahin, Andrei Salomatov, Sophia Sandhu, Susan L. Santangelo, Dustin E. Sarver, Jessica Scherr, Robert T. Schultz, Kathryn A. Schweers, Swapnil Shah, Tamim H. Shaikh, Amanda D. Shocklee, Laura Simon, Andrea R. Simon, Vini Singh, Steve Skinner, Kaitlin Smith, Christopher J. Smith, Latha Soorya, Aubrie Soucy, Alexandra N. Stephens, Colleen M. Stock, James S. Sutcliffe, Amy Swanson, Maira Tafolla, Nicole Takahashi, Taylor R. Thomas, Carrie A. Thomas, Samantha Thompson, Jennifer Tjernagel, Bonnie Van Metre, Jeremy Veenstra‐VanderWeele, Brianna M. Vernoia, Jermel Wallace, Corrie H. Walston, Jiayao Wang, Zachary Warren, Lucy Wasserburg, L. Casey White, Sabrina White, Ericka L. Wodka, Simon Xu, Wha S. Yang, Meredith Yinger, Timothy W. Yu, Lan Zang, Hana Zaydens, Haicang Zhang, Haoquan Zhao, Richard A. Gibbs, Evan E. Eichler, Brian J. O’Roak, Jacob J. Michaelson, Natalia Volfovsky, Yufeng Shen, Wendy K. Chung,

Genomic variations and chromosomal abnormalities

Abstract Autism spectrum disorder (ASD) is a genetically heterogeneous condition, caused by a combination of rare de novo and inherited variants as well as common variants in at least several hundred genes. However, significantly larger sample sizes are needed to identify the complete set of genetic risk factors. We conducted a pilot study for SPARK (SPARKForAutism.org) of 457 families with ASD, all consented online. Whole exome sequencing (WES) and genotyping data were generated for each family using DNA from saliva. We identified variants in genes and loci that are clinically recognized causes or significant contributors to ASD in 10.4% of families without previous genetic findings. In addition, we identified variants that are possibly associated with ASD in an additional 3.4% of families. A meta-analysis using the TADA framework at a false discovery rate (FDR) of 0.1 provides statistical support for 26 ASD risk genes. While most of these genes are already known ASD risk genes, BRSK2 has the strongest statistical support and reaches genome-wide significance as a risk gene for ASD ( p -value = 2.3e−06). Future studies leveraging the thousands of individuals with ASD who have enrolled in SPARK are likely to further clarify the genetic risk factors associated with ASD as well as allow accelerate ASD research that incorporates genetic etiology.