Integrated gene analyses of de novo variants from 46,612 trios with autism and developmental disorders
Tianyun Wang, Chang N. Kim, Trygve E. Bakken, Madelyn A. Gillentine, Barbara Henning, Yafei Mao, Christian Gilissen, Tomasz J. Nowakowski, Evan E. Eichler, John Acampado, Andrea J. Ace, Alpha Amatya, Irina Astrovskaya, Asif Bashar, Elizabeth Brooks, Martin E. Butler, Lindsey A. Cartner, Wubin Chin, Wendy K. Chung, Amy M. Daniels, Pamela Feliciano, Chris Fleisch, Swami Ganesan, William B. Jensen, Alex Lash, Richard P. Marini, Vincent J. Myers, Eirene O'Connor, Chris Rigby, B. E. Robertson, Neelay Shah, Swapnil Shah, Emily Singer, LeeAnne Green Snyder, Alexandra N. Stephens, Jennifer Tjernagel, Brianna M. Vernoia, Natalia Volfovsky, L. Casey White, Alexander Hsieh, Yufeng Shen, Xueya Zhou, Tychele N. Turner, Ethan Bahl, Taylor Thomas, Leo Brueggeman, Tanner Koomar, Jacob J. Michaelson, Brian J. O’Roak, Rebecca Barnard, Richard A. Gibbs, Donna M. Muzny, Aniko Sabo, Kelli L. Baalman Ahmed, Evan E. Eichler, Matthew Siegel, Leonard Abbeduto, David G. Amaral, Brittani A. Hilscher, Deana Li, Kaitlin N. Smith, Samantha Thompson, Charles F. Albright, Eric Butter, Sara Eldred, Nathan Hanna, Mark Jones, Daniel L. Coury, Jessica Scherr, Taylor Pifher, Erin Roby, Brandy Dennis, Lorrin Higgins, Melissa A. Brown, Michael Alessandri, Anibal Gutierrez, Melissa N. Hale, Lynette M. Herbert, Hoa Lam Schneider, Giancarla David, Robert D. Annett, Dustin E. Sarver, Ivette Arriaga, Alexies Camba, Amanda C. Gulsrud, Monica Haley, James T. McCracken, Sophia Sandhu, Maira Tafolla, Wha S. Yang, Laura A. Carpenter, Catherine C. Bradley, Frampton Gwynette, Patricia Manning, Rebecca C. Shaffer, Carrie Thomas, Raphael Bernier, Emily A. Fox, Jennifer Gerdts, Micah Pepper
Abstract
Most genetic studies consider autism spectrum disorder (ASD) and developmental disorder (DD) separately despite overwhelming comorbidity and shared genetic etiology. Here, we analyzed de novo variants (DNVs) from 15,560 ASD (6,557 from SPARK) and 31,052 DD trios independently and also combined as broader neurodevelopmental disorders (NDDs) using three models. We identify 615 NDD candidate genes (false discovery rate [FDR] < 0.05) supported by ≥1 models, including 138 reaching Bonferroni exome-wide significance ( P < 3.64e–7) in all models. The genes group into five functional networks associating with different brain developmental lineages based on single-cell nuclei transcriptomic data. We find no evidence for ASD-specific genes in contrast to 18 genes significantly enriched for DD. There are 53 genes that show mutational bias, including enrichments for missense ( n = 41) or truncating ( n = 12) DNVs. We also find 10 genes with evidence of male- or female-bias enrichment, including 4 X chromosome genes with significant female burden ( DDX3X , MECP2 , WDR45 , and HDAC8) . This large-scale integrative analysis identifies candidates and functional subsets of NDD genes.