학술논문
Integrated gene analyses of de novo variants from 46,612 trios with autism and developmental disorders
Document Type
article
Author
Wang, Tianyun; Kim, Chang N; Bakken, Trygve E; Gillentine, Madelyn A; Henning, Barbara; Mao, Yafei; Gilissen, Christian; Consortium, The SPARK; Nowakowski, Tomasz J; Eichler, Evan E; Acampado, John; Ace, Andrea J; Amatya, Alpha; Astrovskaya, Irina; Bashar, Asif; Brooks, Elizabeth; Butler, Martin E; Cartner, Lindsey A; Chin, Wubin; Chung, Wendy K; Daniels, Amy M; Feliciano, Pamela; Fleisch, Chris; Ganesan; Jensen, William; Lash, Alex E; Marini, Richard; Myers, Vincent J; O'Connor, Eirene; Rigby, Chris; Robertson, Beverly E; Shah, Neelay; Shah, Swapnil; Singer, Emily; Snyder, LeeAnne G; Stephens, Alexandra N; Tjernagel, Jennifer; Vernoia, Brianna M; Volfovsky, Natalia; White, Loran Casey; Hsieh, Alexander; Shen, Yufeng; Zhou, Xueya; Turner, Tychele N; Bahl, Ethan; Thomas, Taylor R; Brueggeman, Leo; Koomar, Tanner; Michaelson, Jacob J; O'Roak, Brian J; Barnard, Rebecca A; Gibbs, Richard A; Muzny, Donna; Sabo, Aniko; Ahmed, Kelli L Baalman; Siegel, Matthew; Abbeduto, Leonard; Amaral, David G; Hilscher, Brittani A; Li, Deana; Smith, Kaitlin; Thompson, Samantha; Albright, Charles; Butter, Eric M; Eldred, Sara; Hanna, Nathan; Jones, Mark; Coury, Daniel Lee; Scherr, Jessica; Pifher, Taylor; Roby, Erin; Dennis, Brandy; Higgins, Lorrin; Brown, Melissa; Alessandri, Michael; Gutierrez, Anibal; Hale, Melissa N; Herbert, Lynette M; Schneider, Hoa Lam; David, Giancarla; Annett, Robert D; Sarver, Dustin E; Arriaga, Ivette; Camba, Alexies; Gulsrud, Amanda C; Haley, Monica; McCracken, James T; Sandhu, Sophia; Tafolla, Maira; Yang, Wha S; Carpenter, Laura A; Bradley, Catherine C; Gwynette, Frampton; Manning, Patricia; Shaffer, Rebecca; Thomas, Carrie; Bernier, Raphael A; Fox, Emily A; Gerdts, Jennifer A
Source
Proceedings of the National Academy of Sciences of the United States of America. 119(46)
Subject
Language
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.