Integrated gene analyses of de novo variants from 46,612 trios with autism and developmental disorders

• DOI: 10.1073/pnas.2203491119
• Publication Date: 2022-11-09T18:48:31Z
• Authors: Tianyun Wang; Chang N. Kim; Trygve E. Bakken; Madelyn A. Gillen...; 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 Jensen; Alex E. Lash; Richard Marini; Vincent J. Myers; Eirene O'Connor; Chris Rigby; Beverly E. Robertson; Neelay Shah; Swapnil Shah; Emily Singer; LeeAnne G. Snyder; Alexandra N. Step...; Jennifer Tjernagel; Brianna M. Vernoia; Natalia Volfovsky; Loran Casey White; Alexander Hsieh; Yufeng Shen; Xueya Zhou; Tychele N. Turner; Ethan Bahl; Taylor R. Thomas; Leo Brueggeman; Tanner Koomar; Jacob J. Michaelson; Brian J. O'Roak; Rebecca A. Barnard; Richard A. Gibbs; Donna Muzny; Aniko Sabo; Kelli L. Baalman ...; Evan E. Eichler; Matthew Siegel; Leonard Abbeduto; David G. Amaral; Brittani A. Hilscher; Deana Li; Kaitlin Smith; Samantha Thompson; Charles Albright; Eric M. Butter; Sara Eldred; Nathan Hanna; Mark Jones; Daniel Lee Coury; Jessica Scherr; Taylor Pifher; Erin Roby; Brandy Dennis; Lorrin Higgins; Melissa 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 Shaffer; Carrie Thomas; Raphael A. Bernier; Emily A. Fox; Jennifer A. Gerdts; Micah Pepper; Theodore Ho; Daniel Cho; Joseph Piven; Holly Lechniak; Latha V. Soorya; Rachel Gordon; Allison Wainer; Lisa Yeh; Cesar Ochoa-Lubinoff; Nicole Russo; Elizabeth Berry-K...; Stephanie Booker; Craig A. Erickson; Lisa M. Prock; Katherine G. Pawl...; Emily T. Matthews; Stephanie J. Brew...; Margaret A. Hojlo; Evi Abada; Elena Lamarche; Tianyun Wang; Shwetha C. Murali; William T. Harvey; Hannah E. Kaplan; Karen L. Pierce; Lindsey DeMarco; Susannah Horner; Juhi Pandey; Samantha Plate; Mustafa Sahin; Katherine D. Riley; Erin Carmody; Julia Constantini; Amy Esler; Ali Fatemi; Hanna Hutter; Rebecca J. Landa; Alexander P. McKe...; Jason Neely; Vini Singh; Bonnie Van Metre; Ericka L. Wodka; Eric J. Fombonne; Lark Y. Huang-Storms; Lillian D. Pacheco; Sarah A. Mastel; Leigh A. Coppola; Sunday Francis; Andrea Jarrett; Suma Jacob; Natasha Lillie; Jaclyn Gunderson; Dalia Istephanous; Laura Simon; Ori Wasserberg; Angela L. Rachubi...; Cordelia R. Rosen...; Stephen M. Kanne; Amanda D. Shocklee; Nicole Takahashi; Shelby L. Bridwell; Rebecca L. Klimczac; Melissa A. Mahurin; Hannah E. Cotrell; Cortaiga A. Grant; Samantha G. Hunter; Christa Lese Martin; Cora M. Taylor; Lauren K. Walsh; Katherine A. Dent; Andrew Mason; Anthony Sziklay; Christopher J. Smith
• Keywords: Heritability of autism

Most genetic studies consider autism spectrum disorder (ASD) and developmental (DD) separately despite overwhelming comorbidity shared etiology. Here, we analyzed de novo variants (DNVs) from 15,560 ASD (6,557 SPARK) 31,052 DD trios independently 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 The group into five functional networks associating with different brain lineages based on single-cell nuclei transcriptomic data. find no evidence for ASD-specific contrast to 18 significantly enriched DD. There are 53 that show mutational bias, enrichments missense (n = 41) or truncating 12) DNVs. 10 of male- female-bias enrichment, 4 X chromosome significant female burden (DDX3X, MECP2, WDR45, HDAC8). This large-scale integrative analysis identifies candidates subsets genes.