Integrated gene analyses of de novo variants from 46,612 trios with autism and developmental disorders
Authors: Wang Tianyun , Kim Chang N. , Bakken Trygve E. , Gillentine Madelyn A. , Henning Barbara , Mao Yafei , Gilissen Christian ,   The SPARK Consortium, 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 Swami , 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 , Eichler Evan E. , 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. , Pepper Micah , Ho Theodore , Cho Daniel , Piven Joseph , Lechniak Holly , Soorya Latha V. , Gordon Rachel , Wainer Allison , Yeh Lisa , Ochoa-Lubinoff Cesar , Russo Nicole , Berry-Kravis Elizabeth , Booker Stephanie , Erickson Craig A. , Prock Lisa M. , Pawlowski Katherine G. , Matthews Emily T. , Brewster Stephanie J. , Hojlo Margaret A. , Abada Evi , Lamarche Elena , Wang Tianyun , Murali Shwetha C. , Harvey William T. , Kaplan Hannah E. , Pierce Karen L. , DeMarco Lindsey , Horner Susannah , Pandey Juhi , Plate Samantha , Sahin Mustafa , Riley Katherine D. , Carmody Erin , Constantini Julia , Esler Amy , Fatemi Ali , Hutter Hanna , Landa Rebecca J. , McKenzie Alexander P. , Neely Jason , Singh Vini , Van Metre Bonnie , Wodka Ericka L. , Fombonne Eric J. , Huang-Storms Lark Y. , Pacheco Lillian D. , Mastel Sarah A. , Coppola Leigh A. , Francis Sunday , Jarrett Andrea , Jacob Suma , Lillie Natasha , Gunderson Jaclyn , Istephanous Dalia , Simon Laura , Wasserberg Ori , Rachubinski Angela L. , Rosenberg Cordelia R. , Kanne Stephen M. , Shocklee Amanda D. , Takahashi Nicole , Bridwell Shelby L. , Klimczac Rebecca L. , Mahurin Melissa A. , Cotrell Hannah E. , Grant Cortaiga A. , Hunter Samantha G. , Martin Christa Lese , Taylor Cora M. , Walsh Lauren K. , Dent Katherine A. , Mason Andrew , Sziklay Anthony , Smith Christopher J. 
Published: November 2022

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.