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 mutations (DNMs) from 15,560 ASD (6,557 are new) and 31,052 DD trios independently and combined as broader neurodevelopmental disorders (NDD) using three models. We identify 615 candidate genes (FDR 5%, 189 potentially novel) by one or more models, including 138 reaching exome-wide significance (p < 3.64e-07) in all models. We find no evidence for ASD-specific genes in contrast to 18 genes significantly enriched for DD. There are 53 genes show particular mutational-bias including enrichments for missense (n=41) or truncating DNM (n=12). We find 22 genes with evidence of sex-bias including five X chromosome genes also with significant female burden (DDX3X, MECP2, SMC1A, WDR45, and HDAC8). NDD risk genes group into five functional networks associating with different brain developmental lineages based on single-cell nuclei transcriptomic data, which provides important insights into disease subtypes and future functional studies.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
↵† A full list of consortium members appears at the end of the paper.
ABBREVIATIONS
- DNM
- de novo mutation
- NDD
- Neurodevelopmental disorder
- ASD
- Autism spectrum disorder
- DD
- Developmental disorder
- ID
- Intellectual disability
- WES
- Whole-exome sequencing
- WGS
- Whole-genome sequencing
- CCDG
- Centers for Common Disease Genomics
- SFARI
- Simons Foundation Autism Research Initiative
- SPARK
- Simons Foundation Powering Autism Research for Knowledge
- SSC
- Simons Simplex Collection
- ASC
- Autism Sequencing Consortium
- DDD
- Deciphering Developmental Disorders
- RUMC
- Radboud University Medical Center
- CADD score
- combined annotation dependent depletion score
- LGD
- likely gene-disruptive
- dnLGD
- de novo LGD variant
- dnSYN
- de novo synonymous variant
- dnMIS
- de novo missense variant
- dnMIS30
- de novo missense variant with CADD score greater than 30
- FDR
- False discovery rate
- FWER
- Family-wise error rate
- PPI
- Protein-protein interaction
- CSEA
- Cell-type-specific expression analysis
- TSEA
- Tissue-specific expression analysis
- DDG2P
- Development Disorder Genotype - Phenotype Database
- OMIM
- Online Mendelian Inheritance in Man
- LC615
- The 615 genes are with a lower confidence at the union significance (FDR 5%) by one or more of the three models
- HC138
- The 138 genes are with the highest confidence at the intersection significance (FWER 5%) supported by all three models, which are a subset of the LC615 genes