Genome-wide de novo risk score implicates promoter variation in autism spectrum disorder

Abstract

Whole-genome sequencing (WGS) has facilitated the first genome-wide evaluations of the contribution of de novo noncoding mutations to complex disorders. Using WGS, we assess genetic variation from 7,608 samples in 1,902 autism spectrum disorder (ASD) families, identifying 255,106 de novo mutations. In contrast to coding mutations, no noncoding functional annotation category, analyzed in isolation, is significantly associated with ASD. Casting noncoding variation in the context of a de novo risk score across multiple annotation categories, however, does demonstrate association with mutations localized to promoter regions. The strongest driver of this promoter signal emanates from evolutionarily conserved transcription factor binding sites distal to the transcription start site. These data suggest that de novo mutations in promoter regions, characterized by evolutionary and functional signatures, contribute to ASD.

De novo variants in population constrained fetal brain enhancers and intellectual disability

“…An average of 60 high quality DNVs per proband were identified, which includes 55.2 SNVs and 4.8 indels per proband (Table S2). The number of DNVs identified in this study is similar to the number of DNVs identified per proband in previous GS studies on neurodevelopmental disorders 4,11,37 . It has been shown that de novo copy number variants (CNVs) play a significant role in severe ID 4 .…”

“…Aggregation of a minority of disease-causing variants with the majority of benign regulatory variants nullifies any signal from disease-causing variants in non proteincoding genomic regions in disease cohorts. It is noteworthy that in protein coding regions of the genome only protein-truncating variants, but not other protein-coding variants, show significant enrichment in neurodevelopmental disorders 11,67 . The analysis of DNVs in selected monogenic phenotypes provides a powerful analysis instrument, because it can focus on a relatively small number of variants that have increased likelihood of being disease-causing.…”

“…A systematic analysis of variants in evolutionarily ultra-conserved regions of the genome has estimated that around 1-3% of the developmental disorder patients without disease-causing coding variants would carry disease-causing DNVs in fetal brain-active regulatory elements 10 . A large-scale genome sequencing of patients with autism spectrum disorder (ASD) demonstrate that DNVs in conserved promoter regions contribute to ASD, while no significant association was found between enhancer variants and ASD 11 .…”

“…Simons Simplex Collection (SSC) has sequenced GS of 1,902 ASD families (quads)11 , while the MSSNG database has compiled GS of 2,281 ASD trios37 . Within the SSC cohort, four DNVs from four unrelated ASD cases were located in the CSMD1 enhancer cluster, while no DNVs in the CSMD1 enhancer cluster were found in 1,902 unaffected siblings.…”

Cross-species regulatory sequence activity prediction

“…To explore the utility of this procedure for studying human disease, we retrieved a recent dataset of 1902 quartet families from the Simons Simplex Collection (28) with whole genome sequencing of a mother, father, child affected by autism, and unaffected sibling. In these data, the offspring have an average of 67 de novo mutations, which have a slight enrichment in promoters (29). Recent work demonstrated that variant effect predictions further differentiate autism cases from their unaffected sibling controls (30).…”