Advancing the understanding of autism disease mechanisms through genetics

Torre-Ubieta, Luis de la; Won, Hyejung; Stein, Jason L.; Geschwind, Daniel H.

doi:10.1038/nm.4071

Cited by 726 publications

(646 citation statements)

References 300 publications

(304 reference statements)

Supporting

Mentioning

620

Contrasting

Unclassified

Order By: Relevance

“…The highly polygenic nature of ASD (3)(4)(5) suggests that the analysis of the full spectrum of sequence variants in hundreds of genes will be necessary for deeper understanding of disrupted neuronal function. Prioritization of ASD risk genes initially focused on known pathways with recognized relevance to pathogenesis of ASD, such as synaptic function and neuronal development (6).…”

mentioning

confidence: 99%

Increased burden of deleterious variants in essential genes in autism spectrum disorder

Xiao

Kember

Brown

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Autism spectrum disorder (ASD) is a heterogeneous, highly heritable neurodevelopmental syndrome characterized by impaired social interaction, communication, and repetitive behavior. It is estimated that hundreds of genes contribute to ASD. We asked if genes with a strong effect on survival and fitness contribute to ASD risk. Human orthologs of genes with an essential role in pre-and postnatal development in the mouse [essential genes (EGs)] are enriched for disease genes and under strong purifying selection relative to human orthologs of mouse genes with a known nonlethal phenotype [nonessential genes (NEGs)]. This intolerance to deleterious mutations, commonly observed haploinsufficiency, and the importance of EGs in development suggest a possible cumulative effect of deleterious variants in EGs on complex neurodevelopmental disorders. With a comprehensive catalog of 3,915 mammalian EGs, we provide compelling evidence for a stronger contribution of EGs to ASD risk compared with NEGs. By examining the exonic de novo and inherited variants from 1,781 ASD quartet families, we show a significantly higher burden of damaging mutations in EGs in ASD probands compared with their non-ASD siblings. The analysis of EGs in the developing brain identified clusters of coexpressed EGs implicated in ASD. Finally, we suggest a high-priority list of 29 EGs with potential ASD risk as targets for future functional and behavioral studies. Overall, we show that large-scale studies of gene function in model organisms provide a powerful approach for prioritization of genes and pathogenic variants identified by sequencing studies of human disease.essential genes | mouse knockouts | mutational burden | autism spectrum disorder | coexpression modules A utism spectrum disorder (ASD) is a heterogeneous, heritable neurodevelopmental syndrome characterized by impaired social interaction, communication, and repetitive behavior (1, 2). The highly polygenic nature of ASD (3-5) suggests that the analysis of the full spectrum of sequence variants in hundreds of genes will be necessary for deeper understanding of disrupted neuronal function. Prioritization of ASD risk genes initially focused on known pathways with recognized relevance to pathogenesis of ASD, such as synaptic function and neuronal development (6). However, combined analyses of de novo, inherited, and case-control variation in over 2,500 ASD parentchild nuclear families identified around 100 genes contributing to ASD risk (7-9), converging on pathways implicated in transcriptional regulation and chromatin modeling in addition to synaptic function.The main challenge in the current understanding of genetic architecture of ASD comes from a need to study the interplay between variants with a high effect (for example, recurrent de novo variants) and a background of variants with an intermediate effect but that nevertheless still disrupt proper neuronal development. Essential genes (EGs) or genes that are necessary for successful completion of pre-and postnatal development are prime candi...

show abstract

mentioning

confidence: 99%

Increased burden of deleterious variants in essential genes in autism spectrum disorder

Xiao

Kember

Brown

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…The interface of human genetics and neuroscience has typically focused on rare, highly penetrant variants that permit generation of transgenic animals with a robust phenotype 5,[31][32][33][34] . Neuroscientists now face the challenge of obtaining biological insights through investigation of the multiple weakly penetrant variants, identified through modern genomics, that act through unknown neurological mechanisms, in a manner highly dependent on genetic background 35 .…”

Section: Implications For Neuroscientistsmentioning

confidence: 99%

Whole Genome Sequencing in Psychiatric Disorders: the WGSPD Consortium

Sanders

Neale

Huang

et al. 2017

Preprint

View full text Add to dashboard Cite

As technology advances, whole genome sequencing (WGS) is likely to supersede other genotyping technologies. The rate of this change depends on its relative cost and utility. Variants identified uniquely through WGS may reveal novel biological pathways underlying complex disorders and provide high-resolution insight into when, where, and in which cell type these pathways are affected. Alternatively, cheaper and less computationally intensive approaches may yield equivalent insights. Understanding the role of rare variants in the noncoding gene-regulating genome, through pilot WGS projects, will be critical to determine which of these two extremes best represents reality. With large cohorts, well-defined risk loci, and a compelling need to understand the underlying biology, psychiatric disorders have a role to play in this preliminary WGS assessment. The WGSPD consortium will integrate data for 18,000 individuals with psychiatric disorders, beginning with autism spectrum disorder, schizophrenia, bipolar disorder, and major depressive disorder, along with over 150,000 controls.

show abstract

“…Early twin and family studies have shown that ASD is highly heritable [15], suggesting a strong genetic predisposition. In addition to inherited mutations, recent advances in genetics and genomics have identified a large number of de novo copy-number variations and singlebase-pair mutations in ASD patients, increasing the estimated proportion of patients with identifiable genetic mutations to 20%-40% [15][16][17][18][19][20].…”

mentioning

confidence: 99%

“…In addition to inherited mutations, recent advances in genetics and genomics have identified a large number of de novo copy-number variations and singlebase-pair mutations in ASD patients, increasing the estimated proportion of patients with identifiable genetic mutations to 20%-40% [15][16][17][18][19][20]. As many ASD genes are known to regulate brain development and/or synapse function, theories of ASD relating to synaptic dysfunction, including excitatory/inhibitory imbalance and dysfunctional feedback regulation have been proposed [15,[21][22][23][24]. Since deficits in social behavior are hallmarks of ASD, molecules and circuits underlying social behavior have received special attention [25,26].…”

mentioning

confidence: 99%

“…Rodent models of ASD, mostly mimicking the genetic abnormalities identified in patients, including lossof-function mutations, gene duplications, and mis-sense point mutations, have contributed significantly to our understanding of the synaptic, circuit, and behavioral basis of ASD [15,16,22,43,44]. A number of mouse models of syndromic ASD display social impairment and repetitive behavior, the core features of ASD, although they vary widely in additional co-morbidities, and in alternations in excitatory and inhibitory synaptic transmission in various neuronal circuits.…”

mentioning

confidence: 99%

See 1 more Smart Citation