Browsing by Author "Devlin, B."

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Open Access
Insights into autism spectrum disorder genomic architecture and biology from 71 risk loci
(Cell Press, 2015) Sanders, S. J.; He, X.; Willsey, A. J.; Ercan-Sencicek, A. G.; Samocha, K. E.; Cicek, A. E.; Murtha, M. T.; Bal, V. H.; Bishop, S. L.; Dong, S.; Goldberg, A. P.; Jinlu, C.; Keaney, J. F.; Keaney III, J. F.; Mandell, J. D.; Moreno-De-Luca, D.; Poultney, C. S.; Robinson, E. B.; Smith L.; Solli-Nowlan, T.; Su, M. Y.; Teran, N. A.; Walker, M. F.; Werling, D. M.; Beaudet, A. L.; Cantor, R. M.; Fombonne, E.; Geschwind, D. H.; Grice, D. E.; Lord, C.; Lowe, J. K.; Mane, S. M.; Martin, D.M.; Morrow, E. M.; Talkowski, M. E.; Sutcliffe, J. S.; Walsh, C. A.; Yu, T. W.; Ledbetter, D. H.; Martin, C. L.; Cook, E. H.; Buxbaum, J. D.; Daly, M. J.; Devlin, B.; Roeder, K.; State, M. W.
Analysis of de novo CNVs (dnCNVs) from the full Simons Simplex Collection (SSC) (N = 2,591 families) replicates prior findings of strong association with autism spectrum disorders (ASDs) and confirms six risk loci (1q21.1, 3q29, 7q11.23, 16p11.2, 15q11.2-13, and 22q11.2). The addition of published CNV data from the Autism Genome Project (AGP) and exome sequencing data from the SSC and the Autism Sequencing Consortium (ASC) shows that genes within small de novo deletions, but not within large dnCNVs, significantly overlap the high-effect risk genes identified by sequencing. Alternatively, large dnCNVs are found likely to contain multiple modest-effect risk genes. Overall, we find strong evidence that de novo mutations are associated with ASD apart from the risk for intellectual disability. Extending the transmission and de novo association test (TADA) to include small de novo deletions reveals 71 ASD risk loci, including 6 CNV regions (noted above) and 65 risk genes (FDR ≤ 0.1). Through analysis of de novo mutations in autism spectrum disorder (ASD), Sanders et al. find that small deletions, but not large deletions/duplications, contain one critical gene. Combining CNV and sequencing data, they identify 6 loci and 65 genes associated with ASD.
Open Access
Large-scale exome sequencing study implicates both developmental and functional changes in the neurobiology of autism
(Elsevier, 2020-02-06) Satterstrom, F. K.; Kosmicki, J. A.; Wang, J.; Breen, M. S.; De Rubeis, S.; An, J. - Y.; Peng, M.; Collins, R.; Grove, J.; Klei, L.; Stevens, C.; Reichert, J.; Mulhern, M. S.; Artomov, M.; Gerges, S.; Sheppard, B.; Xu, X.; Bhaduri, A.; Norman, Utku; Brand, H.; Schwartz, G.; Nguyen, R.; Guerrero, E. E.; Dias, C.; Autism Sequencing Consortium; iPSYCH-Broad Consortium; Betancur, C; Cook, E; Gallagher, L; Gill, M; Sutcliffe, J; Thurm, A; Zwick, M; State, M; Çicek, A. Ercüment; Talkowski, M; Cutler, D; Devlin, B.; Sanders, S; Roeder, K.; Daly, M; Buxbaum, J.
We present the largest exome sequencing study ofautism spectrum disorder (ASD) to date (n = 35,584total samples, 11,986 with ASD). Using an enhancedanalytical framework to integratedenovoand case-control rare variation, we identify 102 risk genes at afalse discovery rate of 0.1 or less. Of these genes, 49show higher frequencies of disruptivedenovovari-ants in individuals ascertained to have severe neuro-developmental delay, whereas 53 show higher fre-quencies in individuals ascertained to have ASD;comparing ASD cases with mutations in thesegroups reveals phenotypic differences. Expressedearly in brain development, most risk genes haveroles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelop-mental and neurophysiological changes), and 13 fallwithin loci recurrently hit by copy number variants.In cells from the human cortex, expression of riskgenes is enriched in excitatory and inhibitoryneuronal lineages, consistent with multiple paths toan excitatory-inhibitory imbalance underlying ASD.
Open Access
De novo insertions and deletions of predominantly paternal origin are associated with autism spectrum disorder
(Elsevier, 2014) Dong, S.; Walker, M.F.; Carriero, N.J.; DiCola, M.; Willsey, A.; Ye, A.Y.; Waqar, Z.; Gonzalez L.E.; Overton J.D.; Frahm, S.; Keaney J.F.; III, Teran, N.A.; Dea J.; Mandell J.D.; HusBal V.; Sullivan, C.A.; DiLullo, N.M.; Khalil, R.O.; Gockley J.; Yuksel, Z.; Sertel, S.M.; Ercan-Sencicek, A.G.; Gupta, A.R.; Mane, S.M.; Sheldon, M.; Brooks, A.I.; Roeder, K.; Devlin, B.; State, M.W.; Wei L.; Sanders, S.J.
Whole-exome sequencing (WES) studies have demonstrated the contribution of de novo loss-of-function single-nucleotide variants (SNVs) to autism spectrum disorder (ASD). However, challenges in the reliable detection of de novo insertions and deletions (indels) have limited inclusion of these variants in prior analyses. By applying a robust indel detection method to WES data from 787 ASD families (2,963 individuals), we demonstrate that de novo frameshift indels contribute to ASD risk (OR= 1.6; 95% CI= 1.0-2.7; p= 0.03), are more common in female probands (p= 0.02), are enriched among genes encoding FMRP targets (p= 6× 10-9), and arise predominantly on the paternal chromosome (p< 0.001). On the basis of mutation rates in probands versus unaffected siblings, we conclude that de novo frameshift indels contribute to risk in approximately 3% of individuals with ASD. Finally, by observing clustering of mutations in unrelated probands, we uncover two ASD-associated genes: KMT2E (MLL5), a chromatin regulator, and RIMS1, a regulator of synaptic vesicle release. © 2014 The Authors.
Open Access
De novo missense variants disrupting protein–protein interactions affect risk for autism through gene co-expression and protein networks in neuronal cell types
(BioMed Central, 2020) Chen, S.; Wang, J.; Çiçek, Ercüment; Roeder, K.; Yu, H.; Devlin, B.
Background: Whole-exome sequencing studies have been useful for identifying genes that, when mutated, affect risk for autism spectrum disorder (ASD). Nonetheless, the association signal primarily arises from de novo protein-truncating variants, as opposed to the more common missense variants. Despite their commonness in humans, determining which missense variants affect phenotypes and how remains a challenge. We investigate the functional relevance of de novo missense variants, specifically whether they are likely to disrupt protein interactions, and nominate novel genes in risk for ASD through integrated genomic, transcriptomic, and proteomic analyses. Methods: Utilizing our previous interactome perturbation predictor, we identify a set of missense variants that are likely disruptive to protein–protein interactions. For genes encoding the disrupted interactions, we evaluate their expression patterns across developing brains and within specific cell types, using both bulk and inferred cell-type-specific brain transcriptomes. Connecting all disrupted pairs of proteins, we construct an “ASD disrupted network.” Finally, we integrate protein interactions and cell-type-specific co-expression networks together with published association data to implicate novel genes in ASD risk in a cell-type-specific manner. Results: Extending earlier work, we show that de novo missense variants that disrupt protein interactions are enriched in individuals with ASD, often affecting hub proteins and disrupting hub interactions. Genes encoding disrupted complementary interactors tend to be risk genes, and an interaction network built from these proteins is enriched for ASD proteins. Consistent with other studies, genes identified by disrupted protein interactions are expressed early in development and in excitatory and inhibitory neuronal lineages. Using inferred gene co-expression for three neuronal cell types—excitatory, inhibitory, and neural progenitor—we implicate several hundred genes in risk (FDR ≤≤0.05), ~ 60% novel, with characteristics of genuine ASD genes. Across cell types, these genes affect neuronal morphogenesis and neuronal communication, while neural progenitor cells show strong enrichment for development of the limbic system. Limitations: Some analyses use the imperfect guilt-by-association principle; results are statistical, not functional. Conclusions: Disrupted protein interactions identify gene sets involved in risk for ASD. Their gene expression during brain development and within cell types highlights how they relate to ASD.
Open Access
Whole-genome and RNA sequencing reveal variation and transcriptomic coordination in the developing human prefrontal cortex
(Elsevier, 2020-04) Werling, D. M.; Pochareddy, S.; Choi, J.; An, J.-Y.; Sheppard, B.; Peng, M.; Li, Z.; Dastmalchi, C.; Santpere, G.; Sousa, A. M. M.; Tebbenkamp, A. T. N.; Kaur, N.; Gulden, F. O.; Breen, M. S.; Liang, L.; Gilson, M. C.; Zhao, X.; Dong, S.; Klei, L.; Çiçek, A. Ercüment; Buxbaum, J. D.; Adle-Biassette, H.; Thomas, J.-L.; Aldinger, K. A.; O’Day, D. R.; Glass, I. A.; Zaitlen, N. A.; Talkowski, M. E.; Roeder, K.; State, M. W.; Devlin, B.; Sanders, S. J.; Sestan, N.
Gene expression levels vary across developmental stage, cell type, and region in the brain. Genomic variants also contribute to the variation in expression, and some neuropsychiatric disorder loci may exert their effects through this mechanism. To investigate these relationships, we present BrainVar, a unique resource of paired whole-genome and bulk tissue RNA sequencing from the dorsolateral prefrontal cortex of 176 individuals across prenatal and postnatal development. Here we identify common variants that alter gene expression (expression quantitative trait loci [eQTLs]) constantly across development or predominantly during prenatal or postnatal stages. Both “constant” and “temporal-predominant” eQTLs are enriched for loci associated with neuropsychiatric traits and disorders and colocalize with specific variants. Expression levels of more than 12,000 genes rise or fall in a concerted late-fetal transition, with the transitional genes enriched for cell-type-specific genes and neuropsychiatric risk loci, underscoring the importance of cataloging developmental trajectories in understanding cortical physiology and pathology.