Browsing by Author "Werling, D. M."

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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
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.