An analytical framework for whole-genome sequence association studies and its implications for autism spectrum disorder. Werling, D. M, Brand, H., An, J., Stone, M. R, Zhu, L., Glessner, J. T, Collins, R. L, Dong, S., Layer, R. M, Markenscoff-Papadimitriou, E., Farrell, A., Schwartz, G. B, Wang, H. Z, Currall, B. B, Zhao, X., Dea, J., Duhn, C., Erdman, C. A, Gilson, M. C, Yadav, R., Handsaker, R. E, Kashin, S., Klei, L., Mandell, J. D, Nowakowski, T. J, Liu, Y., Pochareddy, S., Smith, L., Walker, M. F, Waterman, M. J, He, X., Kriegstein, A. R, Rubenstein, J. L, Sestan, N., McCarroll, S. A, Neale, B. M, Coon, H., Willsey, A J., Buxbaum, J., Daly, M. J, State, Matthew W, Quinlan, A. R, Marth, G. T, Roeder, K., Devlin, B., Talkowski, M. E, & Sanders, S. J Nat Genet, 50(5):727–736, April, 2018.
abstract   bibtex   
Genomic association studies of common or rare protein-coding variation have established robust statistical approaches to account for multiple testing. Here we present a comparable framework to evaluate rare and de novo noncoding single-nucleotide variants, insertion/deletions, and all classes of structural variation from whole-genome sequencing (WGS). Integrating genomic annotations at the level of nucleotides, genes, and regulatory regions, we define 51,801 annotation categories. Analyses of 519 autism spectrum disorder families did not identify association with any categories after correction for 4,123 effective tests. Without appropriate correction, biologically plausible associations are observed in both cases and controls. Despite excluding previously identified gene-disrupting mutations, coding regions still exhibited the strongest associations. Thus, in autism, the contribution of de novo noncoding variation is probably modest in comparison to that of de novo coding variants. Robust results from future WGS studies will require large cohorts and comprehensive analytical strategies that consider the substantial multiple-testing burden.
@ARTICLE{Werling2018-yd,
  title    = "An analytical framework for whole-genome sequence association
              studies and its implications for autism spectrum disorder",
  author   = "Werling, Donna M and Brand, Harrison and An, Joon-Yong and Stone,
              Matthew R and Zhu, Lingxue and Glessner, Joseph T and Collins,
              Ryan L and Dong, Shan and Layer, Ryan M and
              Markenscoff-Papadimitriou, Eirene and Farrell, Andrew and
              Schwartz, Grace B and Wang, Harold Z and Currall, Benjamin B and
              Zhao, Xuefang and Dea, Jeanselle and Duhn, Clif and Erdman,
              Carolyn A and Gilson, Michael C and Yadav, Rachita and Handsaker,
              Robert E and Kashin, Seva and Klei, Lambertus and Mandell,
              Jeffrey D and Nowakowski, Tomasz J and Liu, Yuwen and Pochareddy,
              Sirisha and Smith, Louw and Walker, Michael F and Waterman,
              Matthew J and He, Xin and Kriegstein, Arnold R and Rubenstein,
              John L and Sestan, Nenad and McCarroll, Steven A and Neale,
              Benjamin M and Coon, Hilary and Willsey, A Jeremy and Buxbaum,
              Jose and Daly, Mark J and {State, Matthew W} and Quinlan, Aaron R
              and Marth, Gabor T and Roeder, Kathryn and Devlin, Bernie and
              Talkowski, Michael E and Sanders, Stephan J",
  abstract = "Genomic association studies of common or rare protein-coding
              variation have established robust statistical approaches to
              account for multiple testing. Here we present a comparable
              framework to evaluate rare and de novo noncoding
              single-nucleotide variants, insertion/deletions, and all classes
              of structural variation from whole-genome sequencing (WGS).
              Integrating genomic annotations at the level of nucleotides,
              genes, and regulatory regions, we define 51,801 annotation
              categories. Analyses of 519 autism spectrum disorder families did
              not identify association with any categories after correction for
              4,123 effective tests. Without appropriate correction,
              biologically plausible associations are observed in both cases
              and controls. Despite excluding previously identified
              gene-disrupting mutations, coding regions still exhibited the
              strongest associations. Thus, in autism, the contribution of de
              novo noncoding variation is probably modest in comparison to that
              of de novo coding variants. Robust results from future WGS
              studies will require large cohorts and comprehensive analytical
              strategies that consider the substantial multiple-testing burden.",
  journal  = "Nat Genet",
  volume   =  50,
  number   =  5,
  pages    = "727--736",
  month    =  apr,
  year     =  2018,
  language = "en"
}
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