The DOI matches its Crossref record; 83 of the 83 references it cites were found in a registry or an index.
An analytical framework for whole-genome sequence association studies and its implications for autism spectrum disorder
Open accessAbstract
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.
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“even its application leaves the majority of ASD cases “genetically unsolved”2,19–21.”
From Genome-wide detection of tandem DNA repeats that are expanded in autism (2020) · cites this paper as [21]
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Long-read sequencing for neurological disorders: opportunities, challenges, and future directions
Geiger, H. U., Furuta, Y., Perera, B. L. A., Stewart, R., Tinker, R. J., & Phillips, J. A. (2026) · Neurological Sciences · doi:10.1007/s10072-026-09283-y
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Metadata
- Authors
- Werling, D. M., Brand, H., An, J.-Y., 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. D., Daly, M. J., State, M. W., Quinlan, A. R., Marth, G. T., Roeder, K., Devlin, B., Talkowski, M. E., & Sanders, S. J.
- Affiliations
- University of California, San Francisco (US)
- Broad Institute (US)
- Massachusetts General Hospital (US)
- Carnegie Mellon University (US)
- Harvard University (US)
- University of Utah (US)
- University of Pittsburgh (US)
- University of Chicago (US)
- Yale University (US)
- Eastern Nazarene College (US)
- Icahn School of Medicine at Mount Sinai (US)
- Corresponding author
- Devlin, Bernie
- Talkowski, Michael E.
- Sanders, Stephan J.
- ORCID
- Werling, Donna M.
- Brand, Harrison
- An, Joon-Yong
- Stone, Matthew R.
- Zhu, Lingxue
- Glessner, Joseph T.
- Collins, Ryan L.
- Dong, Shan
- Layer, Ryan M.
- Markenscoff-Papadimitriou, Eirene
- Farrell, Andrew
- Schwartz, Grace B.
- Currall, Benjamin B.
- Zhao, Xuefang
- Dea, Jeanselle
- Duhn, Clif
- Gilson, Michael C.
- Yadav, Rachita
- Handsaker, Robert E.
- Kashin, Seva
- Klei, Lambertus
- Mandell, Jeffrey D.
- Nowakowski, Tomasz J.
- Liu, Yuwen
- Pochareddy, Sirisha
- He, Xin
- Kriegstein, Arnold R.
- Rubenstein, John L.
- Sestan, Nenad
- McCarroll, Steven A.
- Neale, Benjamin M.
- Coon, Hilary
- Willsey, A. Jeremy
- Buxbaum, Joseph D.
- Daly, Mark J.
- State, Matthew W.
- Quinlan, Aaron R.
- Marth, Gabor T.
- Roeder, Kathryn
- Devlin, Bernie
- Talkowski, Michael E.
- Sanders, Stephan J.
- Venue
- Nature Genetics
- Published
- 2018-04-26
- Volume
- 50
- Issue
- 5
- Pages
- 727-736
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC5961723
- OpenAlex
- W2799448805
- Cited by
- 293
- References
- 81
- Citations by year
- 2026: 11 · 2025: 27 · 2024: 21 · 2023: 40 · 2022: 42 · 2021: 52 · 2020: 40 · 2019: 40 · 2018: 20
- FWCI
- 22.78
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- March of Dimes Foundation
- Simons Foundation Autism Research Initiative
- National Institutes of Health (388196, GM061354, HD081256)
- National Institute of Mental Health (U01MH111661, U01MH100229, R01MH109900, R01MH109904, U01MH111658, R01MH109901, R37MH057881, U01MH100239, U01MH111662, U01MH111660, R01MH110928, U01MH105575)
- National Institute of General Medical Sciences (P01GM061354)
- National Institute of Neurological Disorders and Stroke (R35NS097305)
- National Institute of Dental and Craniofacial Research (K99DE026824)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD081256)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- autism spectrum disorder, whole genome sequencing, de novo mutations, structural variants, insertion-deletion variants, multiple testing correction, genome annotation, regulatory elements, statistical power
- MeSH terms
- Autism Spectrum Disorder, Female, Humans, Male, Genome, Genetic Predisposition to Disease, Protein Isoforms, Polymorphism, Single Nucleotide, INDEL Mutation, Genome-Wide Association Study
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