An analytical framework for whole-genome sequence association studies and its implications for autism spectrum disorder

Donna M. Werling; Harrison Brand; Joon Yong An; Matthew R. Stone; Lingxue Zhu; Joseph T. Glessner; Ryan L. Collins; Shan Dong; Ryan M. Layer; Eirene Markenscoff-Papadimitriou; Andrew Farrell; Grace B. Schwartz; Harold Z. Wang; Benjamin B. Currall; Xuefang Zhao; Jeanselle Dea; Clif Duhn; Carolyn A. Erdman; Michael C. Gilson; Rachita Yadav; Robert E. Handsaker; Seva Kashin; Lambertus Klei; Jeffrey D. Mandell; Tomasz J. Nowakowski; Yuwen Liu; Sirisha Pochareddy; Louw Smith; Michael F. Walker; Matthew J. Waterman; Xin He; Arnold R. Kriegstein; John L. Rubenstein; Nenad Sestan; Steven A. McCarroll; Benjamin M. Neale; Hilary Coon; A. Jeremy Willsey; Joseph D. Buxbaum; Mark J. Daly; Matthew W. State; Aaron R. Quinlan; Gabor T. Marth; Kathryn Roeder; Bernie Devlin; Michael E. Talkowski; Stephan J. Sanders

doi:10.1038/s41588-018-0107-y

An analytical framework for whole-genome sequence association studies and its implications for autism spectrum disorder

Donna M. Werling, Harrison Brand, Joon Yong An, Matthew R. Stone, Lingxue Zhu, Joseph T. Glessner, Ryan L. Collins, Shan Dong, Ryan M. Layer, Eirene Markenscoff-Papadimitriou, Andrew Farrell, Grace B. Schwartz, Harold Z. Wang, Benjamin B. Currall, Xuefang Zhao, Jeanselle Dea, Clif Duhn, Carolyn A. Erdman, Michael C. Gilson, Rachita YadavRobert E. Handsaker, Seva Kashin, Lambertus Klei, Jeffrey D. Mandell, Tomasz J. Nowakowski, Yuwen Liu, Sirisha Pochareddy, Louw Smith, Michael F. Walker, Matthew J. Waterman, Xin He, Arnold R. Kriegstein, John L. Rubenstein, Nenad Sestan, Steven A. McCarroll, Benjamin M. Neale, Hilary Coon, A. Jeremy Willsey, Joseph D. Buxbaum, Mark J. Daly, Matthew W. State, Aaron R. Quinlan, Gabor T. Marth, Kathryn Roeder, Bernie Devlin, Michael E. Talkowski, Stephan J. Sanders

Research output: Contribution to journal › Article › peer-review

74 Citations (Scopus)

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.

Original language	English
Pages (from-to)	727-736
Number of pages	10
Journal	Nature Genetics
Volume	50
Issue number	5
DOIs	https://doi.org/10.1038/s41588-018-0107-y
Publication status	Published - 2018 May 1
Externally published	Yes

ASJC Scopus subject areas

Genetics

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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., ... Sanders, S. J. (2018). An analytical framework for whole-genome sequence association studies and its implications for autism spectrum disorder. Nature Genetics, 50(5), 727-736. https://doi.org/10.1038/s41588-018-0107-y

An analytical framework for whole-genome sequence association studies and its implications for autism spectrum disorder. / 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.; Wang, Harold Z.; Currall, Benjamin B.; Zhao, Xuefang; Dea, Jeanselle; Duhn, Clif; Erdman, Carolyn A.; Gilson, Michael C.; Yadav, Rachita; Handsaker, Robert E.; Kashin, Seva; Klei, Lambertus; Mandell, Jeffrey D.; Nowakowski, Tomasz J.; Liu, Yuwen; Pochareddy, Sirisha; Smith, Louw; Walker, Michael F.; Waterman, Matthew J.; 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.

In: Nature Genetics, Vol. 50, No. 5, 01.05.2018, p. 727-736.

Research output: Contribution to journal › Article › peer-review

Werling, DM, Brand, H, An, JY, Stone, MR, Zhu, L, Glessner, JT, Collins, RL, Dong, S, Layer, RM, Markenscoff-Papadimitriou, E, Farrell, A, Schwartz, GB, Wang, HZ, Currall, BB, Zhao, X, Dea, J, Duhn, C, Erdman, CA, Gilson, MC, Yadav, R, Handsaker, RE, Kashin, S, Klei, L, Mandell, JD, Nowakowski, TJ, Liu, Y, Pochareddy, S, Smith, L, Walker, MF, Waterman, MJ, He, X, Kriegstein, AR, Rubenstein, JL, Sestan, N, McCarroll, SA, Neale, BM, Coon, H, Willsey, AJ, Buxbaum, JD, Daly, MJ, State, MW, Quinlan, AR, Marth, GT, Roeder, K, Devlin, B, Talkowski, ME & Sanders, SJ 2018, 'An analytical framework for whole-genome sequence association studies and its implications for autism spectrum disorder', Nature Genetics, vol. 50, no. 5, pp. 727-736. https://doi.org/10.1038/s41588-018-0107-y

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. ; Wang, Harold Z. ; Currall, Benjamin B. ; Zhao, Xuefang ; Dea, Jeanselle ; Duhn, Clif ; Erdman, Carolyn A. ; Gilson, Michael C. ; Yadav, Rachita ; Handsaker, Robert E. ; Kashin, Seva ; Klei, Lambertus ; Mandell, Jeffrey D. ; Nowakowski, Tomasz J. ; Liu, Yuwen ; Pochareddy, Sirisha ; Smith, Louw ; Walker, Michael F. ; Waterman, Matthew J. ; 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. / An analytical framework for whole-genome sequence association studies and its implications for autism spectrum disorder. In: Nature Genetics. 2018 ; Vol. 50, No. 5. pp. 727-736.

@article{d76e7916c5a848e5a48e289abf070a36,

title = "An analytical framework for whole-genome sequence association studies and its implications for autism spectrum disorder",

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.",

author = "Werling, {Donna M.} and Harrison Brand and An, {Joon Yong} and Stone, {Matthew R.} and Lingxue Zhu and Glessner, {Joseph T.} and Collins, {Ryan L.} and Shan Dong and Layer, {Ryan M.} and Eirene Markenscoff-Papadimitriou and Andrew Farrell and Schwartz, {Grace B.} and Wang, {Harold Z.} and Currall, {Benjamin B.} and Xuefang Zhao and Jeanselle Dea and Clif Duhn and Erdman, {Carolyn A.} and Gilson, {Michael C.} and Rachita Yadav and Handsaker, {Robert E.} and Seva Kashin and Lambertus Klei and Mandell, {Jeffrey D.} and Nowakowski, {Tomasz J.} and Yuwen Liu and Sirisha Pochareddy and Louw Smith and Walker, {Michael F.} and Waterman, {Matthew J.} and Xin He and Kriegstein, {Arnold R.} and Rubenstein, {John L.} and Nenad Sestan and McCarroll, {Steven A.} and Neale, {Benjamin M.} and Hilary Coon and Willsey, {A. Jeremy} and Buxbaum, {Joseph D.} and Daly, {Mark J.} and State, {Matthew W.} and Quinlan, {Aaron R.} and Marth, {Gabor T.} and Kathryn Roeder and Bernie Devlin and Talkowski, {Michael E.} and Sanders, {Stephan J.}",

note = "Funding Information: We are grateful to the families participating in the Simons Foundation Autism Research Initiative (SFARI) Simplex Collection (SSC). This work was supported by grants from the Simons Foundation for Autism Research Initiative (SFARI 385110 to N.S., A.J.W., M.W.S., S.J.S.; 385027 to M.E.T., J.D.B., B.D., M.J.D., X.H., K.R.; 388196 to G.M., H.C., A.R.Q.; and 346042 to M.E.T.), the US National Institutes of Health (R37MH057881 and U01MH111658 to B.D. and K.R.; HD081256 and GM061354 to M.E.T.; U01MH105575 to M.W.S.; U01MH111662 to M.W.S. and S.J.S.; R01MH110928 and U01MH100239-03S1 to M.W.S., S.J.S., A.J.W.; U01MH111661 to J.D.B.; K99DE026824 to H.B.; U01MH100229 to M.J.D.), the Autism Science Foundation to D.M.W., and the March of Dimes to M.E.T. M.E.T. was also supported by the Desmond and Ann Heathwood MGH Research Scholars award. We thank the SSC principal investigators (A. L. Beaudet, R. Bernier, J. Constantino, E. H. Cook Jr, E. Fombonne, D. Geschwind, D. E. Grice, A. Klin, D. H. Ledbetter, C. Lord, C. L. Martin, D. M. Martin, R. Maxim, J. Miles, O. Ousley, B. Peterson, J. Piggot, C. Saulnier, M. W. State, W. Stone, J. S. Sutcliffe, C. A. Walsh, and E. Wijsman) and the coordinators and staff at the SSC clinical sites; the SFARI staff, in particular N. Volfovsky; D. B. Goldstein for contributing to the experimental design; the Rutgers University Cell and DNA repository for accessing biomaterials; and the New York Genome Center for generating the WGS data.",

year = "2018",

month = may,

day = "1",

doi = "10.1038/s41588-018-0107-y",

language = "English",

volume = "50",

pages = "727--736",

journal = "Nature Genetics",

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TY - JOUR

T1 - An analytical framework for whole-genome sequence association studies and its implications for autism spectrum disorder

AU - Werling, Donna M.

AU - Brand, Harrison

AU - An, Joon Yong

AU - Stone, Matthew R.

AU - Zhu, Lingxue

AU - Glessner, Joseph T.

AU - Collins, Ryan L.

AU - Dong, Shan

AU - Layer, Ryan M.

AU - Markenscoff-Papadimitriou, Eirene

AU - Farrell, Andrew

AU - Schwartz, Grace B.

AU - Wang, Harold Z.

AU - Currall, Benjamin B.

AU - Zhao, Xuefang

AU - Dea, Jeanselle

AU - Duhn, Clif

AU - Erdman, Carolyn A.

AU - Gilson, Michael C.

AU - Yadav, Rachita

AU - Handsaker, Robert E.

AU - Kashin, Seva

AU - Klei, Lambertus

AU - Mandell, Jeffrey D.

AU - Nowakowski, Tomasz J.

AU - Liu, Yuwen

AU - Pochareddy, Sirisha

AU - Smith, Louw

AU - Walker, Michael F.

AU - Waterman, Matthew J.

AU - He, Xin

AU - Kriegstein, Arnold R.

AU - Rubenstein, John L.

AU - Sestan, Nenad

AU - McCarroll, Steven A.

AU - Neale, Benjamin M.

AU - Coon, Hilary

AU - Willsey, A. Jeremy

AU - Buxbaum, Joseph D.

AU - Daly, Mark J.

AU - State, Matthew W.

AU - Quinlan, Aaron R.

AU - Marth, Gabor T.

AU - Roeder, Kathryn

AU - Devlin, Bernie

AU - Talkowski, Michael E.

AU - Sanders, Stephan J.

N1 - Funding Information: We are grateful to the families participating in the Simons Foundation Autism Research Initiative (SFARI) Simplex Collection (SSC). This work was supported by grants from the Simons Foundation for Autism Research Initiative (SFARI 385110 to N.S., A.J.W., M.W.S., S.J.S.; 385027 to M.E.T., J.D.B., B.D., M.J.D., X.H., K.R.; 388196 to G.M., H.C., A.R.Q.; and 346042 to M.E.T.), the US National Institutes of Health (R37MH057881 and U01MH111658 to B.D. and K.R.; HD081256 and GM061354 to M.E.T.; U01MH105575 to M.W.S.; U01MH111662 to M.W.S. and S.J.S.; R01MH110928 and U01MH100239-03S1 to M.W.S., S.J.S., A.J.W.; U01MH111661 to J.D.B.; K99DE026824 to H.B.; U01MH100229 to M.J.D.), the Autism Science Foundation to D.M.W., and the March of Dimes to M.E.T. M.E.T. was also supported by the Desmond and Ann Heathwood MGH Research Scholars award. We thank the SSC principal investigators (A. L. Beaudet, R. Bernier, J. Constantino, E. H. Cook Jr, E. Fombonne, D. Geschwind, D. E. Grice, A. Klin, D. H. Ledbetter, C. Lord, C. L. Martin, D. M. Martin, R. Maxim, J. Miles, O. Ousley, B. Peterson, J. Piggot, C. Saulnier, M. W. State, W. Stone, J. S. Sutcliffe, C. A. Walsh, and E. Wijsman) and the coordinators and staff at the SSC clinical sites; the SFARI staff, in particular N. Volfovsky; D. B. Goldstein for contributing to the experimental design; the Rutgers University Cell and DNA repository for accessing biomaterials; and the New York Genome Center for generating the WGS data.

PY - 2018/5/1

Y1 - 2018/5/1

N2 - 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.

AB - 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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