Statistical and functional convergence of common and rare genetic influences on autism at chromosome 16p

iPSYCH Consortium; ASD Working Group of the Psychiatric Genomics Consortium; ADHD Working Group of the Psychiatric Genomics Consortium

doi:10.1038/s41588-022-01203-y

Statistical and functional convergence of common and rare genetic influences on autism at chromosome 16p

iPSYCH Consortium
, ASD Working Group of the Psychiatric Genomics Consortium
, ADHD Working Group of the Psychiatric Genomics Consortium

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

The canonical paradigm for converting genetic association to mechanism involves iteratively mapping individual associations to the proximal genes through which they act. In contrast, in the present study we demonstrate the feasibility of extracting biological insights from a very large region of the genome and leverage this strategy to study the genetic influences on autism. Using a new statistical approach, we identified the 33-Mb p-arm of chromosome 16 (16p) as harboring the greatest excess of autism’s common polygenic influences. The region also includes the mechanistically cryptic and autism-associated 16p11.2 copy number variant. Analysis of RNA-sequencing data revealed that both the common polygenic influences within 16p and the 16p11.2 deletion were associated with decreased average gene expression across 16p. The transcriptional effects of the rare deletion and diffuse common variation were correlated at the level of individual genes and analysis of Hi-C data revealed patterns of chromatin contact that may explain this transcriptional convergence. These results reflect a new approach for extracting biological insight from genetic association data and suggest convergence of common and rare genetic influences on autism at 16p.

Original language	English
Pages (from-to)	1630-1639
Number of pages	10
Journal	Nature genetics
Volume	54
Issue number	11
Early online date	24 Oct 2022
DOIs	https://doi.org/10.1038/s41588-022-01203-y
Publication status	Published - Nov 2022

Bibliographical note

Funding Information:
We thank the following for their generous support of this work: the SFARI (grant no. 704413 to E.B.R. and L.J.O.), the NIMH (grant nos. F30MH129009 to D.J.W., R01MH111813 to E.B.R., R01MH115957 to M.E.T. and 1R01MH124851-01 to A.D.B.), the National Institute of General Medical Sciences (grant nos. T32GM007753 and T32GM144273 to A.N. and D.J.W.), the National Institute of Child Health and Development (grant no. R01HD096326 to M.E.T.), the National Institute of Neurological Disorders and Stroke (grant no. R01NS093200 to M.E.T.), the National Library of Medicine (grant no. T15LM007092 to D.J.W.), the Lundbeck Foundation (grant nos. R102-A9118, R155-2014-1724, and R248-2017-2003 to iPSYCH), the Novo Nordisk Foundation (to the Danish National Biobank) and the universities and university hospitals of Aarhus and Copenhagen. High-performance computer capacity for handling and statistical analysis of iPSYCH data on the GenomeDK HPC facility was provided by the Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing, iSEQ, Aarhus University, Denmark through a grant to A.D.B. Human tissue was obtained from the NIH NeuroBioBank. We thank all the families who participated in the cohorts included in this analysis, without whom this work would not have been possible. We also thank R. Collins and R. Walters for their assistance with these analyses. Finally, we thank the following members of the ADHD Working Group of the PGC: A. R. Hammerschlag, A. Corsico, A. Havdahl, A. Todorov, A. Charach, A. Ashley-Koch, A. Doyle, A. Hervas, A. Miranda, A. Borglum, A. Scherag, A. Thapar, A. Rommel, A. Starnawska, A. Wheeler, A. Rothenberger, A. Arnatkeviciute, B. Franke, B. Neale, C. Liao, C. Hartman, C. Burton, C. Cornforth, C. Bandeira, C. Bau, C. Sanchez, D. Posthuma, F. Cerrato, F. Mulas, F. Degenhardt, G. C. A. Martins, G. P. Stromstad Knudsen, H. C. Steinhausen, H. Hakonarson, H.-C. Steinhausen, H. Roeyers, H.-W. Kim, I. Gizer, I. Waldman, I. Brikell, J. Crosbie, J. Agnew-Blais, J. Martin, J. Gelernter, J. Hebebrand, J. A. Ramos-Quiroga, J. Biederman, J. Sergeant, J. Gamble, J. Pinsonneault, J. Deckert, K. Langley, L. Yang, L. Kent, L. Rohde, M. Mattheisen, M. J. Arranz Calderun, M. Soler Artigas, M. Ribases, M. Mariano, M. Gill, M. O’Donovan, M. Casas, M. Bayes, N. Martin, N. P. Ole Mors, N. Williams, N. Roth Mota, O. A. Andreassen, P. Sham, P. Sullivan, P. Arnold, P. Lichtenstein, P. Rovira, P. Holmans, P. Asherson, P. B. Mortensen, R. Guerra, R. Walters, R. Anney, R. Ebstein, R. Karlsson Linnér, R. Joober, R. Oades, R. Schachar, S. M. Sengupta, S. Johansson, S. H. Witt, S. Nelson, S. Smalley, S. Scherag, T. Zayats, T. Werge, T. Silk, T. Polderman, T. Banaschewski, T. Altar, V. Manikandan, Y. Zhang, Y. Athanasiadis and Y. Wang. Support for the title page creation and format was provided by AuthorArranger, a tool developed at the National Cancer Institute.

Publisher Copyright:
© 2022, The Author(s).

Funding

We thank the following for their generous support of this work: the SFARI (grant no. 704413 to E.B.R. and L.J.O.), the NIMH (grant nos. F30MH129009 to D.J.W., R01MH111813 to E.B.R., R01MH115957 to M.E.T. and 1R01MH124851-01 to A.D.B.), the National Institute of General Medical Sciences (grant nos. T32GM007753 and T32GM144273 to A.N. and D.J.W.), the National Institute of Child Health and Development (grant no. R01HD096326 to M.E.T.), the National Institute of Neurological Disorders and Stroke (grant no. R01NS093200 to M.E.T.), the National Library of Medicine (grant no. T15LM007092 to D.J.W.), the Lundbeck Foundation (grant nos. R102-A9118, R155-2014-1724, and R248-2017-2003 to iPSYCH), the Novo Nordisk Foundation (to the Danish National Biobank) and the universities and university hospitals of Aarhus and Copenhagen. High-performance computer capacity for handling and statistical analysis of iPSYCH data on the GenomeDK HPC facility was provided by the Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing, iSEQ, Aarhus University, Denmark through a grant to A.D.B. Human tissue was obtained from the NIH NeuroBioBank. We thank all the families who participated in the cohorts included in this analysis, without whom this work would not have been possible. We also thank R. Collins and R. Walters for their assistance with these analyses. Finally, we thank the following members of the ADHD Working Group of the PGC: A. R. Hammerschlag, A. Corsico, A. Havdahl, A. Todorov, A. Charach, A. Ashley-Koch, A. Doyle, A. Hervas, A. Miranda, A. Borglum, A. Scherag, A. Thapar, A. Rommel, A. Starnawska, A. Wheeler, A. Rothenberger, A. Arnatkeviciute, B. Franke, B. Neale, C. Liao, C. Hartman, C. Burton, C. Cornforth, C. Bandeira, C. Bau, C. Sanchez, D. Posthuma, F. Cerrato, F. Mulas, F. Degenhardt, G. C. A. Martins, G. P. Stromstad Knudsen, H. C. Steinhausen, H. Hakonarson, H.-C. Steinhausen, H. Roeyers, H.-W. Kim, I. Gizer, I. Waldman, I. Brikell, J. Crosbie, J. Agnew-Blais, J. Martin, J. Gelernter, J. Hebebrand, J. A. Ramos-Quiroga, J. Biederman, J. Sergeant, J. Gamble, J. Pinsonneault, J. Deckert, K. Langley, L. Yang, L. Kent, L. Rohde, M. Mattheisen, M. J. Arranz Calderun, M. Soler Artigas, M. Ribases, M. Mariano, M. Gill, M. O’Donovan, M. Casas, M. Bayes, N. Martin, N. P. Ole Mors, N. Williams, N. Roth Mota, O. A. Andreassen, P. Sham, P. Sullivan, P. Arnold, P. Lichtenstein, P. Rovira, P. Holmans, P. Asherson, P. B. Mortensen, R. Guerra, R. Walters, R. Anney, R. Ebstein, R. Karlsson Linnér, R. Joober, R. Oades, R. Schachar, S. M. Sengupta, S. Johansson, S. H. Witt, S. Nelson, S. Smalley, S. Scherag, T. Zayats, T. Werge, T. Silk, T. Polderman, T. Banaschewski, T. Altar, V. Manikandan, Y. Zhang, Y. Athanasiadis and Y. Wang. Support for the title page creation and format was provided by AuthorArranger, a tool developed at the National Cancer Institute.

Funders	Funder number
Aarhus University, Denmark
Novo Nordisk Fonden
NIH NeuroBioBank
National Institute of Child Health and Human Development	R01HD096326
National Institute of General Medical Sciences	T32GM007753, T32GM144273
Lundbeckfonden	R155-2014-1724, R248-2017-2003, R102-A9118
National Institute of Mental Health	R01MH099134, R01MH122412, R01MH069359, R01MH111813, R01MH115957, R01MH094400, R01MH123619, F30MH129009, R01MH124851
National Institute of Neurological Disorders and Stroke	R01NS093200
U.S. National Library of Medicine	T15LM007092
Simons Foundation Autism Research Initiative	704413

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10.1038/s41588-022-01203-y

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@article{779470a92fe74b1a8ba0e32a848cc09f,

title = "Statistical and functional convergence of common and rare genetic influences on autism at chromosome 16p",

abstract = "The canonical paradigm for converting genetic association to mechanism involves iteratively mapping individual associations to the proximal genes through which they act. In contrast, in the present study we demonstrate the feasibility of extracting biological insights from a very large region of the genome and leverage this strategy to study the genetic influences on autism. Using a new statistical approach, we identified the 33-Mb p-arm of chromosome 16 (16p) as harboring the greatest excess of autism{\textquoteright}s common polygenic influences. The region also includes the mechanistically cryptic and autism-associated 16p11.2 copy number variant. Analysis of RNA-sequencing data revealed that both the common polygenic influences within 16p and the 16p11.2 deletion were associated with decreased average gene expression across 16p. The transcriptional effects of the rare deletion and diffuse common variation were correlated at the level of individual genes and analysis of Hi-C data revealed patterns of chromatin contact that may explain this transcriptional convergence. These results reflect a new approach for extracting biological insight from genetic association data and suggest convergence of common and rare genetic influences on autism at 16p.",

author = "Weiner, \{Daniel J.\} and Emi Ling and Serkan Erdin and Tai, \{Derek J.C.\} and Rachita Yadav and Jakob Grove and Fu, \{Jack M.\} and Ajay Nadig and Caitlin Carey and Nikolas Baya and Jonas Bybjerg-Grauholm and Mortensen, \{Preben B.\} and Thomas Werge and Ditte Demontis and Ole Mors and Merete Nordentoft and Als, \{Thomas D.\} and Marie Baekvad-Hansen and Anders Rosengren and Alexandra Havdahl and Anne Hedemand and Aarno Palotie and Aravinda Chakravarti and Dan Arking and Arvis Sulovari and Anna Starnawska and Bhooma Thiruvahindrapuram and \{de Leeuw\}, Christiaan and Caitlin Carey and Christine Ladd-Acosta and \{van der Merwe\}, Celia and Bernie Devlin and Cook, \{Edwin H.\} and Evan Eichler and Elizabeth Corfield and Gwen Dieleman and Gerard Schellenberg and Hakon Hakonarson and Hilary Coon and Isabel Dziobek and Jacob Vorstman and Jessica Girault and Sutcliffe, \{James S.\} and Jinjie Duan and John Nurnberger and Joachim Hallmayer and Joseph Buxbaum and Joseph Piven and Lauren Weiss and Lea Davis and Magdalena Janecka and Manuel Mattheisen and State, \{Matthew W.\} and Michael Gill and Mark Daly and Mohammed Uddin and Ole Andreassen and Peter Szatmari and Lee, \{Phil Hyoun\} and Richard Anney and Stephan Ripke and Kyle Satterstrom and Susan Santangelo and Susan Kuo and \{van Elst\}, \{Ludger Tebartz\} and Thomas Rolland and Thomas Bougeron and Tinca Polderman and Tychele Turner and Jack Underwood and Veera Manikandan and Vamsee Pillalamarri and Varun Warrier and Alexandra Philipsen and Andreas Reif and Anke Hinney and Bru Cormand and Bau, \{Claiton H.D.\} and Rovaris, \{Diego Luiz\} and Edmund Sonuga-Barke and Elizabeth Corfield and Grevet, \{Eugenio Horacio\} and Giovanni Salum and Henrik Larsson and Jan Buitelaar and Jan Haavik and James McGough and Jonna Kuntsi and Josephine Elia and Lesch, \{Klaus Peter\} and Marieke Klein and Mark Bellgrove and Martin Tesli and Leung, \{Patrick W.L.\} and Pan, \{Pedro M.\} and Soren Dalsgaard and Sandra Loo and Sarah Medland and Faraone, \{Stephen V.\} and Ted Reichborn-Kjennerud and Tobias Banaschewski and Ziarih Hawi and Sabina Berretta and Macosko, \{Evan Z.\} and Jonathan Sebat and O{\textquoteright}Connor, \{Luke J.\} and Hougaard, \{David M.\} and B{\o}rglum, \{Anders D.\} and Talkowski, \{Michael E.\} and McCarroll, \{Steven A.\} and Robinson, \{Elise B.\} and \{iPSYCH Consortium\} and \{ASD Working Group of the Psychiatric Genomics Consortium\} and \{ADHD Working Group of the Psychiatric Genomics Consortium\}",

note = "Funding Information: We thank the following for their generous support of this work: the SFARI (grant no. 704413 to E.B.R. and L.J.O.), the NIMH (grant nos. F30MH129009 to D.J.W., R01MH111813 to E.B.R., R01MH115957 to M.E.T. and 1R01MH124851-01 to A.D.B.), the National Institute of General Medical Sciences (grant nos. T32GM007753 and T32GM144273 to A.N. and D.J.W.), the National Institute of Child Health and Development (grant no. R01HD096326 to M.E.T.), the National Institute of Neurological Disorders and Stroke (grant no. R01NS093200 to M.E.T.), the National Library of Medicine (grant no. T15LM007092 to D.J.W.), the Lundbeck Foundation (grant nos. R102-A9118, R155-2014-1724, and R248-2017-2003 to iPSYCH), the Novo Nordisk Foundation (to the Danish National Biobank) and the universities and university hospitals of Aarhus and Copenhagen. High-performance computer capacity for handling and statistical analysis of iPSYCH data on the GenomeDK HPC facility was provided by the Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing, iSEQ, Aarhus University, Denmark through a grant to A.D.B. Human tissue was obtained from the NIH NeuroBioBank. We thank all the families who participated in the cohorts included in this analysis, without whom this work would not have been possible. We also thank R. Collins and R. Walters for their assistance with these analyses. Finally, we thank the following members of the ADHD Working Group of the PGC: A. R. Hammerschlag, A. Corsico, A. Havdahl, A. Todorov, A. Charach, A. Ashley-Koch, A. Doyle, A. Hervas, A. Miranda, A. Borglum, A. Scherag, A. Thapar, A. Rommel, A. Starnawska, A. Wheeler, A. Rothenberger, A. Arnatkeviciute, B. Franke, B. Neale, C. Liao, C. Hartman, C. Burton, C. Cornforth, C. Bandeira, C. Bau, C. Sanchez, D. Posthuma, F. Cerrato, F. Mulas, F. Degenhardt, G. C. A. Martins, G. P. Stromstad Knudsen, H. C. Steinhausen, H. Hakonarson, H.-C. Steinhausen, H. Roeyers, H.-W. Kim, I. Gizer, I. Waldman, I. Brikell, J. Crosbie, J. Agnew-Blais, J. Martin, J. Gelernter, J. Hebebrand, J. A. Ramos-Quiroga, J. Biederman, J. Sergeant, J. Gamble, J. Pinsonneault, J. Deckert, K. Langley, L. Yang, L. Kent, L. Rohde, M. Mattheisen, M. J. Arranz Calderun, M. Soler Artigas, M. Ribases, M. Mariano, M. Gill, M. O{\textquoteright}Donovan, M. Casas, M. Bayes, N. Martin, N. P. Ole Mors, N. Williams, N. Roth Mota, O. A. Andreassen, P. Sham, P. Sullivan, P. Arnold, P. Lichtenstein, P. Rovira, P. Holmans, P. Asherson, P. B. Mortensen, R. Guerra, R. Walters, R. Anney, R. Ebstein, R. Karlsson Linn{\'e}r, R. Joober, R. Oades, R. Schachar, S. M. Sengupta, S. Johansson, S. H. Witt, S. Nelson, S. Smalley, S. Scherag, T. Zayats, T. Werge, T. Silk, T. Polderman, T. Banaschewski, T. Altar, V. Manikandan, Y. Zhang, Y. Athanasiadis and Y. Wang. Support for the title page creation and format was provided by AuthorArranger, a tool developed at the National Cancer Institute. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = nov,

doi = "10.1038/s41588-022-01203-y",

language = "English",

volume = "54",

pages = "1630--1639",

journal = "Nature genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "11",

}

Statistical and functional convergence of common and rare genetic influences on autism at chromosome 16p. / iPSYCH Consortium; ASD Working Group of the Psychiatric Genomics Consortium; ADHD Working Group of the Psychiatric Genomics Consortium.
In: Nature genetics, Vol. 54, No. 11, 11.2022, p. 1630-1639.

Research output: Contribution to Journal › Article › Academic › peer-review

TY - JOUR

T1 - Statistical and functional convergence of common and rare genetic influences on autism at chromosome 16p

AU - Weiner, Daniel J.

AU - Ling, Emi

AU - Erdin, Serkan

AU - Tai, Derek J.C.

AU - Yadav, Rachita

AU - Grove, Jakob

AU - Fu, Jack M.

AU - Nadig, Ajay

AU - Carey, Caitlin

AU - Baya, Nikolas

AU - Bybjerg-Grauholm, Jonas

AU - Mortensen, Preben B.

AU - Werge, Thomas

AU - Demontis, Ditte

AU - Mors, Ole

AU - Nordentoft, Merete

AU - Als, Thomas D.

AU - Baekvad-Hansen, Marie

AU - Rosengren, Anders

AU - Havdahl, Alexandra

AU - Hedemand, Anne

AU - Palotie, Aarno

AU - Chakravarti, Aravinda

AU - Arking, Dan

AU - Sulovari, Arvis

AU - Starnawska, Anna

AU - Thiruvahindrapuram, Bhooma

AU - de Leeuw, Christiaan

AU - Carey, Caitlin

AU - Ladd-Acosta, Christine

AU - van der Merwe, Celia

AU - Devlin, Bernie

AU - Cook, Edwin H.

AU - Eichler, Evan

AU - Corfield, Elizabeth

AU - Dieleman, Gwen

AU - Schellenberg, Gerard

AU - Hakonarson, Hakon

AU - Coon, Hilary

AU - Dziobek, Isabel

AU - Vorstman, Jacob

AU - Girault, Jessica

AU - Sutcliffe, James S.

AU - Duan, Jinjie

AU - Nurnberger, John

AU - Hallmayer, Joachim

AU - Buxbaum, Joseph

AU - Piven, Joseph

AU - Weiss, Lauren

AU - Davis, Lea

AU - Janecka, Magdalena

AU - Mattheisen, Manuel

AU - State, Matthew W.

AU - Gill, Michael

AU - Daly, Mark

AU - Uddin, Mohammed

AU - Andreassen, Ole

AU - Szatmari, Peter

AU - Lee, Phil Hyoun

AU - Anney, Richard

AU - Ripke, Stephan

AU - Satterstrom, Kyle

AU - Santangelo, Susan

AU - Kuo, Susan

AU - van Elst, Ludger Tebartz

AU - Rolland, Thomas

AU - Bougeron, Thomas

AU - Polderman, Tinca

AU - Turner, Tychele

AU - Underwood, Jack

AU - Manikandan, Veera

AU - Pillalamarri, Vamsee

AU - Warrier, Varun

AU - Philipsen, Alexandra

AU - Reif, Andreas

AU - Hinney, Anke

AU - Cormand, Bru

AU - Bau, Claiton H.D.

AU - Rovaris, Diego Luiz

AU - Sonuga-Barke, Edmund

AU - Corfield, Elizabeth

AU - Grevet, Eugenio Horacio

AU - Salum, Giovanni

AU - Larsson, Henrik

AU - Buitelaar, Jan

AU - Haavik, Jan

AU - McGough, James

AU - Kuntsi, Jonna

AU - Elia, Josephine

AU - Lesch, Klaus Peter

AU - Klein, Marieke

AU - Bellgrove, Mark

AU - Tesli, Martin

AU - Leung, Patrick W.L.

AU - Pan, Pedro M.

AU - Dalsgaard, Soren

AU - Loo, Sandra

AU - Medland, Sarah

AU - Faraone, Stephen V.

AU - Reichborn-Kjennerud, Ted

AU - Banaschewski, Tobias

AU - Hawi, Ziarih

AU - Berretta, Sabina

AU - Macosko, Evan Z.

AU - Sebat, Jonathan

AU - O’Connor, Luke J.

AU - Hougaard, David M.

AU - Børglum, Anders D.

AU - Talkowski, Michael E.

AU - McCarroll, Steven A.

AU - Robinson, Elise B.

AU - iPSYCH Consortium

AU - ASD Working Group of the Psychiatric Genomics Consortium

AU - ADHD Working Group of the Psychiatric Genomics Consortium

N1 - Funding Information: We thank the following for their generous support of this work: the SFARI (grant no. 704413 to E.B.R. and L.J.O.), the NIMH (grant nos. F30MH129009 to D.J.W., R01MH111813 to E.B.R., R01MH115957 to M.E.T. and 1R01MH124851-01 to A.D.B.), the National Institute of General Medical Sciences (grant nos. T32GM007753 and T32GM144273 to A.N. and D.J.W.), the National Institute of Child Health and Development (grant no. R01HD096326 to M.E.T.), the National Institute of Neurological Disorders and Stroke (grant no. R01NS093200 to M.E.T.), the National Library of Medicine (grant no. T15LM007092 to D.J.W.), the Lundbeck Foundation (grant nos. R102-A9118, R155-2014-1724, and R248-2017-2003 to iPSYCH), the Novo Nordisk Foundation (to the Danish National Biobank) and the universities and university hospitals of Aarhus and Copenhagen. High-performance computer capacity for handling and statistical analysis of iPSYCH data on the GenomeDK HPC facility was provided by the Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing, iSEQ, Aarhus University, Denmark through a grant to A.D.B. Human tissue was obtained from the NIH NeuroBioBank. We thank all the families who participated in the cohorts included in this analysis, without whom this work would not have been possible. We also thank R. Collins and R. Walters for their assistance with these analyses. Finally, we thank the following members of the ADHD Working Group of the PGC: A. R. Hammerschlag, A. Corsico, A. Havdahl, A. Todorov, A. Charach, A. Ashley-Koch, A. Doyle, A. Hervas, A. Miranda, A. Borglum, A. Scherag, A. Thapar, A. Rommel, A. Starnawska, A. Wheeler, A. Rothenberger, A. Arnatkeviciute, B. Franke, B. Neale, C. Liao, C. Hartman, C. Burton, C. Cornforth, C. Bandeira, C. Bau, C. Sanchez, D. Posthuma, F. Cerrato, F. Mulas, F. Degenhardt, G. C. A. Martins, G. P. Stromstad Knudsen, H. C. Steinhausen, H. Hakonarson, H.-C. Steinhausen, H. Roeyers, H.-W. Kim, I. Gizer, I. Waldman, I. Brikell, J. Crosbie, J. Agnew-Blais, J. Martin, J. Gelernter, J. Hebebrand, J. A. Ramos-Quiroga, J. Biederman, J. Sergeant, J. Gamble, J. Pinsonneault, J. Deckert, K. Langley, L. Yang, L. Kent, L. Rohde, M. Mattheisen, M. J. Arranz Calderun, M. Soler Artigas, M. Ribases, M. Mariano, M. Gill, M. O’Donovan, M. Casas, M. Bayes, N. Martin, N. P. Ole Mors, N. Williams, N. Roth Mota, O. A. Andreassen, P. Sham, P. Sullivan, P. Arnold, P. Lichtenstein, P. Rovira, P. Holmans, P. Asherson, P. B. Mortensen, R. Guerra, R. Walters, R. Anney, R. Ebstein, R. Karlsson Linnér, R. Joober, R. Oades, R. Schachar, S. M. Sengupta, S. Johansson, S. H. Witt, S. Nelson, S. Smalley, S. Scherag, T. Zayats, T. Werge, T. Silk, T. Polderman, T. Banaschewski, T. Altar, V. Manikandan, Y. Zhang, Y. Athanasiadis and Y. Wang. Support for the title page creation and format was provided by AuthorArranger, a tool developed at the National Cancer Institute. Publisher Copyright: © 2022, The Author(s).

PY - 2022/11

Y1 - 2022/11

N2 - The canonical paradigm for converting genetic association to mechanism involves iteratively mapping individual associations to the proximal genes through which they act. In contrast, in the present study we demonstrate the feasibility of extracting biological insights from a very large region of the genome and leverage this strategy to study the genetic influences on autism. Using a new statistical approach, we identified the 33-Mb p-arm of chromosome 16 (16p) as harboring the greatest excess of autism’s common polygenic influences. The region also includes the mechanistically cryptic and autism-associated 16p11.2 copy number variant. Analysis of RNA-sequencing data revealed that both the common polygenic influences within 16p and the 16p11.2 deletion were associated with decreased average gene expression across 16p. The transcriptional effects of the rare deletion and diffuse common variation were correlated at the level of individual genes and analysis of Hi-C data revealed patterns of chromatin contact that may explain this transcriptional convergence. These results reflect a new approach for extracting biological insight from genetic association data and suggest convergence of common and rare genetic influences on autism at 16p.

AB - The canonical paradigm for converting genetic association to mechanism involves iteratively mapping individual associations to the proximal genes through which they act. In contrast, in the present study we demonstrate the feasibility of extracting biological insights from a very large region of the genome and leverage this strategy to study the genetic influences on autism. Using a new statistical approach, we identified the 33-Mb p-arm of chromosome 16 (16p) as harboring the greatest excess of autism’s common polygenic influences. The region also includes the mechanistically cryptic and autism-associated 16p11.2 copy number variant. Analysis of RNA-sequencing data revealed that both the common polygenic influences within 16p and the 16p11.2 deletion were associated with decreased average gene expression across 16p. The transcriptional effects of the rare deletion and diffuse common variation were correlated at the level of individual genes and analysis of Hi-C data revealed patterns of chromatin contact that may explain this transcriptional convergence. These results reflect a new approach for extracting biological insight from genetic association data and suggest convergence of common and rare genetic influences on autism at 16p.

UR - https://www.scopus.com/pages/publications/85140719036

UR - https://www.scopus.com/pages/publications/85140719036#tab=citedBy

U2 - 10.1038/s41588-022-01203-y

DO - 10.1038/s41588-022-01203-y

M3 - Article

C2 - 36280734

AN - SCOPUS:85140719036

SN - 1061-4036

VL - 54

SP - 1630

EP - 1639

JO - Nature genetics

JF - Nature genetics

IS - 11

ER -

Statistical and functional convergence of common and rare genetic influences on autism at chromosome 16p

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