Cargando…

Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders

Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case–control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By c...

Descripción completa

Detalles Bibliográficos
Autores principales: Wang, Tianyun, Hoekzema, Kendra, Vecchio, Davide, Wu, Huidan, Sulovari, Arvis, Coe, Bradley P., Gillentine, Madelyn A., Wilfert, Amy B., Perez-Jurado, Luis A., Kvarnung, Malin, Sleyp, Yoeri, Earl, Rachel K., Rosenfeld, Jill A., Geisheker, Madeleine R., Han, Lin, Du, Bing, Barnett, Chris, Thompson, Elizabeth, Shaw, Marie, Carroll, Renee, Friend, Kathryn, Catford, Rachael, Palmer, Elizabeth E., Zou, Xiaobing, Ou, Jianjun, Li, Honghui, Guo, Hui, Gerdts, Jennifer, Avola, Emanuela, Calabrese, Giuseppe, Elia, Maurizio, Greco, Donatella, Lindstrand, Anna, Nordgren, Ann, Anderlid, Britt-Marie, Vandeweyer, Geert, Van Dijck, Anke, Van der Aa, Nathalie, McKenna, Brooke, Hancarova, Miroslava, Bendova, Sarka, Havlovicova, Marketa, Malerba, Giovanni, Bernardina, Bernardo Dalla, Muglia, Pierandrea, van Haeringen, Arie, Hoffer, Mariette J. V., Franke, Barbara, Cappuccio, Gerarda, Delatycki, Martin, Lockhart, Paul J., Manning, Melanie A., Liu, Pengfei, Scheffer, Ingrid E., Brunetti-Pierri, Nicola, Rommelse, Nanda, Amaral, David G., Santen, Gijs W. E., Trabetti, Elisabetta, Sedláček, Zdeněk, Michaelson, Jacob J., Pierce, Karen, Courchesne, Eric, Kooy, R. Frank, Nordenskjöld, Magnus, Romano, Corrado, Peeters, Hilde, Bernier, Raphael A., Gecz, Jozef, Xia, Kun, Eichler, Evan E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530681/
https://www.ncbi.nlm.nih.gov/pubmed/33004838
http://dx.doi.org/10.1038/s41467-020-18723-y
_version_ 1783589615812214784
author Wang, Tianyun
Hoekzema, Kendra
Vecchio, Davide
Wu, Huidan
Sulovari, Arvis
Coe, Bradley P.
Gillentine, Madelyn A.
Wilfert, Amy B.
Perez-Jurado, Luis A.
Kvarnung, Malin
Sleyp, Yoeri
Earl, Rachel K.
Rosenfeld, Jill A.
Geisheker, Madeleine R.
Han, Lin
Du, Bing
Barnett, Chris
Thompson, Elizabeth
Shaw, Marie
Carroll, Renee
Friend, Kathryn
Catford, Rachael
Palmer, Elizabeth E.
Zou, Xiaobing
Ou, Jianjun
Li, Honghui
Guo, Hui
Gerdts, Jennifer
Avola, Emanuela
Calabrese, Giuseppe
Elia, Maurizio
Greco, Donatella
Lindstrand, Anna
Nordgren, Ann
Anderlid, Britt-Marie
Vandeweyer, Geert
Van Dijck, Anke
Van der Aa, Nathalie
McKenna, Brooke
Hancarova, Miroslava
Bendova, Sarka
Havlovicova, Marketa
Malerba, Giovanni
Bernardina, Bernardo Dalla
Muglia, Pierandrea
van Haeringen, Arie
Hoffer, Mariette J. V.
Franke, Barbara
Cappuccio, Gerarda
Delatycki, Martin
Lockhart, Paul J.
Manning, Melanie A.
Liu, Pengfei
Scheffer, Ingrid E.
Brunetti-Pierri, Nicola
Rommelse, Nanda
Amaral, David G.
Santen, Gijs W. E.
Trabetti, Elisabetta
Sedláček, Zdeněk
Michaelson, Jacob J.
Pierce, Karen
Courchesne, Eric
Kooy, R. Frank
Nordenskjöld, Magnus
Romano, Corrado
Peeters, Hilde
Bernier, Raphael A.
Gecz, Jozef
Xia, Kun
Eichler, Evan E.
author_facet Wang, Tianyun
Hoekzema, Kendra
Vecchio, Davide
Wu, Huidan
Sulovari, Arvis
Coe, Bradley P.
Gillentine, Madelyn A.
Wilfert, Amy B.
Perez-Jurado, Luis A.
Kvarnung, Malin
Sleyp, Yoeri
Earl, Rachel K.
Rosenfeld, Jill A.
Geisheker, Madeleine R.
Han, Lin
Du, Bing
Barnett, Chris
Thompson, Elizabeth
Shaw, Marie
Carroll, Renee
Friend, Kathryn
Catford, Rachael
Palmer, Elizabeth E.
Zou, Xiaobing
Ou, Jianjun
Li, Honghui
Guo, Hui
Gerdts, Jennifer
Avola, Emanuela
Calabrese, Giuseppe
Elia, Maurizio
Greco, Donatella
Lindstrand, Anna
Nordgren, Ann
Anderlid, Britt-Marie
Vandeweyer, Geert
Van Dijck, Anke
Van der Aa, Nathalie
McKenna, Brooke
Hancarova, Miroslava
Bendova, Sarka
Havlovicova, Marketa
Malerba, Giovanni
Bernardina, Bernardo Dalla
Muglia, Pierandrea
van Haeringen, Arie
Hoffer, Mariette J. V.
Franke, Barbara
Cappuccio, Gerarda
Delatycki, Martin
Lockhart, Paul J.
Manning, Melanie A.
Liu, Pengfei
Scheffer, Ingrid E.
Brunetti-Pierri, Nicola
Rommelse, Nanda
Amaral, David G.
Santen, Gijs W. E.
Trabetti, Elisabetta
Sedláček, Zdeněk
Michaelson, Jacob J.
Pierce, Karen
Courchesne, Eric
Kooy, R. Frank
Nordenskjöld, Magnus
Romano, Corrado
Peeters, Hilde
Bernier, Raphael A.
Gecz, Jozef
Xia, Kun
Eichler, Evan E.
author_sort Wang, Tianyun
collection PubMed
description Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case–control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By combining these with published data, we assess a total of 125 genes in over 16,000 NDD cases and compare the mutation burden to nonpsychiatric controls from ExAC. We identify 48 genes (25 newly reported) showing significant burden of ultra-rare (MAF < 0.01%) gene-disruptive mutations (FDR 5%), six of which reach family-wise error rate (FWER) significance (p < 1.25E−06). Among these 125 targeted genes, we also reevaluate DNM excess in 17,426 NDD trios with 6,499 new autism trios. We identify 90 genes enriched for DNMs (FDR 5%; e.g., GABRG2 and UIMC1); of which, 61 reach FWER significance (p < 3.64E−07; e.g., CASZ1). In addition to doubling the number of patients for many NDD risk genes, we present phenotype–genotype correlations for seven risk genes (CTCF, HNRNPU, KCNQ3, ZBTB18, TCF12, SPEN, and LEO1) based on this large-scale targeted sequencing effort.
format Online
Article
Text
id pubmed-7530681
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-75306812020-10-19 Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang, Tianyun Hoekzema, Kendra Vecchio, Davide Wu, Huidan Sulovari, Arvis Coe, Bradley P. Gillentine, Madelyn A. Wilfert, Amy B. Perez-Jurado, Luis A. Kvarnung, Malin Sleyp, Yoeri Earl, Rachel K. Rosenfeld, Jill A. Geisheker, Madeleine R. Han, Lin Du, Bing Barnett, Chris Thompson, Elizabeth Shaw, Marie Carroll, Renee Friend, Kathryn Catford, Rachael Palmer, Elizabeth E. Zou, Xiaobing Ou, Jianjun Li, Honghui Guo, Hui Gerdts, Jennifer Avola, Emanuela Calabrese, Giuseppe Elia, Maurizio Greco, Donatella Lindstrand, Anna Nordgren, Ann Anderlid, Britt-Marie Vandeweyer, Geert Van Dijck, Anke Van der Aa, Nathalie McKenna, Brooke Hancarova, Miroslava Bendova, Sarka Havlovicova, Marketa Malerba, Giovanni Bernardina, Bernardo Dalla Muglia, Pierandrea van Haeringen, Arie Hoffer, Mariette J. V. Franke, Barbara Cappuccio, Gerarda Delatycki, Martin Lockhart, Paul J. Manning, Melanie A. Liu, Pengfei Scheffer, Ingrid E. Brunetti-Pierri, Nicola Rommelse, Nanda Amaral, David G. Santen, Gijs W. E. Trabetti, Elisabetta Sedláček, Zdeněk Michaelson, Jacob J. Pierce, Karen Courchesne, Eric Kooy, R. Frank Nordenskjöld, Magnus Romano, Corrado Peeters, Hilde Bernier, Raphael A. Gecz, Jozef Xia, Kun Eichler, Evan E. Nat Commun Article Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case–control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By combining these with published data, we assess a total of 125 genes in over 16,000 NDD cases and compare the mutation burden to nonpsychiatric controls from ExAC. We identify 48 genes (25 newly reported) showing significant burden of ultra-rare (MAF < 0.01%) gene-disruptive mutations (FDR 5%), six of which reach family-wise error rate (FWER) significance (p < 1.25E−06). Among these 125 targeted genes, we also reevaluate DNM excess in 17,426 NDD trios with 6,499 new autism trios. We identify 90 genes enriched for DNMs (FDR 5%; e.g., GABRG2 and UIMC1); of which, 61 reach FWER significance (p < 3.64E−07; e.g., CASZ1). In addition to doubling the number of patients for many NDD risk genes, we present phenotype–genotype correlations for seven risk genes (CTCF, HNRNPU, KCNQ3, ZBTB18, TCF12, SPEN, and LEO1) based on this large-scale targeted sequencing effort. Nature Publishing Group UK 2020-10-01 /pmc/articles/PMC7530681/ /pubmed/33004838 http://dx.doi.org/10.1038/s41467-020-18723-y Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Wang, Tianyun
Hoekzema, Kendra
Vecchio, Davide
Wu, Huidan
Sulovari, Arvis
Coe, Bradley P.
Gillentine, Madelyn A.
Wilfert, Amy B.
Perez-Jurado, Luis A.
Kvarnung, Malin
Sleyp, Yoeri
Earl, Rachel K.
Rosenfeld, Jill A.
Geisheker, Madeleine R.
Han, Lin
Du, Bing
Barnett, Chris
Thompson, Elizabeth
Shaw, Marie
Carroll, Renee
Friend, Kathryn
Catford, Rachael
Palmer, Elizabeth E.
Zou, Xiaobing
Ou, Jianjun
Li, Honghui
Guo, Hui
Gerdts, Jennifer
Avola, Emanuela
Calabrese, Giuseppe
Elia, Maurizio
Greco, Donatella
Lindstrand, Anna
Nordgren, Ann
Anderlid, Britt-Marie
Vandeweyer, Geert
Van Dijck, Anke
Van der Aa, Nathalie
McKenna, Brooke
Hancarova, Miroslava
Bendova, Sarka
Havlovicova, Marketa
Malerba, Giovanni
Bernardina, Bernardo Dalla
Muglia, Pierandrea
van Haeringen, Arie
Hoffer, Mariette J. V.
Franke, Barbara
Cappuccio, Gerarda
Delatycki, Martin
Lockhart, Paul J.
Manning, Melanie A.
Liu, Pengfei
Scheffer, Ingrid E.
Brunetti-Pierri, Nicola
Rommelse, Nanda
Amaral, David G.
Santen, Gijs W. E.
Trabetti, Elisabetta
Sedláček, Zdeněk
Michaelson, Jacob J.
Pierce, Karen
Courchesne, Eric
Kooy, R. Frank
Nordenskjöld, Magnus
Romano, Corrado
Peeters, Hilde
Bernier, Raphael A.
Gecz, Jozef
Xia, Kun
Eichler, Evan E.
Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders
title Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders
title_full Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders
title_fullStr Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders
title_full_unstemmed Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders
title_short Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders
title_sort large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530681/
https://www.ncbi.nlm.nih.gov/pubmed/33004838
http://dx.doi.org/10.1038/s41467-020-18723-y
work_keys_str_mv AT wangtianyun largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT hoekzemakendra largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT vecchiodavide largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT wuhuidan largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT sulovariarvis largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT coebradleyp largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT gillentinemadelyna largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT wilfertamyb largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT perezjuradoluisa largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT kvarnungmalin largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT sleypyoeri largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT earlrachelk largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT rosenfeldjilla largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT geishekermadeleiner largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT hanlin largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT dubing largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT barnettchris largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT thompsonelizabeth largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT shawmarie largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT carrollrenee largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT friendkathryn largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT catfordrachael largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT palmerelizabethe largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT zouxiaobing largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT oujianjun largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT lihonghui largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT guohui largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT gerdtsjennifer largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT avolaemanuela largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT calabresegiuseppe largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT eliamaurizio largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT grecodonatella largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT lindstrandanna largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT nordgrenann largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT anderlidbrittmarie largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT vandeweyergeert largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT vandijckanke largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT vanderaanathalie largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT mckennabrooke largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT hancarovamiroslava largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT bendovasarka largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT havlovicovamarketa largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT malerbagiovanni largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT bernardinabernardodalla largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT mugliapierandrea largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT vanhaeringenarie largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT hoffermariettejv largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT frankebarbara largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT cappucciogerarda largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT delatyckimartin largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT lockhartpaulj largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT manningmelaniea largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT liupengfei largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT schefferingride largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT brunettipierrinicola largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT rommelsenanda largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT amaraldavidg largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT santengijswe largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT trabettielisabetta largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT sedlacekzdenek largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT michaelsonjacobj largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT piercekaren largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT courchesneeric largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT kooyrfrank largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT nordenskjoldmagnus largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT romanocorrado largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT peetershilde largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT bernierraphaela largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT geczjozef largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT xiakun largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders
AT eichlerevane largescaletargetedsequencingidentifiesriskgenesforneurodevelopmentaldisorders