Autism genome-wide copy number variation reveals ubiquitin and neuronal genes

Joseph T. Glessner; Kai Wang; Guiqing Cai; Olena Korvatska; Cecilia E. Kim; Shawn Wood; Haitao Zhang; Annette Estes; Camille W. Brune; Jonathan P. Bradfield; Marcin Imielinski; Edward C. Frackelton; Jennifer Reichert; Emily L. Crawford; Jeffrey Munson; Patrick M A Sleiman; Rosetta Chiavacci; Kiran Annaiah; Kelly Thomas; Cuiping Hou; Wendy Glaberson; James Flory; Frederick Otieno; Maria Garris; Latha Soorya; Lambertus Klei; Joseph Piven; Kacie J. Meyer; Evdokia Anagnostou; Takeshi Sakurai; Rachel M. Game; Danielle S. Rudd; Danielle Zurawiecki; Christopher J. McDougle; Lea K. Davis; Judith Miller; David J. Posey; Shana Michaels; Alexander Kolevzon; Jeremy M. Silverman; Raphael Bernier; Susan E. Levy; Robert T. Schultz; Geraldine Dawson; Thomas Owley; William M. McMahon; Thomas H. Wassink; John A. Sweeney; John I. Nurnberger; Hilary Coon; James S. Sutcliffe; Nancy J. Minshew; Struan F A Grant; Maja Bucan; Edwin H. Cook; Joseph D. Buxbaum; Bernie Devlin; Gerard D. Schellenberg; Hakon Hakonarson

doi:10.1038/nature07953

Autism genome-wide copy number variation reveals ubiquitin and neuronal genes

Joseph T. Glessner, Kai Wang, Guiqing Cai, Olena Korvatska, Cecilia E. Kim, Shawn Wood, Haitao Zhang, Annette Estes, Camille W. Brune, Jonathan P. Bradfield, Marcin Imielinski, Edward C. Frackelton, Jennifer Reichert, Emily L. Crawford, Jeffrey Munson, Patrick M A Sleiman, Rosetta Chiavacci, Kiran Annaiah, Kelly Thomas, Cuiping HouWendy Glaberson, James Flory, Frederick Otieno, Maria Garris, Latha Soorya, Lambertus Klei, Joseph Piven, Kacie J. Meyer, Evdokia Anagnostou, Takeshi Sakurai, Rachel M. Game, Danielle S. Rudd, Danielle Zurawiecki, Christopher J. McDougle, Lea K. Davis, Judith Miller, David J. Posey, Shana Michaels, Alexander Kolevzon, Jeremy M. Silverman, Raphael Bernier, Susan E. Levy, Robert T. Schultz, Geraldine Dawson, Thomas Owley, William M. McMahon, Thomas H. Wassink, John A. Sweeney, John I. Nurnberger, Hilary Coon, James S. Sutcliffe, Nancy J. Minshew, Struan F A Grant, Maja Bucan, Edwin H. Cook, Joseph D. Buxbaum, Bernie Devlin, Gerard D. Schellenberg, Hakon Hakonarson

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Abstract

Autism spectrum disorders (ASDs) are childhood neurodevelopmental disorders with complex genetic origins. Previous studies focusing on candidate genes or genomic regions have identified several copy number variations (CNVs) that are associated with an increased risk of ASDs. Here we present the results from a whole-genome CNV study on a cohort of 859 ASD cases and 1,409 healthy children of European ancestry who were genotyped with 550,000 single nucleotide polymorphism markers, in an attempt to comprehensively identify CNVs conferring susceptibility to ASDs. Positive findings were evaluated in an independent cohort of 1,336 ASD cases and 1,110 controls of European ancestry. Besides previously reported ASD candidate genes, such as NRXN1 (ref. 10) and CNTN4 (refs 11, 12), several new susceptibility genes encoding neuronal cell-adhesion molecules, including NLGN1 and ASTN2, were enriched with CNVs in ASD cases compared to controls (P = 9.5 × 10-3). Furthermore, CNVs within or surrounding genes involved in the ubiquitin pathways, including UBE3A, PARK2, RFWD2 and FBXO40, were affected by CNVs not observed in controls (P = 3.3 × 10-3). We also identified duplications 55 kilobases upstream of complementary DNA AK123120 (P = 3.6 × 10-6). Although these variants may be individually rare, they target genes involved in neuronal cell-adhesion or ubiquitin degradation, indicating that these two important gene networks expressed within the central nervous system may contribute to the genetic susceptibility of ASD.

Original language	English (US)
Pages (from-to)	569-572
Number of pages	4
Journal	Nature
Volume	459
Issue number	7246
DOIs	https://doi.org/10.1038/nature07953
State	Published - May 28 2009

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Glessner, J. T., Wang, K., Cai, G., Korvatska, O., Kim, C. E., Wood, S., Zhang, H., Estes, A., Brune, C. W., Bradfield, J. P., Imielinski, M., Frackelton, E. C., Reichert, J., Crawford, E. L., Munson, J., Sleiman, P. M. A., Chiavacci, R., Annaiah, K., Thomas, K., ... Hakonarson, H. (2009). Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature, 459(7246), 569-572. https://doi.org/10.1038/nature07953

Glessner, JT, Wang, K, Cai, G, Korvatska, O, Kim, CE, Wood, S, Zhang, H, Estes, A, Brune, CW, Bradfield, JP, Imielinski, M, Frackelton, EC, Reichert, J, Crawford, EL, Munson, J, Sleiman, PMA, Chiavacci, R, Annaiah, K, Thomas, K, Hou, C, Glaberson, W, Flory, J, Otieno, F, Garris, M, Soorya, L, Klei, L, Piven, J, Meyer, KJ, Anagnostou, E, Sakurai, T, Game, RM, Rudd, DS, Zurawiecki, D, McDougle, CJ, Davis, LK, Miller, J, Posey, DJ, Michaels, S, Kolevzon, A, Silverman, JM, Bernier, R, Levy, SE, Schultz, RT, Dawson, G, Owley, T, McMahon, WM, Wassink, TH, Sweeney, JA, Nurnberger, JI, Coon, H, Sutcliffe, JS, Minshew, NJ, Grant, SFA, Bucan, M, Cook, EH, Buxbaum, JD, Devlin, B, Schellenberg, GD & Hakonarson, H 2009, 'Autism genome-wide copy number variation reveals ubiquitin and neuronal genes', Nature, vol. 459, no. 7246, pp. 569-572. https://doi.org/10.1038/nature07953

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title = "Autism genome-wide copy number variation reveals ubiquitin and neuronal genes",

abstract = "Autism spectrum disorders (ASDs) are childhood neurodevelopmental disorders with complex genetic origins. Previous studies focusing on candidate genes or genomic regions have identified several copy number variations (CNVs) that are associated with an increased risk of ASDs. Here we present the results from a whole-genome CNV study on a cohort of 859 ASD cases and 1,409 healthy children of European ancestry who were genotyped with 550,000 single nucleotide polymorphism markers, in an attempt to comprehensively identify CNVs conferring susceptibility to ASDs. Positive findings were evaluated in an independent cohort of 1,336 ASD cases and 1,110 controls of European ancestry. Besides previously reported ASD candidate genes, such as NRXN1 (ref. 10) and CNTN4 (refs 11, 12), several new susceptibility genes encoding neuronal cell-adhesion molecules, including NLGN1 and ASTN2, were enriched with CNVs in ASD cases compared to controls (P = 9.5 × 10-3). Furthermore, CNVs within or surrounding genes involved in the ubiquitin pathways, including UBE3A, PARK2, RFWD2 and FBXO40, were affected by CNVs not observed in controls (P = 3.3 × 10-3). We also identified duplications 55 kilobases upstream of complementary DNA AK123120 (P = 3.6 × 10-6). Although these variants may be individually rare, they target genes involved in neuronal cell-adhesion or ubiquitin degradation, indicating that these two important gene networks expressed within the central nervous system may contribute to the genetic susceptibility of ASD.",

author = "Glessner, {Joseph T.} and Kai Wang and Guiqing Cai and Olena Korvatska and Kim, {Cecilia E.} and Shawn Wood and Haitao Zhang and Annette Estes and Brune, {Camille W.} and Bradfield, {Jonathan P.} and Marcin Imielinski and Frackelton, {Edward C.} and Jennifer Reichert and Crawford, {Emily L.} and Jeffrey Munson and Sleiman, {Patrick M A} and Rosetta Chiavacci and Kiran Annaiah and Kelly Thomas and Cuiping Hou and Wendy Glaberson and James Flory and Frederick Otieno and Maria Garris and Latha Soorya and Lambertus Klei and Joseph Piven and Meyer, {Kacie J.} and Evdokia Anagnostou and Takeshi Sakurai and Game, {Rachel M.} and Rudd, {Danielle S.} and Danielle Zurawiecki and McDougle, {Christopher J.} and Davis, {Lea K.} and Judith Miller and Posey, {David J.} and Shana Michaels and Alexander Kolevzon and Silverman, {Jeremy M.} and Raphael Bernier and Levy, {Susan E.} and Schultz, {Robert T.} and Geraldine Dawson and Thomas Owley and McMahon, {William M.} and Wassink, {Thomas H.} and Sweeney, {John A.} and Nurnberger, {John I.} and Hilary Coon and Sutcliffe, {James S.} and Minshew, {Nancy J.} and Grant, {Struan F A} and Maja Bucan and Cook, {Edwin H.} and Buxbaum, {Joseph D.} and Bernie Devlin and Schellenberg, {Gerard D.} and Hakon Hakonarson",

year = "2009",

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doi = "10.1038/nature07953",

language = "English (US)",

volume = "459",

pages = "569--572",

journal = "Nature",

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T1 - Autism genome-wide copy number variation reveals ubiquitin and neuronal genes

AU - Glessner, Joseph T.

AU - Wang, Kai

AU - Cai, Guiqing

AU - Korvatska, Olena

AU - Kim, Cecilia E.

AU - Wood, Shawn

AU - Zhang, Haitao

AU - Estes, Annette

AU - Brune, Camille W.

AU - Bradfield, Jonathan P.

AU - Imielinski, Marcin

AU - Frackelton, Edward C.

AU - Reichert, Jennifer

AU - Crawford, Emily L.

AU - Munson, Jeffrey

AU - Sleiman, Patrick M A

AU - Chiavacci, Rosetta

AU - Annaiah, Kiran

AU - Thomas, Kelly

AU - Hou, Cuiping

AU - Glaberson, Wendy

AU - Flory, James

AU - Otieno, Frederick

AU - Garris, Maria

AU - Soorya, Latha

AU - Klei, Lambertus

AU - Piven, Joseph

AU - Meyer, Kacie J.

AU - Anagnostou, Evdokia

AU - Sakurai, Takeshi

AU - Game, Rachel M.

AU - Rudd, Danielle S.

AU - Zurawiecki, Danielle

AU - McDougle, Christopher J.

AU - Davis, Lea K.

AU - Miller, Judith

AU - Posey, David J.

AU - Michaels, Shana

AU - Kolevzon, Alexander

AU - Silverman, Jeremy M.

AU - Bernier, Raphael

AU - Levy, Susan E.

AU - Schultz, Robert T.

AU - Dawson, Geraldine

AU - Owley, Thomas

AU - McMahon, William M.

AU - Wassink, Thomas H.

AU - Sweeney, John A.

AU - Nurnberger, John I.

AU - Coon, Hilary

AU - Sutcliffe, James S.

AU - Minshew, Nancy J.

AU - Grant, Struan F A

AU - Bucan, Maja

AU - Cook, Edwin H.

AU - Buxbaum, Joseph D.

AU - Devlin, Bernie

AU - Schellenberg, Gerard D.

AU - Hakonarson, Hakon

PY - 2009/5/28

Y1 - 2009/5/28

N2 - Autism spectrum disorders (ASDs) are childhood neurodevelopmental disorders with complex genetic origins. Previous studies focusing on candidate genes or genomic regions have identified several copy number variations (CNVs) that are associated with an increased risk of ASDs. Here we present the results from a whole-genome CNV study on a cohort of 859 ASD cases and 1,409 healthy children of European ancestry who were genotyped with 550,000 single nucleotide polymorphism markers, in an attempt to comprehensively identify CNVs conferring susceptibility to ASDs. Positive findings were evaluated in an independent cohort of 1,336 ASD cases and 1,110 controls of European ancestry. Besides previously reported ASD candidate genes, such as NRXN1 (ref. 10) and CNTN4 (refs 11, 12), several new susceptibility genes encoding neuronal cell-adhesion molecules, including NLGN1 and ASTN2, were enriched with CNVs in ASD cases compared to controls (P = 9.5 × 10-3). Furthermore, CNVs within or surrounding genes involved in the ubiquitin pathways, including UBE3A, PARK2, RFWD2 and FBXO40, were affected by CNVs not observed in controls (P = 3.3 × 10-3). We also identified duplications 55 kilobases upstream of complementary DNA AK123120 (P = 3.6 × 10-6). Although these variants may be individually rare, they target genes involved in neuronal cell-adhesion or ubiquitin degradation, indicating that these two important gene networks expressed within the central nervous system may contribute to the genetic susceptibility of ASD.

AB - Autism spectrum disorders (ASDs) are childhood neurodevelopmental disorders with complex genetic origins. Previous studies focusing on candidate genes or genomic regions have identified several copy number variations (CNVs) that are associated with an increased risk of ASDs. Here we present the results from a whole-genome CNV study on a cohort of 859 ASD cases and 1,409 healthy children of European ancestry who were genotyped with 550,000 single nucleotide polymorphism markers, in an attempt to comprehensively identify CNVs conferring susceptibility to ASDs. Positive findings were evaluated in an independent cohort of 1,336 ASD cases and 1,110 controls of European ancestry. Besides previously reported ASD candidate genes, such as NRXN1 (ref. 10) and CNTN4 (refs 11, 12), several new susceptibility genes encoding neuronal cell-adhesion molecules, including NLGN1 and ASTN2, were enriched with CNVs in ASD cases compared to controls (P = 9.5 × 10-3). Furthermore, CNVs within or surrounding genes involved in the ubiquitin pathways, including UBE3A, PARK2, RFWD2 and FBXO40, were affected by CNVs not observed in controls (P = 3.3 × 10-3). We also identified duplications 55 kilobases upstream of complementary DNA AK123120 (P = 3.6 × 10-6). Although these variants may be individually rare, they target genes involved in neuronal cell-adhesion or ubiquitin degradation, indicating that these two important gene networks expressed within the central nervous system may contribute to the genetic susceptibility of ASD.

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Autism genome-wide copy number variation reveals ubiquitin and neuronal genes

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