Genome-wide analysis identifies a role for common copy number variants in specific language impairment

Nuala H Simpson, Fabiola Ceroni, Rose H Reader, Laura E Covill, Julian C Knight, Elizabeth R Hennessy, Patrick F Bolton, Gina Conti-Ramsden, Anne O'Hare, Gillian Baird, Simon E Fisher, Dianne F Newbury, R Nudel, AP Monaco, E Simonoff, PF Bolton, A Pickles, V Slonims, K Dworzynski, A Everitt & 8 others A Clark, J Watson, J Seckl, H Cowie, W Cohen, J. Nasir, DVM Bishop, Z Simkin

Research output: Contribution to journalArticle

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Abstract

An exploratory genome-wide copy number variant (CNV) study was performed in 127 independent cases with specific language impairment (SLI), their first-degree relatives (385 individuals) and 269 population controls. Language-impaired cases showed an increased CNV burden in terms of the average number of events (11.28 vs 10.01, empirical P=0.003), the total length of CNVs (717 vs 513 Kb, empirical P=0.0001), the average CNV size (63.75 vs 51.6 Kb, empirical P=0.0005) and the number of genes spanned (14.29 vs 10.34, empirical P=0.0007) when compared with population controls, suggesting that CNVs may contribute to SLI risk. A similar trend was observed in first-degree relatives regardless of affection status. The increased burden found in our study was not driven by large or de novo events, which have been described as causative in other neurodevelopmental disorders. Nevertheless, de novo CNVs might be important on a case-by-case basis, as indicated by identification of events affecting relevant genes, such as ACTR2 and CSNK1A1, and small events within known micro-deletion/-duplication syndrome regions, such as chr8p23.1. Pathway analysis of the genes present within the CNVs of the independent cases identified significant overrepresentation of acetylcholine binding, cyclic-nucleotide phosphodiesterase activity and MHC proteins as compared with controls. Taken together, our data suggest that the majority of the risk conferred by CNVs in SLI is via common, inherited events within a 'common disorder-common variant' model. Therefore the risk conferred by CNVs will depend upon the combination of events inherited (both CNVs and SNPs), the genetic background of the individual and the environmental factors.

LanguageEnglish
Pages1370-1377
Number of pages8
JournalEuropean Journal of Human Genetics
Volume23
Issue number10
Early online date14 Jan 2015
DOIs
Publication statusPublished - 22 Oct 2015

Fingerprint

Language
Genome
Population Control
Genes
Cyclic Nucleotides
Phosphoric Diester Hydrolases
Acetylcholine
Single Nucleotide Polymorphism
Proteins

Keywords

  • specific language impairment
  • copy number variants
  • apraxia of speech

Cite this

Simpson, N. H., Ceroni, F., Reader, R. H., Covill, L. E., Knight, J. C., Hennessy, E. R., ... Simkin, Z. (2015). Genome-wide analysis identifies a role for common copy number variants in specific language impairment. European Journal of Human Genetics, 23(10), 1370-1377. https://doi.org/10.1038/ejhg.2014.296
Simpson, Nuala H ; Ceroni, Fabiola ; Reader, Rose H ; Covill, Laura E ; Knight, Julian C ; Hennessy, Elizabeth R ; Bolton, Patrick F ; Conti-Ramsden, Gina ; O'Hare, Anne ; Baird, Gillian ; Fisher, Simon E ; Newbury, Dianne F ; Nudel, R ; Monaco, AP ; Simonoff, E ; Bolton, PF ; Pickles, A ; Slonims, V ; Dworzynski, K ; Everitt, A ; Clark, A ; Watson, J ; Seckl, J ; Cowie, H ; Cohen, W ; Nasir, J. ; Bishop, DVM ; Simkin, Z. / Genome-wide analysis identifies a role for common copy number variants in specific language impairment. In: European Journal of Human Genetics. 2015 ; Vol. 23, No. 10. pp. 1370-1377.
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abstract = "An exploratory genome-wide copy number variant (CNV) study was performed in 127 independent cases with specific language impairment (SLI), their first-degree relatives (385 individuals) and 269 population controls. Language-impaired cases showed an increased CNV burden in terms of the average number of events (11.28 vs 10.01, empirical P=0.003), the total length of CNVs (717 vs 513 Kb, empirical P=0.0001), the average CNV size (63.75 vs 51.6 Kb, empirical P=0.0005) and the number of genes spanned (14.29 vs 10.34, empirical P=0.0007) when compared with population controls, suggesting that CNVs may contribute to SLI risk. A similar trend was observed in first-degree relatives regardless of affection status. The increased burden found in our study was not driven by large or de novo events, which have been described as causative in other neurodevelopmental disorders. Nevertheless, de novo CNVs might be important on a case-by-case basis, as indicated by identification of events affecting relevant genes, such as ACTR2 and CSNK1A1, and small events within known micro-deletion/-duplication syndrome regions, such as chr8p23.1. Pathway analysis of the genes present within the CNVs of the independent cases identified significant overrepresentation of acetylcholine binding, cyclic-nucleotide phosphodiesterase activity and MHC proteins as compared with controls. Taken together, our data suggest that the majority of the risk conferred by CNVs in SLI is via common, inherited events within a 'common disorder-common variant' model. Therefore the risk conferred by CNVs will depend upon the combination of events inherited (both CNVs and SNPs), the genetic background of the individual and the environmental factors.",
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Simpson, NH, Ceroni, F, Reader, RH, Covill, LE, Knight, JC, Hennessy, ER, Bolton, PF, Conti-Ramsden, G, O'Hare, A, Baird, G, Fisher, SE, Newbury, DF, Nudel, R, Monaco, AP, Simonoff, E, Bolton, PF, Pickles, A, Slonims, V, Dworzynski, K, Everitt, A, Clark, A, Watson, J, Seckl, J, Cowie, H, Cohen, W, Nasir, J, Bishop, DVM & Simkin, Z 2015, 'Genome-wide analysis identifies a role for common copy number variants in specific language impairment' European Journal of Human Genetics, vol. 23, no. 10, pp. 1370-1377. https://doi.org/10.1038/ejhg.2014.296

Genome-wide analysis identifies a role for common copy number variants in specific language impairment. / Simpson, Nuala H; Ceroni, Fabiola; Reader, Rose H; Covill, Laura E; Knight, Julian C; Hennessy, Elizabeth R; Bolton, Patrick F; Conti-Ramsden, Gina; O'Hare, Anne; Baird, Gillian; Fisher, Simon E; Newbury, Dianne F; Nudel, R; Monaco, AP; Simonoff, E; Bolton, PF; Pickles, A; Slonims, V; Dworzynski, K; Everitt, A; Clark, A; Watson, J; Seckl, J; Cowie, H; Cohen, W; Nasir, J.; Bishop, DVM; Simkin, Z.

In: European Journal of Human Genetics, Vol. 23, No. 10, 22.10.2015, p. 1370-1377.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Genome-wide analysis identifies a role for common copy number variants in specific language impairment

AU - Simpson, Nuala H

AU - Ceroni, Fabiola

AU - Reader, Rose H

AU - Covill, Laura E

AU - Knight, Julian C

AU - Hennessy, Elizabeth R

AU - Bolton, Patrick F

AU - Conti-Ramsden, Gina

AU - O'Hare, Anne

AU - Baird, Gillian

AU - Fisher, Simon E

AU - Newbury, Dianne F

AU - Nudel, R

AU - Monaco, AP

AU - Simonoff, E

AU - Bolton, PF

AU - Pickles, A

AU - Slonims, V

AU - Dworzynski, K

AU - Everitt, A

AU - Clark, A

AU - Watson, J

AU - Seckl, J

AU - Cowie, H

AU - Cohen, W

AU - Nasir, J.

AU - Bishop, DVM

AU - Simkin, Z

PY - 2015/10/22

Y1 - 2015/10/22

N2 - An exploratory genome-wide copy number variant (CNV) study was performed in 127 independent cases with specific language impairment (SLI), their first-degree relatives (385 individuals) and 269 population controls. Language-impaired cases showed an increased CNV burden in terms of the average number of events (11.28 vs 10.01, empirical P=0.003), the total length of CNVs (717 vs 513 Kb, empirical P=0.0001), the average CNV size (63.75 vs 51.6 Kb, empirical P=0.0005) and the number of genes spanned (14.29 vs 10.34, empirical P=0.0007) when compared with population controls, suggesting that CNVs may contribute to SLI risk. A similar trend was observed in first-degree relatives regardless of affection status. The increased burden found in our study was not driven by large or de novo events, which have been described as causative in other neurodevelopmental disorders. Nevertheless, de novo CNVs might be important on a case-by-case basis, as indicated by identification of events affecting relevant genes, such as ACTR2 and CSNK1A1, and small events within known micro-deletion/-duplication syndrome regions, such as chr8p23.1. Pathway analysis of the genes present within the CNVs of the independent cases identified significant overrepresentation of acetylcholine binding, cyclic-nucleotide phosphodiesterase activity and MHC proteins as compared with controls. Taken together, our data suggest that the majority of the risk conferred by CNVs in SLI is via common, inherited events within a 'common disorder-common variant' model. Therefore the risk conferred by CNVs will depend upon the combination of events inherited (both CNVs and SNPs), the genetic background of the individual and the environmental factors.

AB - An exploratory genome-wide copy number variant (CNV) study was performed in 127 independent cases with specific language impairment (SLI), their first-degree relatives (385 individuals) and 269 population controls. Language-impaired cases showed an increased CNV burden in terms of the average number of events (11.28 vs 10.01, empirical P=0.003), the total length of CNVs (717 vs 513 Kb, empirical P=0.0001), the average CNV size (63.75 vs 51.6 Kb, empirical P=0.0005) and the number of genes spanned (14.29 vs 10.34, empirical P=0.0007) when compared with population controls, suggesting that CNVs may contribute to SLI risk. A similar trend was observed in first-degree relatives regardless of affection status. The increased burden found in our study was not driven by large or de novo events, which have been described as causative in other neurodevelopmental disorders. Nevertheless, de novo CNVs might be important on a case-by-case basis, as indicated by identification of events affecting relevant genes, such as ACTR2 and CSNK1A1, and small events within known micro-deletion/-duplication syndrome regions, such as chr8p23.1. Pathway analysis of the genes present within the CNVs of the independent cases identified significant overrepresentation of acetylcholine binding, cyclic-nucleotide phosphodiesterase activity and MHC proteins as compared with controls. Taken together, our data suggest that the majority of the risk conferred by CNVs in SLI is via common, inherited events within a 'common disorder-common variant' model. Therefore the risk conferred by CNVs will depend upon the combination of events inherited (both CNVs and SNPs), the genetic background of the individual and the environmental factors.

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