A genome-wide study shows a limited contribution of rare copy number variants to Alzheimer's disease risk.

Elliott Rees; Dobril Ivanov; George Kirov; Denise Harold; Rebecca Sims; Amy Gerrish; Jade Chapman; Valentina Moskvina; Richard Abraham; Paul Hollingworth; Marian Hamshere; Jaspreet Singh Pahwa; Kimberley Dowzell; Amy Williams; Nicola Jones; Charlene Thomas; Alexandra Stretton; Angharad Morgan; Kate Williams; Sophie Thomas; Simon Lovestone; John Powell; Petroula Proitsi; Michelle K Lupton; Carol Brayne; David C Rubinsztein; Michael Gill; Brian Lawlor; Aoibhinn Lynch; Kevin Morgan; Kristelle Brown; Peter Passmore; David Craig; Bernadette McGuinness; Janet A Johnston; Stephen Todd; Clive Holmes; David Mann; A David Smith; Seth Love; Patrick G Kehoe; John Hardy; Rita Guerreiro; Andrew Singleton; Simon Mead; Nick Fox; Martin Rossor; John Collinge; Wolfgang Maier; Frank Jessen; Reiner Heun; Heike Kölsch; Britta Schürmann; Alfredo Ramirez; Hendrik van den Bussche; Isabella Heuser; Johannes Kornhuber; Jens Wiltfang; Martin Dichgans; Lutz Frölich; Harald Hampel; Michael Hüll; Dan Rujescu; Alison Goate; John S K Kauwe; Carlos Cruchaga; Petra Nowotny; John C Morris; Kevin Mayo; Gill Livingston; Nicholas J Bass; Hugh Gurling; Andrew McQuillin; Rhian Gwilliam; Panagiotis Deloukas; Markus M Nöthen; Peter Holmans; Michael O'Donovan; Michael J Owen; Julie Williams

doi:10.1093/hmg/dds476

A genome-wide study shows a limited contribution of rare copy number variants to Alzheimer's disease risk.

Elliott Rees, Dobril Ivanov, George Kirov, Denise Harold (Collaborator), Rebecca Sims (Collaborator), Amy Gerrish (Collaborator), Jade Chapman (Collaborator), Valentina Moskvina (Collaborator), Richard Abraham (Collaborator), Paul Hollingworth (Collaborator), Marian Hamshere (Collaborator), Jaspreet Singh Pahwa (Collaborator), Kimberley Dowzell (Collaborator), Amy Williams (Collaborator), Nicola Jones (Collaborator), Charlene Thomas (Collaborator), Alexandra Stretton (Collaborator), Angharad Morgan (Collaborator), Kate Williams (Collaborator), Sophie Thomas (Collaborator)Simon Lovestone (Collaborator), John Powell (Collaborator), Petroula Proitsi (Collaborator), Michelle K Lupton (Collaborator), Carol Brayne (Collaborator), David C Rubinsztein (Collaborator), Michael Gill (Collaborator), Brian Lawlor (Collaborator), Aoibhinn Lynch (Collaborator), Kevin Morgan (Collaborator), Kristelle Brown (Collaborator), Peter Passmore (Collaborator), David Craig (Collaborator), Bernadette McGuinness (Collaborator), Janet A Johnston (Collaborator), Stephen Todd (Collaborator), Clive Holmes (Collaborator), David Mann (Collaborator), A David Smith (Collaborator), Seth Love (Collaborator), Patrick G Kehoe (Collaborator), John Hardy (Collaborator), Rita Guerreiro (Collaborator), Andrew Singleton (Collaborator), Simon Mead (Collaborator), Nick Fox (Collaborator), Martin Rossor (Collaborator), John Collinge (Collaborator), Wolfgang Maier (Collaborator), Frank Jessen (Collaborator), Reiner Heun (Collaborator), Heike Kölsch (Collaborator), Britta Schürmann (Collaborator), Alfredo Ramirez (Collaborator), Hendrik van den Bussche (Collaborator), Isabella Heuser (Collaborator), Johannes Kornhuber (Collaborator), Jens Wiltfang (Collaborator), Martin Dichgans (Collaborator), Lutz Frölich (Collaborator), Harald Hampel (Collaborator), Michael Hüll (Collaborator), Dan Rujescu (Collaborator), Alison Goate (Collaborator), John S K Kauwe (Collaborator), Carlos Cruchaga (Collaborator), Petra Nowotny (Collaborator), John C Morris (Collaborator), Kevin Mayo (Collaborator), Gill Livingston (Collaborator), Nicholas J Bass (Collaborator), Hugh Gurling (Collaborator), Andrew McQuillin (Collaborator), Rhian Gwilliam (Collaborator), Panagiotis Deloukas (Collaborator), Markus M Nöthen (Collaborator), Peter Holmans (Collaborator), Michael O'Donovan (Collaborator), Michael J Owen (Collaborator), Julie Williams (Collaborator)

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

Abstract

We assessed the role of rare copy number variants (CNVs) in Alzheimer's disease (AD) using intensity data from 3260 AD cases and 1290 age-matched controls from the genome-wide association study (GWAS) conducted by the Genetic and Environmental Risk for Alzheimer's disease Consortium (GERAD). We did not observe a significant excess of rare CNVs in cases, although we did identify duplications overlapping APP and CR1 which may be pathogenic. We looked for an excess of CNVs in loci which have been highlighted in previous AD CNV studies, but did not replicate previous findings. Through pathway analyses, we observed suggestive evidence for biological overlap between single nucleotide polymorphisms and CNVs in AD susceptibility. We also identified that our sample of elderly controls harbours significantly fewer deletions >1 Mb than younger control sets in previous CNV studies on schizophrenia and bipolar disorder (P = 8.9 × 10(-4) and 0.024, respectively), raising the possibility that healthy elderly individuals have a reduced rate of large deletions. Thus, in contrast to diseases such as schizophrenia, autism and attention deficit/hyperactivity disorder, CNVs do not appear to make a significant contribution to the development of AD.

Original language	English
Article number	dds476
Pages (from-to)	816-824
Number of pages	8
Journal	Human Molecular Genetics
Volume	22
Issue number	4
DOIs	https://doi.org/10.1093/hmg/dds476
Publication status	Published - 15 Feb 2013

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10.1093/hmg/dds476

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Rees, E., Ivanov, D., Kirov, G., Harold, D., Sims, R., Gerrish, A., Chapman, J., Moskvina, V., Abraham, R., Hollingworth, P., Hamshere, M., Pahwa, J. S., Dowzell, K., Williams, A., Jones, N., Thomas, C., Stretton, A., Morgan, A., Williams, K., ... Williams, J. (2013). A genome-wide study shows a limited contribution of rare copy number variants to Alzheimer's disease risk. Human Molecular Genetics, 22(4), 816-824. Article dds476. https://doi.org/10.1093/hmg/dds476

@article{5326da647ed34062be49d9d2bcae6751,

title = "A genome-wide study shows a limited contribution of rare copy number variants to Alzheimer's disease risk.",

abstract = "We assessed the role of rare copy number variants (CNVs) in Alzheimer's disease (AD) using intensity data from 3260 AD cases and 1290 age-matched controls from the genome-wide association study (GWAS) conducted by the Genetic and Environmental Risk for Alzheimer's disease Consortium (GERAD). We did not observe a significant excess of rare CNVs in cases, although we did identify duplications overlapping APP and CR1 which may be pathogenic. We looked for an excess of CNVs in loci which have been highlighted in previous AD CNV studies, but did not replicate previous findings. Through pathway analyses, we observed suggestive evidence for biological overlap between single nucleotide polymorphisms and CNVs in AD susceptibility. We also identified that our sample of elderly controls harbours significantly fewer deletions >1 Mb than younger control sets in previous CNV studies on schizophrenia and bipolar disorder (P = 8.9 × 10(-4) and 0.024, respectively), raising the possibility that healthy elderly individuals have a reduced rate of large deletions. Thus, in contrast to diseases such as schizophrenia, autism and attention deficit/hyperactivity disorder, CNVs do not appear to make a significant contribution to the development of AD.",

author = "Elliott Rees and Dobril Ivanov and George Kirov and Denise Harold and Rebecca Sims and Amy Gerrish and Jade Chapman and Valentina Moskvina and Richard Abraham and Paul Hollingworth and Marian Hamshere and Pahwa, {Jaspreet Singh} and Kimberley Dowzell and Amy Williams and Nicola Jones and Charlene Thomas and Alexandra Stretton and Angharad Morgan and Kate Williams and Sophie Thomas and Simon Lovestone and John Powell and Petroula Proitsi and Lupton, {Michelle K} and Carol Brayne and Rubinsztein, {David C} and Michael Gill and Brian Lawlor and Aoibhinn Lynch and Kevin Morgan and Kristelle Brown and Peter Passmore and David Craig and Bernadette McGuinness and Johnston, {Janet A} and Stephen Todd and Clive Holmes and David Mann and Smith, {A David} and Seth Love and Kehoe, {Patrick G} and John Hardy and Rita Guerreiro and Andrew Singleton and Simon Mead and Nick Fox and Martin Rossor and John Collinge and Wolfgang Maier and Frank Jessen and Reiner Heun and Heike K{\"o}lsch and Britta Sch{\"u}rmann and Alfredo Ramirez and {van den Bussche}, Hendrik and Isabella Heuser and Johannes Kornhuber and Jens Wiltfang and Martin Dichgans and Lutz Fr{\"o}lich and Harald Hampel and Michael H{\"u}ll and Dan Rujescu and Alison Goate and Kauwe, {John S K} and Carlos Cruchaga and Petra Nowotny and Morris, {John C} and Kevin Mayo and Gill Livingston and Bass, {Nicholas J} and Hugh Gurling and Andrew McQuillin and Rhian Gwilliam and Panagiotis Deloukas and N{\"o}then, {Markus M} and Peter Holmans and Michael O'Donovan and Owen, {Michael J} and Julie Williams",

note = "095317, Wellcome Trust, United KingdomG0300429, Medical Research Council, United KingdomG0902227, Medical Research Council, United KingdomGR082604MA, Wellcome Trust, United KingdomMC_U123192748, Medical Research Council, United KingdomP01-AG026276, NIA NIH HHS, United StatesP01-AG03991, NIA NIH HHS, United StatesP50-AG05681, NIA NIH HHS, United StatesR01-AG16208, NIA NIH HHS, United StatesU24 AG021886, NIA NIH HHS, United States",

year = "2013",

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doi = "10.1093/hmg/dds476",

language = "English",

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journal = "Human Molecular Genetics",

issn = "1460-2083",

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Rees, E, Ivanov, D, Kirov, G, Harold, D, Sims, R, Gerrish, A, Chapman, J, Moskvina, V, Abraham, R, Hollingworth, P, Hamshere, M, Pahwa, JS, Dowzell, K, Williams, A, Jones, N, Thomas, C, Stretton, A, Morgan, A, Williams, K, Thomas, S, Lovestone, S, Powell, J, Proitsi, P, Lupton, MK, Brayne, C, Rubinsztein, DC, Gill, M, Lawlor, B, Lynch, A, Morgan, K, Brown, K, Passmore, P, Craig, D, McGuinness, B, Johnston, JA, Todd, S, Holmes, C, Mann, D, Smith, AD, Love, S, Kehoe, PG, Hardy, J, Guerreiro, R, Singleton, A, Mead, S, Fox, N, Rossor, M, Collinge, J, Maier, W, Jessen, F, Heun, R, Kölsch, H, Schürmann, B, Ramirez, A, van den Bussche, H, Heuser, I, Kornhuber, J, Wiltfang, J, Dichgans, M, Frölich, L, Hampel, H, Hüll, M, Rujescu, D, Goate, A, Kauwe, JSK, Cruchaga, C, Nowotny, P, Morris, JC, Mayo, K, Livingston, G, Bass, NJ, Gurling, H, McQuillin, A, Gwilliam, R, Deloukas, P, Nöthen, MM, Holmans, P, O'Donovan, M, Owen, MJ & Williams, J 2013, 'A genome-wide study shows a limited contribution of rare copy number variants to Alzheimer's disease risk.', Human Molecular Genetics, vol. 22, no. 4, dds476, pp. 816-824. https://doi.org/10.1093/hmg/dds476

TY - JOUR

T1 - A genome-wide study shows a limited contribution of rare copy number variants to Alzheimer's disease risk.

AU - Rees, Elliott

AU - Ivanov, Dobril

AU - Kirov, George

A2 - Harold, Denise

A2 - Sims, Rebecca

A2 - Gerrish, Amy

A2 - Chapman, Jade

A2 - Moskvina, Valentina

A2 - Abraham, Richard

A2 - Hollingworth, Paul

A2 - Hamshere, Marian

A2 - Pahwa, Jaspreet Singh

A2 - Dowzell, Kimberley

A2 - Williams, Amy

A2 - Jones, Nicola

A2 - Thomas, Charlene

A2 - Stretton, Alexandra

A2 - Morgan, Angharad

A2 - Williams, Kate

A2 - Thomas, Sophie

A2 - Lovestone, Simon

A2 - Powell, John

A2 - Proitsi, Petroula

A2 - Lupton, Michelle K

A2 - Brayne, Carol

A2 - Rubinsztein, David C

A2 - Gill, Michael

A2 - Lawlor, Brian

A2 - Lynch, Aoibhinn

A2 - Morgan, Kevin

A2 - Brown, Kristelle

A2 - Passmore, Peter

A2 - Craig, David

A2 - McGuinness, Bernadette

A2 - Johnston, Janet A

A2 - Todd, Stephen

A2 - Holmes, Clive

A2 - Mann, David

A2 - Smith, A David

A2 - Love, Seth

A2 - Kehoe, Patrick G

A2 - Hardy, John

A2 - Guerreiro, Rita

A2 - Singleton, Andrew

A2 - Mead, Simon

A2 - Fox, Nick

A2 - Rossor, Martin

A2 - Collinge, John

A2 - Maier, Wolfgang

A2 - Jessen, Frank

A2 - Heun, Reiner

A2 - Kölsch, Heike

A2 - Schürmann, Britta

A2 - Ramirez, Alfredo

A2 - van den Bussche, Hendrik

A2 - Heuser, Isabella

A2 - Kornhuber, Johannes

A2 - Wiltfang, Jens

A2 - Dichgans, Martin

A2 - Frölich, Lutz

A2 - Hampel, Harald

A2 - Hüll, Michael

A2 - Rujescu, Dan

A2 - Goate, Alison

A2 - Kauwe, John S K

A2 - Cruchaga, Carlos

A2 - Nowotny, Petra

A2 - Morris, John C

A2 - Mayo, Kevin

A2 - Livingston, Gill

A2 - Bass, Nicholas J

A2 - Gurling, Hugh

A2 - McQuillin, Andrew

A2 - Gwilliam, Rhian

A2 - Deloukas, Panagiotis

A2 - Nöthen, Markus M

A2 - Holmans, Peter

A2 - O'Donovan, Michael

A2 - Owen, Michael J

A2 - Williams, Julie

N1 - 095317, Wellcome Trust, United KingdomG0300429, Medical Research Council, United KingdomG0902227, Medical Research Council, United KingdomGR082604MA, Wellcome Trust, United KingdomMC_U123192748, Medical Research Council, United KingdomP01-AG026276, NIA NIH HHS, United StatesP01-AG03991, NIA NIH HHS, United StatesP50-AG05681, NIA NIH HHS, United StatesR01-AG16208, NIA NIH HHS, United StatesU24 AG021886, NIA NIH HHS, United States

PY - 2013/2/15

Y1 - 2013/2/15

N2 - We assessed the role of rare copy number variants (CNVs) in Alzheimer's disease (AD) using intensity data from 3260 AD cases and 1290 age-matched controls from the genome-wide association study (GWAS) conducted by the Genetic and Environmental Risk for Alzheimer's disease Consortium (GERAD). We did not observe a significant excess of rare CNVs in cases, although we did identify duplications overlapping APP and CR1 which may be pathogenic. We looked for an excess of CNVs in loci which have been highlighted in previous AD CNV studies, but did not replicate previous findings. Through pathway analyses, we observed suggestive evidence for biological overlap between single nucleotide polymorphisms and CNVs in AD susceptibility. We also identified that our sample of elderly controls harbours significantly fewer deletions >1 Mb than younger control sets in previous CNV studies on schizophrenia and bipolar disorder (P = 8.9 × 10(-4) and 0.024, respectively), raising the possibility that healthy elderly individuals have a reduced rate of large deletions. Thus, in contrast to diseases such as schizophrenia, autism and attention deficit/hyperactivity disorder, CNVs do not appear to make a significant contribution to the development of AD.

AB - We assessed the role of rare copy number variants (CNVs) in Alzheimer's disease (AD) using intensity data from 3260 AD cases and 1290 age-matched controls from the genome-wide association study (GWAS) conducted by the Genetic and Environmental Risk for Alzheimer's disease Consortium (GERAD). We did not observe a significant excess of rare CNVs in cases, although we did identify duplications overlapping APP and CR1 which may be pathogenic. We looked for an excess of CNVs in loci which have been highlighted in previous AD CNV studies, but did not replicate previous findings. Through pathway analyses, we observed suggestive evidence for biological overlap between single nucleotide polymorphisms and CNVs in AD susceptibility. We also identified that our sample of elderly controls harbours significantly fewer deletions >1 Mb than younger control sets in previous CNV studies on schizophrenia and bipolar disorder (P = 8.9 × 10(-4) and 0.024, respectively), raising the possibility that healthy elderly individuals have a reduced rate of large deletions. Thus, in contrast to diseases such as schizophrenia, autism and attention deficit/hyperactivity disorder, CNVs do not appear to make a significant contribution to the development of AD.

U2 - 10.1093/hmg/dds476

DO - 10.1093/hmg/dds476

M3 - Article

C2 - 23148125

SN - 1460-2083

VL - 22

SP - 816

EP - 824

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 4

M1 - dds476

ER -

A genome-wide study shows a limited contribution of rare copy number variants to Alzheimer's disease risk.

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