Closing the case of APOE in multiple sclerosis: No association with disease risk in over 29 000 subjects

Australia and New Zealand Multiple Sclerosis Genetics Consortium (ANZgene)

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18 Citations (Scopus)

Abstract

Background: Single nucleotide polymorphisms (SNPs) rs429358 (ε4) and rs7412 (ε2), both invoking changes in the amino-acid sequence of the apolipoprotein E (APOE) gene, have previously been tested for association with multiple sclerosis (MS) risk. However, none of these studies was sufficiently powered to detect modest effect sizes at acceptable type-I error rates. As both SNPs are only imperfectly captured on commonly used microarray genotyping platforms, their evaluation in the context of genome-wide association studies has been hindered until recently. Methods: We genotyped 12 740 subjects hitherto not studied for their APOE status, imputed raw genotype data from 8739 subjects from five independent genomewide association studies datasets using the most recent high-resolution reference panels, and extracted genotype data for 8265 subjects from previous candidate gene assessments. Results: Despite sufficient power to detect associations at genome-wide significance thresholds across a range of ORs, our analyses did not support a role of rs429358 or rs7412 on MS susceptibility. This included meta-analyses of the combined data across 13 913 MS cases and 15 831 controls (OR=0.95, p=0.259, and OR 1.07, p=0.0569, for rs429358 and rs7412, respectively). Conclusion: Given the large sample size of our analyses, it is unlikely that the two APOE missense SNPs studied here exert any relevant effects on MS susceptibility.

Original languageEnglish
Pages (from-to)558-562
Number of pages5
JournalJournal of Medical Genetics
Volume49
Issue number9
DOIs
Publication statusPublished - 1 Sep 2012
Externally publishedYes

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Apolipoproteins E
Multiple Sclerosis
Single Nucleotide Polymorphism
Genotype
Genome-Wide Association Study
Sample Size
Genes
Meta-Analysis
Amino Acid Sequence
Genome

Cite this

Australia and New Zealand Multiple Sclerosis Genetics Consortium (ANZgene). / Closing the case of APOE in multiple sclerosis : No association with disease risk in over 29 000 subjects. In: Journal of Medical Genetics. 2012 ; Vol. 49, No. 9. pp. 558-562.
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abstract = "Background: Single nucleotide polymorphisms (SNPs) rs429358 (ε4) and rs7412 (ε2), both invoking changes in the amino-acid sequence of the apolipoprotein E (APOE) gene, have previously been tested for association with multiple sclerosis (MS) risk. However, none of these studies was sufficiently powered to detect modest effect sizes at acceptable type-I error rates. As both SNPs are only imperfectly captured on commonly used microarray genotyping platforms, their evaluation in the context of genome-wide association studies has been hindered until recently. Methods: We genotyped 12 740 subjects hitherto not studied for their APOE status, imputed raw genotype data from 8739 subjects from five independent genomewide association studies datasets using the most recent high-resolution reference panels, and extracted genotype data for 8265 subjects from previous candidate gene assessments. Results: Despite sufficient power to detect associations at genome-wide significance thresholds across a range of ORs, our analyses did not support a role of rs429358 or rs7412 on MS susceptibility. This included meta-analyses of the combined data across 13 913 MS cases and 15 831 controls (OR=0.95, p=0.259, and OR 1.07, p=0.0569, for rs429358 and rs7412, respectively). Conclusion: Given the large sample size of our analyses, it is unlikely that the two APOE missense SNPs studied here exert any relevant effects on MS susceptibility.",
author = "{Australia and New Zealand Multiple Sclerosis Genetics Consortium (ANZgene)} and Lill, {Christina M.} and Tian Liu and Schjeide, {Brit Maren M.} and Roehr, {Johannes T.} and Akkad, {Denis A.} and Vincent Damotte and Antonio Alcina and Ortiz, {Miguel A.} and Rafa Arroyo and {de Lapuente}, {Aitzkoa Lopez} and Paul Blaschke and Alexander Winkelmann and Gerdes, {Lisa Ann} and Felix Luessi and Oscar Fernadez and Guillermo Izquierdo and Alfredo Antig{\"u}edad and Sabine Hoffjan and Isabelle Cournu-Rebeix and Silvana Grom{\"o}ller and Hans Faber and Maria Liebsch and Esther Meissner and Coralie Chanvillard and Emmanuel Touze and Fernando Pico and Philippe Corcia and Thomas D{\"o}rner and Elisabeth Steinhagen-Thiessen and Lars Baeckman and Heekeren, {Hauke R.} and Li, {Shu Chen} and Ulman Lindenberger and Andrew Chan and Hartung, {Hans Peter} and Orhan Aktas and Peter Lohse and Tania K{\"u}mpfel and Christian Kubisch and Epplen, {Joerg T.} and Zettl, {Uwe K.} and Bertrand Fontaine and Koen Vandenbroeck and Fuencisla Matesanz and Elena Urcelay and Lars Bertram and Frauke Zipp and Melanie Bahlo and Booth, {David R.} and Broadley, {Simon A.} and Brown, {Matthew A.} and Browning, {Brian L.} and Browning, {Sharon R.} and Helmut Butzkueven and Carroll, {William M.} and Cox, {Mathew B.} and Caron Chapman and Glynnis Clarke and Patrick Danoy and Karen Drysdale and Judith Field and Foote, {Simon J.} and Greer, {Judith M.} and Griffiths, {Lyn R.} and Jensen, {Cathy J.} and Johnson, {Laura J.} and Kermode, {Allan G.} and Heard, {Robert N.} and Kilpatrick, {Trevor J.} and Jeanette Lechner-Scott and Mark Marriott and Deborah Mason and Pablo Moscato and Pender, {Michael P.} and Perreau, {Victoria M.} and Rubio, {Justin P.} and Scott, {Rodney J.} and Mark Slee and Jim Stankovich and Stewart, {Graeme J.} and Lotfi Tajouri and Taylor, {Bruce V.} and James Wiley and Wilkins, {Ella J.}",
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Closing the case of APOE in multiple sclerosis : No association with disease risk in over 29 000 subjects. / Australia and New Zealand Multiple Sclerosis Genetics Consortium (ANZgene).

In: Journal of Medical Genetics, Vol. 49, No. 9, 01.09.2012, p. 558-562.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Closing the case of APOE in multiple sclerosis

T2 - No association with disease risk in over 29 000 subjects

AU - Australia and New Zealand Multiple Sclerosis Genetics Consortium (ANZgene)

AU - Lill, Christina M.

AU - Liu, Tian

AU - Schjeide, Brit Maren M.

AU - Roehr, Johannes T.

AU - Akkad, Denis A.

AU - Damotte, Vincent

AU - Alcina, Antonio

AU - Ortiz, Miguel A.

AU - Arroyo, Rafa

AU - de Lapuente, Aitzkoa Lopez

AU - Blaschke, Paul

AU - Winkelmann, Alexander

AU - Gerdes, Lisa Ann

AU - Luessi, Felix

AU - Fernadez, Oscar

AU - Izquierdo, Guillermo

AU - Antigüedad, Alfredo

AU - Hoffjan, Sabine

AU - Cournu-Rebeix, Isabelle

AU - Gromöller, Silvana

AU - Faber, Hans

AU - Liebsch, Maria

AU - Meissner, Esther

AU - Chanvillard, Coralie

AU - Touze, Emmanuel

AU - Pico, Fernando

AU - Corcia, Philippe

AU - Dörner, Thomas

AU - Steinhagen-Thiessen, Elisabeth

AU - Baeckman, Lars

AU - Heekeren, Hauke R.

AU - Li, Shu Chen

AU - Lindenberger, Ulman

AU - Chan, Andrew

AU - Hartung, Hans Peter

AU - Aktas, Orhan

AU - Lohse, Peter

AU - Kümpfel, Tania

AU - Kubisch, Christian

AU - Epplen, Joerg T.

AU - Zettl, Uwe K.

AU - Fontaine, Bertrand

AU - Vandenbroeck, Koen

AU - Matesanz, Fuencisla

AU - Urcelay, Elena

AU - Bertram, Lars

AU - Zipp, Frauke

AU - Bahlo, Melanie

AU - Booth, David R.

AU - Broadley, Simon A.

AU - Brown, Matthew A.

AU - Browning, Brian L.

AU - Browning, Sharon R.

AU - Butzkueven, Helmut

AU - Carroll, William M.

AU - Cox, Mathew B.

AU - Chapman, Caron

AU - Clarke, Glynnis

AU - Danoy, Patrick

AU - Drysdale, Karen

AU - Field, Judith

AU - Foote, Simon J.

AU - Greer, Judith M.

AU - Griffiths, Lyn R.

AU - Jensen, Cathy J.

AU - Johnson, Laura J.

AU - Kermode, Allan G.

AU - Heard, Robert N.

AU - Kilpatrick, Trevor J.

AU - Lechner-Scott, Jeanette

AU - Marriott, Mark

AU - Mason, Deborah

AU - Moscato, Pablo

AU - Pender, Michael P.

AU - Perreau, Victoria M.

AU - Rubio, Justin P.

AU - Scott, Rodney J.

AU - Slee, Mark

AU - Stankovich, Jim

AU - Stewart, Graeme J.

AU - Tajouri, Lotfi

AU - Taylor, Bruce V.

AU - Wiley, James

AU - Wilkins, Ella J.

PY - 2012/9/1

Y1 - 2012/9/1

N2 - Background: Single nucleotide polymorphisms (SNPs) rs429358 (ε4) and rs7412 (ε2), both invoking changes in the amino-acid sequence of the apolipoprotein E (APOE) gene, have previously been tested for association with multiple sclerosis (MS) risk. However, none of these studies was sufficiently powered to detect modest effect sizes at acceptable type-I error rates. As both SNPs are only imperfectly captured on commonly used microarray genotyping platforms, their evaluation in the context of genome-wide association studies has been hindered until recently. Methods: We genotyped 12 740 subjects hitherto not studied for their APOE status, imputed raw genotype data from 8739 subjects from five independent genomewide association studies datasets using the most recent high-resolution reference panels, and extracted genotype data for 8265 subjects from previous candidate gene assessments. Results: Despite sufficient power to detect associations at genome-wide significance thresholds across a range of ORs, our analyses did not support a role of rs429358 or rs7412 on MS susceptibility. This included meta-analyses of the combined data across 13 913 MS cases and 15 831 controls (OR=0.95, p=0.259, and OR 1.07, p=0.0569, for rs429358 and rs7412, respectively). Conclusion: Given the large sample size of our analyses, it is unlikely that the two APOE missense SNPs studied here exert any relevant effects on MS susceptibility.

AB - Background: Single nucleotide polymorphisms (SNPs) rs429358 (ε4) and rs7412 (ε2), both invoking changes in the amino-acid sequence of the apolipoprotein E (APOE) gene, have previously been tested for association with multiple sclerosis (MS) risk. However, none of these studies was sufficiently powered to detect modest effect sizes at acceptable type-I error rates. As both SNPs are only imperfectly captured on commonly used microarray genotyping platforms, their evaluation in the context of genome-wide association studies has been hindered until recently. Methods: We genotyped 12 740 subjects hitherto not studied for their APOE status, imputed raw genotype data from 8739 subjects from five independent genomewide association studies datasets using the most recent high-resolution reference panels, and extracted genotype data for 8265 subjects from previous candidate gene assessments. Results: Despite sufficient power to detect associations at genome-wide significance thresholds across a range of ORs, our analyses did not support a role of rs429358 or rs7412 on MS susceptibility. This included meta-analyses of the combined data across 13 913 MS cases and 15 831 controls (OR=0.95, p=0.259, and OR 1.07, p=0.0569, for rs429358 and rs7412, respectively). Conclusion: Given the large sample size of our analyses, it is unlikely that the two APOE missense SNPs studied here exert any relevant effects on MS susceptibility.

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U2 - 10.1136/jmedgenet-2012-101175

DO - 10.1136/jmedgenet-2012-101175

M3 - Article

VL - 49

SP - 558

EP - 562

JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

SN - 0022-2593

IS - 9

ER -