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

Research output: Contribution to journalArticle


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 genome-wide 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.


  • Christina M Lill
  • Tian Liu
  • Brit-Maren M Schjeide
  • Johannes T Roehr
  • Denis A Akkad
  • Vincent Damotte
  • Antonio Alcina
  • Miguel A Ortiz
  • Rafa Arroyo
  • Aitzkoa Lopez de Lapuente
  • Paul Blaschke
  • Alexander Winkelmann
  • Lisa-Ann Gerdes
  • Felix Luessi
  • Oscar Fernadez
  • Guillermo Izquierdo
  • Alfredo Antigüedad
  • Sabine Hoffjan
  • Isabelle Cournu-Rebeix
  • Silvana Gromöller
  • Hans Faber
  • Maria Liebsch
  • Esther Meissner
  • Coralie Chanvillard
  • Emmanuel Touze
  • Fernando Pico
  • Philippe Corcia
  • Thomas Dörner
  • Elisabeth Steinhagen-Thiessen
  • Lars Baeckman
  • Hauke R Heekeren
  • Shu-Chen Li
  • Ulman Lindenberger
  • Andrew Chan
  • Hans-Peter Hartung
  • Orhan Aktas
  • Peter Lohse
  • Tania Kümpfel
  • Christian Kubisch
  • Joerg T Epplen
  • Uwe K Zettl
  • Bertrand Fontaine
  • Koen Vandenbroeck
  • Fuencisla Matesanz
  • Elena Urcelay
  • Lars Bertram
  • Frauke Zipp
  • ANZgene Consortium
External organisations
  • University of the Basque Country
Research areas and keywords


  • Apolipoproteins E/genetics, Databases, Genetic, European Continental Ancestry Group/genetics, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Multiple Sclerosis/genetics, Polymorphism, Single Nucleotide/genetics, Risk Factors
Original languageEnglish
Pages (from-to)558-62
JournalJournal of Medical Genetics
Issue number9
Publication statusPublished - 2012 Sep
Publication categoryResearch
Externally publishedYes