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

journal contribution
posted on 2023-05-17, 15:54 authored by Lill, CM, Liu, T, Schjeide, B-MM, Roehr, JT, Akkad, DA, Damotte, V, Alcina, A, Ortiz, MA, Arroyo, R, de Lapuente, AL, Blaschke, P, Winkelmann, A, Gerdes, L-A, Luessi, F, Fernadez, O, Izquierdo, G, Antiguedad, A, Hoffjan, S, Cournu-Rebeix, I, Gromoller, S, Faber, H, Liebsch, M, Meissner, E, Chanvillard, C, Touze, E, Pico, F, Corcia, P, Bahlo, M, Booth, DR, Broadley, SA, Brown, MA, Browning, BL, Browning, SR, Butzkueven, H, Carroll, WM, Cox, MB, Chapman, C, Clarke, G, Danoy, P, Drysdale, K, Field, J, Simon James FooteSimon James Foote, Greer, JM, Griffiths, LR, Hadler, J, Jensen, CJ, Johnson, LJ, Kermode, AG, Heard, RN, Kilpatrick, TJ, Lechner-Scott, J, Marriott, M, Mason, D, Moscato, P, Pender, MP, Perreau, VM, Rubio, JP, Scott, RJ, Slee, M, Stankovich, J, Stewart, GJ, Tajouri, L, Bruce TaylorBruce Taylor, Wiley, J, Wilkins, EJ, Dorner, T, Steinhagen-Thiessen, E, Baeckman, L, Heekeren, HR, Li, S-C, Lindenberger, U, Chan, A, Hartung, H-P, Aktas, O, Lohse, P, Kumpfel, T, Kubisch, C, Epplen, JT, Zettl, U, Fontaine, B, Vandenbroeck, K, Matesanz, F, Urcelay, E, Bertram, L, Zipp, F

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.


Publication title

Journal of Medical Genetics










Menzies Institute for Medical Research


BMJ Group

Place of publication

United Kingdom

Rights statement

Copyright 2012 British Medical Journal Publishing Group

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  • Restricted

Socio-economic Objectives

Clinical health not elsewhere classified

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