Fourteen sequence variants that associate with multiple sclerosis discovered by meta-analysis informed by genetic correlations View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2017-12

AUTHORS

Sigurgeir Olafsson, Pernilla Stridh, Steffan Daniël Bos, Andres Ingason, Jack Euesden, Patrick Sulem, Gudmar Thorleifsson, Omar Gustafsson, Ari Johannesson, Arni J. Geirsson, Arni V. Thorsson, Bardur Sigurgeirsson, Bjorn Runar Ludviksson, Elias Olafsson, Helga Kristjansdottir, Jon G. Jonasson, Jon Hjaltalin Olafsson, Kjartan B. Orvar, Rafn Benediktsson, Ragnar Bjarnason, Sjofn Kristjansdottir, Thorarinn Gislason, Trausti Valdimarsson, Evgenia Mikaelsdottir, Snaevar Sigurdsson, Stefan Jonsson, Thorunn Rafnar, Dag Aarsland, Srdjan Djurovic, Tormod Fladby, Gun Peggy Knudsen, Elisabeth G. Celius, Kjell-Morten Myhr, Gerdur Grondal, Kristjan Steinsson, Helgi Valdimarsson, Sigurdur Bjornsson, Unnur S. Bjornsdottir, Einar S Bjornsson, Bjorn Nilsson, Ole A. Andreassen, Lars Alfredsson, Jan Hillert, Ingrid Skelton Kockum, Gisli Masson, Unnur Thorsteinsdottir, Daniel F. Gudbjartsson, Hreinn Stefansson, Haukur Hjaltason, Hanne F. Harbo, Tomas Olsson, Ingileif Jonsdottir, Kari Stefansson

ABSTRACT

A meta-analysis of publicly available summary statistics on multiple sclerosis combined with three Nordic multiple sclerosis cohorts (21,079 cases, 371,198 controls) revealed seven sequence variants associating with multiple sclerosis, not reported previously. Using polygenic risk scores based on public summary statistics of variants outside the major histocompatibility complex region we quantified genetic overlap between common autoimmune diseases in Icelanders and identified disease clusters characterized by autoantibody presence/absence. As multiple sclerosis-polygenic risk scores captures the risk of primary biliary cirrhosis and vice versa (P = 1.6 × 10-7, 4.3 × 10-9) we used primary biliary cirrhosis as a proxy-phenotype for multiple sclerosis, the idea being that variants conferring risk of primary biliary cirrhosis have a prior probability of conferring risk of multiple sclerosis. We tested 255 variants forming the primary biliary cirrhosis-polygenic risk score and found seven multiple sclerosis-associating variants not correlated with any previously established multiple sclerosis variants. Most of the variants discovered are close to or within immune-related genes. One is a low-frequency missense variant in TYK2, another is a missense variant in MTHFR that reduces the function of the encoded enzyme affecting methionine metabolism, reported to be dysregulated in multiple sclerosis brain. More... »

PAGES

24

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41525-017-0027-2

    DOI

    http://dx.doi.org/10.1038/s41525-017-0027-2

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1091025244

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/29263835


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