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

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 pu...

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Published in:npj Genomic Medicine
Main Authors: Ólafsson, Sigurgeir, Stridh, Pernilla, Bos, Steffan Daniël, Ingason, Andrés, Euesden, Jack, sulem, patrick, Thorleifsson, Gudmar, Gústafsson, Ómar, Jóhannesson, Ari, Geirsson, Árni J., Þórsson, Árni V., Sigurgeirsson, Bárður, Ludviksson, Bjorn, Ólafsson, Elías, Kristjansdottir, Helga, Jónasson, Jón G., Ólafsson, Jón Hjaltalín, Örvar, Kjartan B., Benediktsson, Rafn, Bjarnason, Ragnar Grímur, Kristjánsdóttir, Sjöfn, Gislason, Thorarinn, Valdimarsson, Trausti, Mikaelsdóttir, Evgenía, Sigurðsson, Snævar, Jonsson, Stefan, Rafnar, Thorunn, Aarsland, Dag, Djurovic, Srdjan, Fladby, Tormod, Knudsen, Gun Peggy, Celius, Elisabeth G., Myhr, Kjell-Morten, Gröndal, Gerður, Steinsson, Kristján, Valdimarsson, Helgi, Björnsson, Sigurður, Björnsdóttir, Unnur Steina, Björnsson, Einar Stefán, Nilsson, Bjorn, Andreassen, Ole A., Alfredsson, Lars, Hillert, Jan, Kockum, Ingrid Skelton, Másson, Gísli, Thorsteinsdottir, Unnur, Gudbjartsson, Daniel, Stefansson, Hreinn, Hjaltason, Haukur, Harbo, Hanne F.
Other Authors: Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Verkfræði- og náttúruvísindasvið (HÍ), School of Engineering and Natural Sciences (UI), Háskóli Íslands, University of Iceland
Format: Article in Journal/Newspaper
Language:English
Published: Springer Nature 2017
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Online Access:https://hdl.handle.net/20.500.11815/577
https://doi.org/10.1038/s41525-017-0027-2
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Summary: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. We are grateful to all the participants in the study. We thank Theodora Baldursdottir and Ottar M. Bergmann for validating the clinical information on PBC in Iceland. We acknowledge that this work would not have been possible without the important contribution of the staff at recruitment centers and genotyping and informatics facilities in deCODE Genetics and the MS research group at Oslo University Hospital and The Norwegian MS Registry and Biobank, Bergen Norway. We also thank the International MS Genetics Consortium and the Wellcome Trust Case Control Consortium for collaboration in the genotyping of the Norwegian ...