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

2017; Nature Portfolio; Volume: 2; Issue: 1 Linguagem: Inglês

10.1038/s41525-017-0027-2

2056-7944

Sigurgeir Ólafsson, Pernilla Stridh, Steffan D. Bos, Andrés Ingason, Jack Euesden, Patrick Sulem, Guðmar Þorleifsson, Ómar Gústafsson, Ari Jóhannesson, Árni Jón Geirsson, Árni V. Þórsson, Bárður Sigurgeirsson, Bjórn R. Lúdvíksson, Elías Ólafsson, Helga Kristjánsdóttir, Jón G. Jónasson, Jón Ólafsson, Kjartan B. Örvar, Rafn Benediktsson, Ragnar Bjarnason, Sjöfn Kristjánsdóttir, Þórarinn Gíslason, Trausti Valdimarsson, Evgenia Mikaelsdottir, Snævar Sigurðsson, Stefan Jonsson, Þórunn Rafnar, Dag Aarsland, Srdjan Djurovic, Tormod Fladby, Gun Peggy Knudsen, Elisabeth Gulowsen Celius, Kjell-Morten Myhr, Gerður Gröndal, Kristján Steinsson, Helgi Valdimarsson, Sigurður Björnsson, Unnur Steina Björnsdóttir, Einar S. Björnsson, Björn Nilsson, Ole A. Andreassen, Lars Alfredsson, Jan Hillert, Ingrid Kockum, Gísli Másson, Unnur Þorsteinsdóttir, Daníel F. Guðbjartsson, Hreinn Stefánsson, Haukur Hjaltason, Hanne F. Harbo, Tomas Olsson, Ingileif Jónsdóttir, Kári Stéfansson,

Celiac Disease Research and Management

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.