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

Research output: Contribution to journalArticle

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.

Details

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
  • 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
Organisations
External organisations
  • deCODE Genetics/Amgen, Inc.
  • Karolinska Institutet
  • University of Oslo
  • Oslo university hospital
  • King's College London
  • University of Bristol
  • National University Hospital of Iceland
  • University of Iceland
  • Stavanger University Hospital
  • Akershus University Hospital
  • Norwegian Institute of Public Health
  • University of Bergen
  • Haukeland University Hospital
  • Stockholm County Council
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medical Genetics
Original languageEnglish
Article number24
Journalnpj Genomic Medicine
Volume2
Issue number1
Publication statusPublished - 2017 Dec
Publication categoryResearch
Peer-reviewedYes