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NPJ Genom Med. 2017 Aug 8;2:24. doi: 10.1038/s41525-017-0027-2. eCollection 2017.

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

Author information

1
deCODE genetics/Amgen, Reykjavik, Iceland.
2
Department of Clinical Neuroscience, Karolinska Institutet, Center for Molecular Medicine, Stockholm, Sweden.
3
Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
4
Department of Neurology, Oslo University Hospital, Oslo, Norway.
5
MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College, London, UK.
6
Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
7
Department of Medicine, Landspitali, the National University Hospital of Iceland, Reykjavik, Iceland.
8
Center for Rheumatology Research, Landspitali, the National University Hospital of Iceland, Reykjavik, Iceland.
9
Children's Medical Center, Landspitali, the National University Hospital of Iceland, Reykjavik, Iceland.
10
Department of Dermatology, Faculty of Medicine, School of Health Sciences, University of Iceland, Kopavogur, Iceland.
11
Department of Immunology, Landspitali, the National University Hospital of Iceland, Reykjavik, Iceland.
12
Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
13
Department of Neurology, Landspitali, the National University Hospital of Iceland, Reykjavik, Iceland.
14
Department of Pathology, Landspitali, the National University Hospital of Iceland, Reykjavik, Iceland.
15
The Medical Center, Glaesibae, Reykjavik, Iceland.
16
Department of Endocrinology and Metabolic Medicine, Landspitali, the National University Hospital of Iceland, Reykjavik, Iceland.
17
Department of Respiratory Medicine and Sleep, Landspitali, the National University Hospital of Iceland, Reykjavik, Iceland.
18
Department of Medicine, West Iceland Healthcare Centre, Akranes, Iceland.
19
Department of Old Age Psychiatry, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, UK.
20
Division of Psychiatry, Stavanger University Hospital, Stavanger, Norway.
21
Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
22
Department of Neurology, Akershus University Hospital, Lørenskog, Norway.
23
Norwegian Institute of Public Health, Oslo, Norway.
24
Department of Neurology, Oslo University Hospital Ullevål, Oslo, Norway.
25
Institute of Health and Society, Faculty of Medicine, University of Oslo, Oslo, Norway.
26
Department of Clinical Medicine, University of Bergen, Bergen, Norway.
27
Department of Neurology, Norwegian MS-Registry and Biobank, Haukeland University Hospital, Bergen, Norway.
28
Department of Rheumatology, Landspitali, the National University Hospital of Iceland, Reykjavik, Iceland.
29
Department of Laboratory Medicine, Hematology and Transfusion Medicine, BMC, Lund, Sweden.
30
Division of Mental Health and Addiction, NORMENT, KG Jebsen Centre for Psychosis Research, Oslo University Hospital, Oslo, Norway.
31
Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
32
Centre for Occupational and Environmental Medicine, Stockholm County Council, Stockholm, Sweden.
33
School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.

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.

Conflict of interest statement

The authors who are affiliated with deCODE are all employees of deCODE genetics/Amgen Inc.

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