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

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


Titill: Fourteen sequence variants that associate with multiple sclerosis discovered by meta-analysis informed by genetic correlations
Höfundur: Ólafsson, Sigurgeir   orcid.org/0000-0003-1711-2757
Stridh, Pernilla
Bos, Steffan Daniël
Ingason, Andrés
Euesden, Jack
Sulem, Patrick   orcid.org/0000-0001-7123-6123
Thorleifsson, Gudmar   orcid.org/0000-0003-4623-9087
Gústafsson, Ómar
Jóhannesson, Ari
Geirsson, Árni J.
... 43 fleiri höfundar Sýna alla höfunda
Útgáfa: 2017-08-08
Tungumál: Enska
Umfang: 24
Háskóli/Stofnun: Háskóli Íslands
University of Iceland
Svið: Heilbrigðisvísindasvið (HÍ)
School of Health Sciences (UI)
Verkfræði- og náttúruvísindasvið (HÍ)
School of Engineering and Natural Sciences (UI)
Deild: Læknadeild (HÍ)
Faculty of Medicine (UI)
Birtist í: npj Genomic Medicine;2(1)
ISSN: 2056-7944
DOI: 10.1038/s41525-017-0027-2
Efnisorð: Genome-wide association studies; Multiple sclerosis; MS sjúkdómur; Erfðafræði; Rannsóknir
URI: https://hdl.handle.net/20.500.11815/577

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Tilvitnun:

Olafsson, S., Stridh, P., Bos, S. D., Ingason, A., Euesden, J., Sulem, P., . . . Stefansson, K. (2017). Fourteen sequence variants that associate with multiple sclerosis discovered by meta-analysis informed by genetic correlations. npj Genomic Medicine, 2(1), 24. doi:10.1038/s41525-017-0027-2

Útdráttur:

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.

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