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

Olafsson, Sigurgeir; Stridh, Pernilla; Bos, Steffan Daniël; Ingason, Andres; Euesden, Jack; Sulem, Patrick; Thorleifsson, Gudmar; Gustafsson, Omar; Johannesson, Ari and Geirsson, Arni J., et al. (2017) In npj Genomic Medicine 2(1).
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... (More)

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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npj Genomic Medicine
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  • scopus:85042299417
DOI
10.1038/s41525-017-0027-2
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2018-03-09 12:47:51
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@article{e7a61e6b-fa4d-41f2-a091-9e246e6a4b36,
  abstract     = {<p>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<sup>-7</sup>, 4.3 × 10<sup>-9</sup>) 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.</p>},
  articleno    = {24},
  author       = {Olafsson, Sigurgeir and Stridh, Pernilla and Bos, Steffan Daniël and Ingason, Andres and Euesden, Jack and Sulem, Patrick and Thorleifsson, Gudmar and Gustafsson, Omar and Johannesson, Ari and Geirsson, Arni J. and Thorsson, Arni V. and Sigurgeirsson, Bardur and Ludviksson, Bjorn Runar and Olafsson, Elias and Kristjansdottir, Helga and Jonasson, Jon G. and Olafsson, Jon Hjaltalin and Orvar, Kjartan B. and Benediktsson, Rafn and Bjarnason, Ragnar and Kristjansdottir, Sjofn and Gislason, Thorarinn and Valdimarsson, Trausti and Mikaelsdottir, Evgenia and Sigurdsson, Snaevar and Jonsson, Stefan and Rafnar, Thorunn and Aarsland, Dag and Djurovic, Srdjan and Fladby, Tormod and Knudsen, Gun Peggy and Celius, Elisabeth G. and Myhr, Kjell Morten and Grondal, Gerdur and Steinsson, Kristjan and Valdimarsson, Helgi and Bjornsson, Sigurdur and Bjornsdottir, Unnur S. and Bjornsson, Einar S. and Nilsson, Bjorn and Andreassen, Ole A. and Alfredsson, Lars and Hillert, Jan and Kockum, Ingrid Skelton and Masson, Gisli and Thorsteinsdottir, Unnur and Gudbjartsson, Daniel F. and Stefansson, Hreinn and Hjaltason, Haukur and Harbo, Hanne F. and Olsson, Tomas and Jonsdottir, Ingileif and Stefansson, Kari},
  language     = {eng},
  number       = {1},
  publisher    = {Nature Publishing Group},
  series       = {npj Genomic Medicine},
  title        = {Fourteen sequence variants that associate with multiple sclerosis discovered by meta-analysis informed by genetic correlations},
  url          = {http://dx.doi.org/10.1038/s41525-017-0027-2},
  volume       = {2},
  year         = {2017},
}