Elevated genetic risk for multiple sclerosis emerged in steppe pastoralist populations.
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Abstract
Multiple sclerosis (MS) is a neuro-inflammatory and neurodegenerative disease that is most prevalent in Northern Europe. Although it is known that inherited risk for MS is located within or in close proximity to immune-related genes, it is unknown when, where and how this genetic risk originated1. Here, by using a large ancient genome dataset from the Mesolithic period to the Bronze Age2, along with new Medieval and post-Medieval genomes, we show that the genetic risk for MS rose among pastoralists from the Pontic steppe and was brought into Europe by the Yamnaya-related migration approximately 5,000 years ago. We further show that these MS-associated immunogenetic variants underwent positive selection both within the steppe population and later in Europe, probably driven by pathogenic challenges coinciding with changes in diet, lifestyle and population density. This study highlights the critical importance of the Neolithic period and Bronze Age as determinants of modern immune responses and their subsequent effect on the risk of developing MS in a changing environment.
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Acknowledgements: We extend our thanks to all the former and current staff at the Lundbeck Foundation GeoGenetics Centre and the GeoGenetics Sequencing Core and to colleagues across the many institutions detailed below. We are particularly grateful to M. Madrona, L. Hansen and J. Bitz-Thorsen for laboratory assistance; to J. Hansen, S. Mularczyk, K. Thorø Michler and E. Neerup Nielsen for their help with sampling; and to L. Olsen as project manager for the Lundbeck Foundation GeoGenetics Centre project. The Lundbeck Foundation GeoGenetics Centre is supported by grants from the Lundbeck Foundation (R302-2018-2155, R155-2013-16338), the Novo Nordisk Foundation (NNF18SA0035006), the Wellcome Trust (214300), Carlsberg Foundation (CF18-0024), the Danish National Research Foundation (DNRF94, DNRF174), the University of Copenhagen (KU2016 programme), the Rise II project ‘Towards a New European Prehistory’ (M16-0455) and Ferring Pharmaceuticals A/S (to E.W.). We thank UK Biobank for access to the UK Biobank genomic resource. We also thank and acknowledge the participants and investigators of the FinnGen study. We are thankful to Illumina for collaboration. E.W. thanks St John’s College, Cambridge, for providing a stimulating environment of discussion and learning and the Lundbeck Foundation, the Novo Nordisk Foundation, the Wellcome Trust, the Carlsberg Foundation and the Danish National Research Foundation for financial support. R.N. acknowledges US National Institutes of Health grant R01GM138634. K.E.A., A.P.A., A.K.N.I. and L.F. thank the OAK Foundation.
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1476-4687
