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The Capital Region of Denmark - a part of Copenhagen University Hospital
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Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk

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  1. Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

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  2. Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk

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  3. Human Disease Variation in the Light of Population Genomics

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  4. Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes

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  5. Drug-Driven Phenotypic Convergence Supports Rational Treatment Strategies of Chronic Infections

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  1. Automatically generated smartphone data and subjective stress in healthy individuals - a pilot study

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  2. The donors perceived positive and negative effects of blood donation

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  3. MAIT cell subtypes in multiple sclerosis

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  4. Early Intrathecal T Helper 17.1 Cell Activity in Huntington Disease

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Multiple sclerosis is a complex neurological disease, with ∼20% of risk heritability attributable to common genetic variants, including >230 identified by genome-wide association studies. Multiple strands of evidence suggest that much of the remaining heritability is also due to additive effects of common variants rather than epistasis between these variants or mutations exclusive to individual families. Here, we show in 68,379 cases and controls that up to 5% of this heritability is explained by low-frequency variation in gene coding sequence. We identify four novel genes driving MS risk independently of common-variant signals, highlighting key pathogenic roles for regulatory T cell homeostasis and regulation, IFNγ biology, and NFκB signaling. As low-frequency variants do not show substantial linkage disequilibrium with other variants, and as coding variants are more interpretable and experimentally tractable than non-coding variation, our discoveries constitute a rich resource for dissecting the pathobiology of MS.

Original languageEnglish
JournalCell
Volume175
Issue number6
Pages (from-to)1679-1687.e7
ISSN0092-8674
DOIs
Publication statusPublished - 29 Nov 2018

ID: 56321125