Identification of genetic risk loci associated with aquaporin 4-positive neuromyelitis optica spectrum disorder: a genome-wide association study

BACKGROUND: Little is known about the causes of serum aquaporin 4 (AQP4) antibody-positive neuromyelitis optica spectrum disorder (AQP4-positive NMOSD) or how its pathophysiology differs from other demyelinating autoimmune diseases, which limits therapeutic and preventative opportunities despite available diagnostic biomarkers. By performing a pan-ancestry genome-wide association study (GWAS), we aimed to deepen our understanding of the genetic architecture of AQP4-positive NMOSD and to explore shared heritability with other autoimmune diseases. METHODS: We performed a pan-ancestry GWAS in 2833 individuals, including 1573 AQP4-positive NMOSD cases and 1260 controls (comprising non-affected relatives, healthy non-relatives, and those with other autoimmune diseases). Samples were collected from the International NMOSD Genetics Consortium, comprising 36 hospitals and research facilities across the world. All individuals with AQP4-positive NMOSD fulfilled the 2015 international consensus diagnostic criteria for NMOSD, including positive AQP4-IgG status. We also performed a second GWAS with only the 1857 samples of European ancestry (803 cases and 1054 controls). We then compared our GWAS findings to those from other autoimmune diseases. FINDINGS: , OR 2·68, 95% CI 2·22-3·24). A priori testing of the P1104A variant (rs34536443, chr19:10352442:G>C) within the TYK2 gene, which acts upstream in the STAT4 pathway, found it to be protective (p=0·0008, OR 0·52, 95% CI 0·35-0·76 in the pan-ancestry study). Genetic sharing was observed with several comorbid autoimmune diseases for both the complement C4A-associated and STAT4-associated variants, including Sjögren's syndrome and systemic lupus erythematosus. INTERPRETATION: T cells, owing to both a genome-wide significant association of HLA-DRB1*03:01 as well as heritable risk within the TYK2-STAT4 signalling pathway. Having already been shown to be a successful target for treating psoriatic arthritis and, potentially, systemic lupus erythematosus, we propose the TYK2-STAT4 pathway as a possible therapeutic target in AQP4-positive NMOSD. FUNDING: The OAK Foundation, The Guthy Jackson Charitable Trust Foundation, and the UK Medical Research Council.

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Journal
The Lancet Neurology
Published
2026-04-17
DOI
https://doi.org/10.1016/s1474-4422(26)00084-0
Citations
1
Primary Topic
Multiple Sclerosis Research Studies
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article
Field-Weighted Citation Impact
19.85

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article

Identification of genetic risk loci associated with aquaporin 4-positive neuromyelitis optica spectrum disorder: a genome-wide association study

Gil McVean, Andrés Villa, Jacinta M. Behne, Raffaele Federico Iorio et al.
1 citations
The Lancet Neurology
Multiple Sclerosis Research Studies
19.85
article

Identification of genetic risk loci associated with aquaporin 4-positive neuromyelitis optica spectrum disorder: a genome-wide association study

Gil McVean, Andrés Villa, Jacinta M. Behne, Raffaele Federico Iorio, Kathrine E. Attfield, Lou Brundin, Subita Balaram Kuttikkatte, Tania Kümpfel, Patrick Waters, Katrin Giglhuber, Lars Fugger, Alexander Zimprich, Chanjira Satukijchai, Lise Torp Jensen, Maria Hastermann, Nasrin Asgari, Calliope Athena Dendrou, Ellen Iacobaeus, Ayako Sakoda, Sasitorn Siritho, Saif Huda, Ernestina Santos, Markus Reindl, Corinna Trebst, Thomas Korn, Janine Meyer, Pentti J. Tienari, Martin W. Hümmert, Redwan Farooq, Sven Jarius, Jamie Rossjohn, Jyh Yung Hor, Jelena Drulović, Angelos P. Armen, Romain Marignier, Manuel Comabella-López, Anna Francis, Konrad J. Karczewski, Lisa Revie, Luisa Klotz, Mohamad Ali Sahraian, Irena Dujmovic Basuroski, Mohsen Khademi, Yolanda Blanco, Ralf Gold, Been Olafur Sveinsson, Mitsuru Watanabe, Keiko Tanaka, Anu Jacob, Noriko Isobe, Marcelo Matiello, Xavier Montalban, Brian G Weinshenker, Benjamin M Neale, Michael Yeaman, Brigitte Wildemann, Jun-ichi Kira, Angela Vincent, Dagur Inge Jonsson, Maria Sepúlveda, Neil Robertson, Achim Berthele, Paulus Rommer, Friedemann Paul, Orhan Aktas, Ilya Ayzenberg, Masami Tanaka, Maj Lisa Frankenberg, Megan Kenneally, Thomas Berger, Larry Cook, Jacqueline Palace, M Isabel Leite, Marius Ringelstein, Judith Bellmann-Strobl, Tomas Olsson
article en
1 citations

Abstract

BACKGROUND: Little is known about the causes of serum aquaporin 4 (AQP4) antibody-positive neuromyelitis optica spectrum disorder (AQP4-positive NMOSD) or how its pathophysiology differs from other demyelinating autoimmune diseases, which limits therapeutic and preventative opportunities despite available diagnostic biomarkers. By performing a pan-ancestry genome-wide association study (GWAS), we aimed to deepen our understanding of the genetic architecture of AQP4-positive NMOSD and to explore shared heritability with other autoimmune diseases. METHODS: We performed a pan-ancestry GWAS in 2833 individuals, including 1573 AQP4-positive NMOSD cases and 1260 controls (comprising non-affected relatives, healthy non-relatives, and those with other autoimmune diseases). Samples were collected from the International NMOSD Genetics Consortium, comprising 36 hospitals and research facilities across the world. All individuals with AQP4-positive NMOSD fulfilled the 2015 international consensus diagnostic criteria for NMOSD, including positive AQP4-IgG status. We also performed a second GWAS with only the 1857 samples of European ancestry (803 cases and 1054 controls). We then compared our GWAS findings to those from other autoimmune diseases. FINDINGS: , OR 2·68, 95% CI 2·22-3·24). A priori testing of the P1104A variant (rs34536443, chr19:10352442:G>C) within the TYK2 gene, which acts upstream in the STAT4 pathway, found it to be protective (p=0·0008, OR 0·52, 95% CI 0·35-0·76 in the pan-ancestry study). Genetic sharing was observed with several comorbid autoimmune diseases for both the complement C4A-associated and STAT4-associated variants, including Sjögren's syndrome and systemic lupus erythematosus. INTERPRETATION: T cells, owing to both a genome-wide significant association of HLA-DRB1*03:01 as well as heritable risk within the TYK2-STAT4 signalling pathway. Having already been shown to be a successful target for treating psoriatic arthritis and, potentially, systemic lupus erythematosus, we propose the TYK2-STAT4 pathway as a possible therapeutic target in AQP4-positive NMOSD. FUNDING: The OAK Foundation, The Guthy Jackson Charitable Trust Foundation, and the UK Medical Research Council.

The Lancet NeurologyVol. 25(5)
Broad Institute (US), Mayo Clinic (US), Nuffield Orthopaedic Centre (GB), Aarhus University Hospital (DK), TUM Klinikum (DE), John Radcliffe Hospital (GB), University of Oxford (GB), Mayo Clinic in Arizona (US), St. Josef-Hospital (DE), Mayo Clinic in Florida (US), Institute of Infection and Immunity (CA), University of Virginia (US), Ruhr University Bochum (DE)
Oak Foundation, Guthy-Jackson Charitable Foundation, Medical Research Council
Zero hunger
Openalex Percentile: Top 1%
Multiple Sclerosis Research Studies
19.85
DOIOpen Access PDFOpenAlex
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