Genotypic variability based association identifies novel non-additive loci DHCR7 and IRF4 in sero-negative rheumatoid arthritis

Abstract Sero-negative rheumatoid arthritis (RA) is a highly heterogeneous disorder with only a few additive loci identified to date. We report a genotypic variability-based genome-wide association study (vGWAS) of six cohorts of sero-negative RA recruited in Europe and the US that were genotyped wi...

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Autores principales:	Wen-Hua Wei, Sebastien Viatte, Tony R. Merriman, Anne Barton, Jane Worthington
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/8b4958a4495d40b89377dd5449f32cbc
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spelling	oai:doaj.org-article:8b4958a4495d40b89377dd5449f32cbc2021-12-02T12:32:27ZGenotypic variability based association identifies novel non-additive loci DHCR7 and IRF4 in sero-negative rheumatoid arthritis10.1038/s41598-017-05447-12045-2322https://doaj.org/article/8b4958a4495d40b89377dd5449f32cbc2017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-05447-1https://doaj.org/toc/2045-2322Abstract Sero-negative rheumatoid arthritis (RA) is a highly heterogeneous disorder with only a few additive loci identified to date. We report a genotypic variability-based genome-wide association study (vGWAS) of six cohorts of sero-negative RA recruited in Europe and the US that were genotyped with the Immunochip. A two-stage approach was used: (1) a mixed model to partition dichotomous phenotypes into an additive component and non-additive residuals on the liability scale and (2) the Levene’s test to assess equality of the residual variances across genotype groups. The vGWAS identified rs2852853 (P = 1.3e-08, DHCR7) and rs62389423 (P = 1.8e-05, near IRF4) in addition to two previously identified loci (HLA-DQB1 and ANKRD55), which were all statistically validated using cross validation. DHCR7 encodes an enzyme important in cutaneous synthesis of vitamin D and DHCR7 mutations are believed to be important for early humans to adapt to Northern Europe where residents have reduced ultraviolet-B exposure and tend to have light skin color. IRF4 is a key locus responsible for skin color, with a vitamin D receptor-binding interval. These vGWAS results together suggest that vitamin D deficiency is potentially causal of sero-negative RA and provide new insights into the pathogenesis of the disorder.Wen-Hua WeiSebastien ViatteTony R. MerrimanAnne BartonJane WorthingtonNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-7 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Wen-Hua Wei Sebastien Viatte Tony R. Merriman Anne Barton Jane Worthington Genotypic variability based association identifies novel non-additive loci DHCR7 and IRF4 in sero-negative rheumatoid arthritis
description	Abstract Sero-negative rheumatoid arthritis (RA) is a highly heterogeneous disorder with only a few additive loci identified to date. We report a genotypic variability-based genome-wide association study (vGWAS) of six cohorts of sero-negative RA recruited in Europe and the US that were genotyped with the Immunochip. A two-stage approach was used: (1) a mixed model to partition dichotomous phenotypes into an additive component and non-additive residuals on the liability scale and (2) the Levene’s test to assess equality of the residual variances across genotype groups. The vGWAS identified rs2852853 (P = 1.3e-08, DHCR7) and rs62389423 (P = 1.8e-05, near IRF4) in addition to two previously identified loci (HLA-DQB1 and ANKRD55), which were all statistically validated using cross validation. DHCR7 encodes an enzyme important in cutaneous synthesis of vitamin D and DHCR7 mutations are believed to be important for early humans to adapt to Northern Europe where residents have reduced ultraviolet-B exposure and tend to have light skin color. IRF4 is a key locus responsible for skin color, with a vitamin D receptor-binding interval. These vGWAS results together suggest that vitamin D deficiency is potentially causal of sero-negative RA and provide new insights into the pathogenesis of the disorder.
format	article
author	Wen-Hua Wei Sebastien Viatte Tony R. Merriman Anne Barton Jane Worthington
author_facet	Wen-Hua Wei Sebastien Viatte Tony R. Merriman Anne Barton Jane Worthington
author_sort	Wen-Hua Wei
title	Genotypic variability based association identifies novel non-additive loci DHCR7 and IRF4 in sero-negative rheumatoid arthritis
title_short	Genotypic variability based association identifies novel non-additive loci DHCR7 and IRF4 in sero-negative rheumatoid arthritis
title_full	Genotypic variability based association identifies novel non-additive loci DHCR7 and IRF4 in sero-negative rheumatoid arthritis
title_fullStr	Genotypic variability based association identifies novel non-additive loci DHCR7 and IRF4 in sero-negative rheumatoid arthritis
title_full_unstemmed	Genotypic variability based association identifies novel non-additive loci DHCR7 and IRF4 in sero-negative rheumatoid arthritis
title_sort	genotypic variability based association identifies novel non-additive loci dhcr7 and irf4 in sero-negative rheumatoid arthritis
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/8b4958a4495d40b89377dd5449f32cbc
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Genotypic variability based association identifies novel non-additive loci DHCR7 and IRF4 in sero-negative rheumatoid arthritis

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