Identification of sequence variants influencing immunoglobulin levels

Stefan Jonsson; Gardar Sveinbjornsson; Aitzkoa Lopez de Lapuente Portilla; Bhairavi Swaminathan; Rosina Plomp; Gillian Dekkers; Ram Ajore; Mina Ali; Arthur E H Bentlage; Evelina Elmér; Gudmundur Ingi Eyjolfsson; Sigurjon A. Gudjonsson; Urban Gullberg; Arnaldur Gylfason; Bjarni V. Halldorsson; Markus Hansson; Hilma Holm; Åsa Johansson; Ellinor Johnsson; Aslaug Jonasdottir; Bjorn R Ludviksson; Asmundur Oddsson; Isleifur Olafsson; Sigurgeir Olafsson; Olof Sigurdardottir; Asgeir Sigurdsson; Lilja Stefansdottir; Gisli Masson; Patrick Sulem; Manfred Wuhrer; Anna-Karin Wihlborg; Gudmar Thorleifsson; Daniel F. Gudbjartsson; Unnur Thorsteinsdottir; Gestur Vidarsson; Ingileif Jonsdottir; Björn Nilsson; Kari Stefansson

doi:10.1038/ng.3897

Identification of sequence variants influencing immunoglobulin levels

Stefan Jonsson, Gardar Sveinbjornsson, Aitzkoa Lopez de Lapuente Portilla, Bhairavi Swaminathan, Rosina Plomp, Gillian Dekkers, Ram Ajore, Mina Ali, Arthur E H Bentlage, Evelina Elmér, Gudmundur Ingi Eyjolfsson, Sigurjon A. Gudjonsson, Urban Gullberg, Arnaldur Gylfason, Bjarni V. Halldorsson, Markus Hansson, Hilma Holm, Åsa Johansson, Ellinor Johnsson, Aslaug JonasdottirBjorn R Ludviksson, Asmundur Oddsson, Isleifur Olafsson, Sigurgeir Olafsson, Olof Sigurdardottir, Asgeir Sigurdsson, Lilja Stefansdottir, Gisli Masson, Patrick Sulem, Manfred Wuhrer, Anna-Karin Wihlborg, Gudmar Thorleifsson, Daniel F. Gudbjartsson, Unnur Thorsteinsdottir, Gestur Vidarsson, Ingileif Jonsdottir, Björn Nilsson, Kari Stefansson

Research output: Contribution to journal › Article › peer-review

Abstract

Immunoglobulins are the effector molecules of the adaptive humoral immune system. In a genome-wide association study of 19,219 individuals, we found 38 new variants and replicated 5 known variants associating with IgA, IgG or IgM levels or with composite immunoglobulin traits, accounted for by 32 loci. Variants at these loci also affect the risk of autoimmune diseases and blood malignancies and influence blood cell development. Notable associations include a rare variant at RUNX3 decreasing IgA levels by shifting isoform proportions (rs188468174[C>T]: P = 8.3 × 10(-55), β = -0.90 s.d.), a rare in-frame deletion in FCGR2B abolishing IgG binding to the encoded receptor (p.Asn106del: P = 4.2 × 10(-8), β = 1.03 s.d.), four IGH locus variants influencing class switching, and ten new associations with the HLA region. Our results provide new insight into the regulation of humoral immunity.

Original language	English
Pages (from-to)	1182-1191
Journal	Nature Genetics
Volume	49
Issue number	8
Early online date	2017 Jun 19
DOIs	https://doi.org/10.1038/ng.3897
Publication status	Published - 2017

Subject classification (UKÄ)

Immunology in the Medical Area (including Cell and Immunotherapy)

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10.1038/ng.3897

1 Doctoral Thesis (compilation)

Autoimmune disease – phenotypic alterations of peripheral immune cells and clinical correlates
Elmér, E., 2022, Lund: Lund University, Faculty of Medicine. 76 p.
Research output: Thesis › Doctoral Thesis (compilation)

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Genetic predisposition for multiple myeloma
Nilsson, B. (PI), Pertesi, M. (Researcher), Ajore, R. (Researcher), Wihlborg, A.-K. (Researcher), Duran Lozano, L. (Researcher), Cafaro, C. (Researcher), Johnsson, E. (Researcher), Hansson, M. (Researcher), Halvarsson, B.-M. (Researcher) & Niroula, A. (Researcher)
2011/01/03 → …
Project: Research
Genetic variation exposes regulators of blood cell formation in vivo in humans
Nilsson, B. (PI), Lopez de Lapuente Portilla, A. (Researcher), Wihlborg, A.-K. (Researcher), Ekdahl, L. (Researcher), Cafaro, C. (Researcher), Miharada, N. (Researcher), Hansson, M. (Researcher), Johnsson, E. (Researcher), Ali, Z. (Researcher), Larsson, J. (Researcher), Böiers, C. (Researcher) & Niroula, A. (Researcher)
2018/04/01 → 2023/04/30
Project: Research

Cite this

Jonsson, S., Sveinbjornsson, G., de Lapuente Portilla, A. L., Swaminathan, B., Plomp, R., Dekkers, G., Ajore, R., Ali, M., Bentlage, A. E. H., Elmér, E., Eyjolfsson, G. I., Gudjonsson, S. A., Gullberg, U., Gylfason, A., Halldorsson, B. V., Hansson, M., Holm, H., Johansson, Å., Johnsson, E., ... Stefansson, K. (2017). Identification of sequence variants influencing immunoglobulin levels. Nature Genetics, 49(8), 1182-1191. https://doi.org/10.1038/ng.3897

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title = "Identification of sequence variants influencing immunoglobulin levels",

abstract = "Immunoglobulins are the effector molecules of the adaptive humoral immune system. In a genome-wide association study of 19,219 individuals, we found 38 new variants and replicated 5 known variants associating with IgA, IgG or IgM levels or with composite immunoglobulin traits, accounted for by 32 loci. Variants at these loci also affect the risk of autoimmune diseases and blood malignancies and influence blood cell development. Notable associations include a rare variant at RUNX3 decreasing IgA levels by shifting isoform proportions (rs188468174[C>T]: P = 8.3 × 10(-55), β = -0.90 s.d.), a rare in-frame deletion in FCGR2B abolishing IgG binding to the encoded receptor (p.Asn106del: P = 4.2 × 10(-8), β = 1.03 s.d.), four IGH locus variants influencing class switching, and ten new associations with the HLA region. Our results provide new insight into the regulation of humoral immunity.",

author = "Stefan Jonsson and Gardar Sveinbjornsson and {de Lapuente Portilla}, {Aitzkoa Lopez} and Bhairavi Swaminathan and Rosina Plomp and Gillian Dekkers and Ram Ajore and Mina Ali and Bentlage, {Arthur E H} and Evelina Elm{\'e}r and Eyjolfsson, {Gudmundur Ingi} and Gudjonsson, {Sigurjon A.} and Urban Gullberg and Arnaldur Gylfason and Halldorsson, {Bjarni V.} and Markus Hansson and Hilma Holm and {\AA}sa Johansson and Ellinor Johnsson and Aslaug Jonasdottir and Ludviksson, {Bjorn R} and Asmundur Oddsson and Isleifur Olafsson and Sigurgeir Olafsson and Olof Sigurdardottir and Asgeir Sigurdsson and Lilja Stefansdottir and Gisli Masson and Patrick Sulem and Manfred Wuhrer and Anna-Karin Wihlborg and Gudmar Thorleifsson and Gudbjartsson, {Daniel F.} and Unnur Thorsteinsdottir and Gestur Vidarsson and Ingileif Jonsdottir and Bj{\"o}rn Nilsson and Kari Stefansson",

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Jonsson, S, Sveinbjornsson, G, de Lapuente Portilla, AL, Swaminathan, B, Plomp, R, Dekkers, G, Ajore, R, Ali, M, Bentlage, AEH, Elmér, E, Eyjolfsson, GI, Gudjonsson, SA, Gullberg, U, Gylfason, A, Halldorsson, BV, Hansson, M, Holm, H, Johansson, Å, Johnsson, E, Jonasdottir, A, Ludviksson, BR, Oddsson, A, Olafsson, I, Olafsson, S, Sigurdardottir, O, Sigurdsson, A, Stefansdottir, L, Masson, G, Sulem, P, Wuhrer, M, Wihlborg, A-K, Thorleifsson, G, Gudbjartsson, DF, Thorsteinsdottir, U, Vidarsson, G, Jonsdottir, I, Nilsson, B & Stefansson, K 2017, 'Identification of sequence variants influencing immunoglobulin levels', Nature Genetics, vol. 49, no. 8, pp. 1182-1191. https://doi.org/10.1038/ng.3897

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AU - Jonsson, Stefan

AU - Sveinbjornsson, Gardar

AU - de Lapuente Portilla, Aitzkoa Lopez

AU - Swaminathan, Bhairavi

AU - Plomp, Rosina

AU - Dekkers, Gillian

AU - Ajore, Ram

AU - Ali, Mina

AU - Bentlage, Arthur E H

AU - Elmér, Evelina

AU - Eyjolfsson, Gudmundur Ingi

AU - Gudjonsson, Sigurjon A.

AU - Gullberg, Urban

AU - Gylfason, Arnaldur

AU - Halldorsson, Bjarni V.

AU - Hansson, Markus

AU - Holm, Hilma

AU - Johansson, Åsa

AU - Johnsson, Ellinor

AU - Jonasdottir, Aslaug

AU - Ludviksson, Bjorn R

AU - Oddsson, Asmundur

AU - Olafsson, Isleifur

AU - Olafsson, Sigurgeir

AU - Sigurdardottir, Olof

AU - Sigurdsson, Asgeir

AU - Stefansdottir, Lilja

AU - Masson, Gisli

AU - Sulem, Patrick

AU - Wuhrer, Manfred

AU - Wihlborg, Anna-Karin

AU - Thorleifsson, Gudmar

AU - Gudbjartsson, Daniel F.

AU - Thorsteinsdottir, Unnur

AU - Vidarsson, Gestur

AU - Jonsdottir, Ingileif

AU - Nilsson, Björn

AU - Stefansson, Kari

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N2 - Immunoglobulins are the effector molecules of the adaptive humoral immune system. In a genome-wide association study of 19,219 individuals, we found 38 new variants and replicated 5 known variants associating with IgA, IgG or IgM levels or with composite immunoglobulin traits, accounted for by 32 loci. Variants at these loci also affect the risk of autoimmune diseases and blood malignancies and influence blood cell development. Notable associations include a rare variant at RUNX3 decreasing IgA levels by shifting isoform proportions (rs188468174[C>T]: P = 8.3 × 10(-55), β = -0.90 s.d.), a rare in-frame deletion in FCGR2B abolishing IgG binding to the encoded receptor (p.Asn106del: P = 4.2 × 10(-8), β = 1.03 s.d.), four IGH locus variants influencing class switching, and ten new associations with the HLA region. Our results provide new insight into the regulation of humoral immunity.

AB - Immunoglobulins are the effector molecules of the adaptive humoral immune system. In a genome-wide association study of 19,219 individuals, we found 38 new variants and replicated 5 known variants associating with IgA, IgG or IgM levels or with composite immunoglobulin traits, accounted for by 32 loci. Variants at these loci also affect the risk of autoimmune diseases and blood malignancies and influence blood cell development. Notable associations include a rare variant at RUNX3 decreasing IgA levels by shifting isoform proportions (rs188468174[C>T]: P = 8.3 × 10(-55), β = -0.90 s.d.), a rare in-frame deletion in FCGR2B abolishing IgG binding to the encoded receptor (p.Asn106del: P = 4.2 × 10(-8), β = 1.03 s.d.), four IGH locus variants influencing class switching, and ten new associations with the HLA region. Our results provide new insight into the regulation of humoral immunity.

U2 - 10.1038/ng.3897

DO - 10.1038/ng.3897

M3 - Article

C2 - 28628107

SN - 1546-1718

VL - 49

SP - 1182

EP - 1191

JO - Nature Genetics

JF - Nature Genetics

IS - 8

ER -

Identification of sequence variants influencing immunoglobulin levels

Abstract

Subject classification (UKÄ)

Access to Document

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Research output

Autoimmune disease – phenotypic alterations of peripheral immune cells and clinical correlates

Projects

Genetic predisposition for multiple myeloma

Genetic variation exposes regulators of blood cell formation in vivo in humans

Cite this