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The Contribution of the Functional IL6R Polymorphism rs2228145, eQTLs and Other Genome-Wide SNPs to the Heritability of Plasma sIL-6R Levels

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Abstract

The non-synonymous SNP rs2228145 in the IL6R gene on chromosome 1q21.3 is associated with a wide range of common diseases, including asthma, rheumatoid arthritis, type 1 diabetes and coronary heart disease. We examined the contribution of this functional IL6R gene polymorphism rs2228145 versus other genome-wide SNPs to the variance of sIL-6R levels in blood plasma in a large population-based sample (N ~5,000), and conducted an expression QTL analysis to identify SNPs associated with IL6R gene expression. Based on data from 2,360 twin families, the broad heritability of sIL-6R was estimated at 72 and 51 % of the total variance was explained by the functional SNP rs2228145. Converging findings from GWAS, linkage, and GCTA analyses indicate that additional variance of sIL-6R levels can be explained by other variants in the IL6R region, including variants at the 3′-end of IL6R tagged by rs60760897 that are associated with IL6R RNA expression.

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Acknowledgments

This work was supported by: Genotype/phenotype database for behavior genetic and genetic epidemiological studies (ZonMW Middelgroot [911-09-032]); Genetics of Mental Illness: A lifespan approach to the genetics of childhood and adult neuropsychiatric disorders and comorbid conditions [ERC-230374]; multiple grants for genotyping and expression data, funded by Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL) [184.021.007]; the National Instiute for Mental Health (NIMH) [1RC2 MH089951-01: Integration of Genomics & Transcriptomics in Normal Twins & Major Depression, and 1RC2MH089995-01: Genomics of Developmental Trajectories in Twins]; and Nederlandse organisatie voor Wetenschappelijk Onderzoek (NWO) [NWO/SPI 56-464-14192].

Conflict of interest

All authors declare that they have no conflict of interest.

Informed Consent

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki declaration of 1975, as revised in 2000 (5). Informed consent was obtained from all patients for being included in the study.

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Authors and Affiliations

  1. Department of Biological Psychology, VU University Amsterdam, Van der Boechorststraat 1, 1081 BT, Amsterdam, The Netherlands

    Jenny van Dongen, Dirk Smit, Jouke-Jan Hottenga, Hamdi Mbarek, Gonneke Willemsen, Dorret I. Boomsma & Eco J. C. de Geus

  2. EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, The Netherlands

    Jenny van Dongen, Jouke-Jan Hottenga, Hamdi Mbarek, Gonneke Willemsen, Brenda W. J. Penninx, Dorret I. Boomsma & Eco J. C. de Geus

  3. Department of Psychiatry, VU University Medical Center, Amsterdam, The Netherlands

    Rick Jansen & Brenda W. J. Penninx

  4. Neuroscience Campus Amsterdam, Amsterdam, The Netherlands

    Rick Jansen, Dirk Smit, Brenda W. J. Penninx & Dorret I. Boomsma

  5. Good Biomarker Sciences, Leiden, The Netherlands

    Cornelis Kluft

  6. Queensland Institute of Medical Research, Herston, QLD, Australia

    Manuel A. Ferreira

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  1. Jenny van Dongen
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Correspondence to Jenny van Dongen.

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Edited by Sarah Medland.

Dorret I. Boomsma and Eco J. C. de Geus have contributed equally to this study.

Australian Asthma Genetics Consortium (AAGC), the full list of authors is given in the Supplementary material.

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van Dongen, J., Jansen, R., Smit, D. et al. The Contribution of the Functional IL6R Polymorphism rs2228145, eQTLs and Other Genome-Wide SNPs to the Heritability of Plasma sIL-6R Levels. Behav Genet 44, 368–382 (2014). https://doi.org/10.1007/s10519-014-9656-8

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