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Susceptibility to tuberculosis is associated with variants in the ASAP1 gene encoding a regulator of dendritic cell migration

Abstract

Human genetic factors predispose to tuberculosis (TB). We studied 7.6 million genetic variants in 5,530 people with pulmonary TB and in 5,607 healthy controls. In the combined analysis of these subjects and the follow-up cohort (15,087 TB patients and controls altogether), we found an association between TB and variants located in introns of the ASAP1 gene on chromosome 8q24 (P = 2.6 × 10−11 for rs4733781; P = 1.0 × 10−10 for rs10956514). Dendritic cells (DCs) showed high ASAP1 expression that was reduced after Mycobacterium tuberculosis infection, and rs10956514 was associated with the level of reduction of ASAP1 expression. The ASAP1 protein is involved in actin and membrane remodeling and has been associated with podosomes. The ASAP1-depleted DCs showed impaired matrix degradation and migration. Therefore, genetically determined excessive reduction of ASAP1 expression in M. tuberculosis–infected DCs may lead to their impaired migration, suggesting a potential mechanism of predisposition to TB.

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Figure 1: GWAS of susceptibility to TB.
Figure 2: ASAP1 expression in peripheral blood leukocytes and monocyte-derived macrophages and DCs.
Figure 3: In DCs, the ASAP1 protein is partly associated with podosomes, and its depletion leads to impaired matrix degradation and migration.

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Acknowledgements

The study was supported by Wellcome Trust grants 088838/Z/09/Z (to S.N., J.C.B., F.D.) and 095198/Z/10/Z (to S.N.), EU Framework Programme 7 Collaborative grant 201483 (to S.N., F.D., R.D.H., P.N.), European Research Council Starting grant 260477 (to S.N.), and Royal Society grants UF0763346 (to S.N.) and RG090638 (to S.N.). S.N. is a Wellcome Trust Senior Research Fellow in Basic Biomedical Science and is also supported by the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre. This study makes use of data generated by the Wellcome Trust Case-Control Consortium. A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under award 076113, 085475 and 090355.

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Authors and Affiliations

Authors

Contributions

S.N. conceived and supervised the study, participated in sample collection and data analysis, and wrote the first draft of the manuscript. J.C. prepared DNA samples and participated in their genotyping and analysis. Y.L. performed statistical analysis of the GWAS data. J.Z.L. participated in the GWAS data analysis. H.L.Z. and D.C.-L. studied DCs and performed matrix degradation and cell migration experiments. C.W. studied ASAP1 mRNA expression in leukocytes. K.L. performed expression quantitative trait locus (eQTL) analysis in DCs. M.M. and A.A. prepared cells for functional experiments. O.I., Y.B., V.N., R.D.H. and F.D. participated in study design, protocol development and sample collection. E.S. and L.K. participated in DNA sample extraction. I.B. and P.N. participated in genotyping. T.T. and C.G.M. participated in genotyping and analysis of the Ghanaian data. V.P. and J.C.B. participated in and supervised statistical analyses. All authors contributed to the writing of the manuscript.

Corresponding author

Correspondence to Sergey Nejentsev.

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The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Quality control of the GWAS samples by heterozygosity and missing genotypes rate

Dashed red lines represent QC thresholds of more than 2% missing genotype data or excess ± 3.5 standard deviation of heterozygosity rate. Samples circled in red were excluded from the association study.

Supplementary Figure 2 Principal component analysis (PCA) of the Russian GWAS samples

(a) First and second principal components. Russian samples are plotted with ten HapMap3 populations (ASW – African ancestry in Southwest USA; CEU – Utah residents of European ancestry; CHB – Han Chinese in Beijing, China; CHD – Chinese in Metropolitan Denver, Colorado; JPT – Japanese in Tokyo, Japan; GIH – Gujarati Indians in Houston, Texas; LWK – Luhya in Webuye, Kenya; MKK – Maasai in Kinyawa, Kenya; TSI – Tuscans in Italy; YRI – Yoruba in Ibadan, Nigeria).

(b) All GWAS samples plotted on the first two principal components colored by the city of sample origin.

(c) Russian TB cases and controls projected onto the first two principal components using SNP weights precomputed from European samples in the 1000 Genomes Phase III project (CEU — Utah residents with Northern and Western European ancestry; IBS — Iberian populations in Spain; FIN — Finnish in Finland; GBR — British in England and Scotland; and TSI — Toscani in Italy) using SNPweights (Chen, C.Y. et al. Improved ancestry inference using weights from external reference panels. Bioinformatics 29, 1399-1406 (2013)).

Supplementary Figure 3 The quantile - quantile plot of the observed versus the expected –log10P-values under the null for 7,614,862 SNPs from the GWAS results after genotype imputation

The diagonal black line is y = x, and the grey shapes show 95% confidence interval under the null. The overall distribution has a genomic inflation factor (λGC) of 1.10.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–3 (PDF 391 kb)

Supplementary Tables

Supplementary Tables 1–3 and 5–7 (PDF 215 kb)

Supplementary Table 4

TB association in the Russian GWAS for loci that previously were associated with Inflammatory Bowel Disease (XLS 48 kb)

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Curtis, J., Luo, Y., Zenner, H. et al. Susceptibility to tuberculosis is associated with variants in the ASAP1 gene encoding a regulator of dendritic cell migration. Nat Genet 47, 523–527 (2015). https://doi.org/10.1038/ng.3248

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