Genome-wide association study identifies susceptibility loci for IgA nephropathy

Abstract

We carried out a genome-wide association study of IgA nephropathy, a major cause of kidney failure worldwide. We studied 1,194 cases and 902 controls of Chinese Han ancestry, with targeted follow up in Chinese and European cohorts comprising 1,950 cases and 1,920 controls. We identified three independent loci in the major histocompatibility complex, as well as a common deletion of CFHR1 and CFHR3 at chromosome 1q32 and a locus at chromosome 22q12 that each surpassed genome-wide significance (P values for association between 1.59 × 10−26 and 4.84 × 10−9 and minor allele odds ratios of 0.63–0.80). These five loci explain 4–7% of the disease variance and up to a tenfold variation in interindividual risk. Many of the alleles that protect against IgA nephropathy impart increased risk for other autoimmune or infectious diseases, and IgA nephropathy risk allele frequencies closely parallel the variation in disease prevalence among Asian, European and African populations, suggesting complex selective pressures.

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Figure 1: Manhattan plot of P values for SNP associations to IgA nephropathy.
Figure 2: High-resolution view of MHC locus.
Figure 3: Analysis of the chromosome 1 and chromosome 22 loci.
Figure 4: Differences in the distributions of protective alleles by subject ancestry.

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Acknowledgements

We are grateful to all study participants for their contribution to this work. We also thank the staff of the Yale West Campus Center for Genome Analysis for their excellent support. We also appreciate the assistance of C.V. Barker and S.Y. Woodford with sample collection. This study was supported by RC1DK087445 (A.G.G., R.P.L.), R01DK082753 (A.G.G., J.N., B.A.J. and R.J.W.) and KL2 RR24157 (K.K.), the Center for Glomerular Diseases at Columbia University, the Yale Center Translational Science Award and the Yale Center for Human Genetics and Genomics. R.P.L. is an investigator of the Howard Hughes Medical Institute.

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Contributions

Subject clinical characterization, recruitment and contribution of samples: P.H., J.X., S.S.C., B.A.J., R.J.W., J.N., J.C.H., H.W., J.L., L.Z., W.W., Z.W., S.S., R. Magistroni, G.M.G., M.B., P.R., C.P., L.A., G.B., G.F., A. Amore, L.P., R.C., C.I., B.F.V., E.P., M.S., R. Mignani, L.G., F.B., P.M., A. Amoroso, F.S., N.C. and H.Z.

DNA preparation: Y.L., P.H., J.X., F.L., I.B., K.K., C.J.M. and M.C.

Genotyping and wet lab experiments: S.M., S.U., I.T., C.J.M., M.C., P.H., J.X. and Y.L.

Data management: K.K., Y.L., S.S.C. and M.C.

Data analysis: K.K., M.C., A.G.G. and R.P.L.

Analytical support and discussion: K.Y. and M.G.

Manuscript preparation: A.G.G., K.K., M.C. and R.P.L.

Conception and overall supervision of project: A.G.G. and R.P.L.

Corresponding authors

Correspondence to Ali G Gharavi or Richard P Lifton.

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The authors declare no competing financial interests.

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Supplementary Note, Supplementary Tables 1–17 and Supplementary Figures 1–8. (PDF 2083 kb)

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Gharavi, A., Kiryluk, K., Choi, M. et al. Genome-wide association study identifies susceptibility loci for IgA nephropathy. Nat Genet 43, 321–327 (2011). https://doi.org/10.1038/ng.787

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