Geographic differences in genetic susceptibility to IgA nephropathy

GWAS replication study and geospatial risk analysis

Krzysztof Kiryluk, Yifu Li, Simone Sanna-Cherchi, Mersedeh Rohanizadegan, Hitoshi Suzuki, Frank Eitner, Holly J. Snyder, Murim Choi, Ping Hou, Francesco Scolari, Claudia Izzi, Maddalena Gigante, Loreto Gesualdo, Silvana Savoldi, Antonio Amoroso, Daniele Cusi, Pasquale Zamboli, Bruce A. Julian, Jan Novak, Robert J. Wyatt & 28 others Krzysztof Mucha, Markus Perola, Kati Kristiansson, Alexander Viktorin, Patrik K. Magnusson, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Kari Stefansson, Anne Boland, Marie Metzger, Lise Thibaudin, Christoph Wanner, Kitty J. Jager, Shin Goto, Dita Maixnerova, Hussein H. Karnib, J. Nagy, Ulf Panzer, Jingyuan Xie, Nan Chen, Vladimir Tesar, Ichiei Narita, Francois Berthoux, Jürgen Floege, Benedicte Stengel, Hong Zhang, Richard P. Lifton, Ali G. Gharavi

Research output: Contribution to journalArticle

172 Citations (Scopus)

Abstract

IgA nephropathy (IgAN), major cause of kidney failure worldwide, is common in Asians, moderately prevalent in Europeans, and rare in Africans. It is not known if these differences represent variation in genes, environment, or ascertainment. In a recent GWAS, we localized five IgAN susceptibility loci on Chr.6p21 (HLA-DQB1/DRB1, PSMB9/TAP1, and DPA1/DPB2 loci), Chr.1q32 (CFHR3/R1 locus), and Chr.22q12 (HORMAD2 locus). These IgAN loci are associated with risk of other immune-mediated disorders such as type I diabetes, multiple sclerosis, or inflammatory bowel disease. We tested association of these loci in eight new independent cohorts of Asian, European, and African-American ancestry (N = 4,789), followed by meta-analysis with risk-score modeling in 12 cohorts (N = 10,755) and geospatial analysis in 85 world populations. Four susceptibility loci robustly replicated and all five loci were genome-wide significant in the combined cohort (P = 5×10-32-3×10-10), with heterogeneity detected only at the PSMB9/TAP1 locus (I2 = 0.60). Conditional analyses identified two new independent risk alleles within the HLA-DQB1/DRB1 locus, defining multiple risk and protective haplotypes within this interval. We also detected a significant genetic interaction, whereby the odds ratio for the HORMAD2 protective allele was reversed in homozygotes for a CFHR3/R1 deletion (P = 2.5×10-4). A seven-SNP genetic risk score, which explained 4.7% of overall IgAN risk, increased sharply with Eastward and Northward distance from Africa (r = 0.30, P = 3×10-128). This model paralleled the known East-West gradient in disease risk. Moreover, the prediction of a South-North axis was confirmed by registry data showing that the prevalence of IgAN-attributable kidney failure is increased in Northern Europe, similar to multiple sclerosis and type I diabetes. Variation at IgAN susceptibility loci correlates with differences in disease prevalence among world populations. These findings inform genetic, biological, and epidemiological investigations of IgAN and permit cross-comparison with other complex traits that share genetic risk loci and geographic patterns with IgAN.

Original languageEnglish
Article numbere1002765
JournalPLoS Genetics
Volume8
Issue number6
DOIs
Publication statusPublished - Jun 2012

Fingerprint

risk analysis
Genome-Wide Association Study
Genetic Predisposition to Disease
kidney diseases
Immunoglobulin A
loci
HLA-DRB1 Chains
diabetes
Type 1 Diabetes Mellitus
Multiple Sclerosis
Renal Insufficiency
allele
insulin-dependent diabetes mellitus
Alleles
sclerosis
renal failure
disease prevalence
Genetic Loci
African American
Immune System Diseases

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

Kiryluk, K., Li, Y., Sanna-Cherchi, S., Rohanizadegan, M., Suzuki, H., Eitner, F., ... Gharavi, A. G. (2012). Geographic differences in genetic susceptibility to IgA nephropathy: GWAS replication study and geospatial risk analysis. PLoS Genetics, 8(6), [e1002765]. https://doi.org/10.1371/journal.pgen.1002765

Geographic differences in genetic susceptibility to IgA nephropathy : GWAS replication study and geospatial risk analysis. / Kiryluk, Krzysztof; Li, Yifu; Sanna-Cherchi, Simone; Rohanizadegan, Mersedeh; Suzuki, Hitoshi; Eitner, Frank; Snyder, Holly J.; Choi, Murim; Hou, Ping; Scolari, Francesco; Izzi, Claudia; Gigante, Maddalena; Gesualdo, Loreto; Savoldi, Silvana; Amoroso, Antonio; Cusi, Daniele; Zamboli, Pasquale; Julian, Bruce A.; Novak, Jan; Wyatt, Robert J.; Mucha, Krzysztof; Perola, Markus; Kristiansson, Kati; Viktorin, Alexander; Magnusson, Patrik K.; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Stefansson, Kari; Boland, Anne; Metzger, Marie; Thibaudin, Lise; Wanner, Christoph; Jager, Kitty J.; Goto, Shin; Maixnerova, Dita; Karnib, Hussein H.; Nagy, J.; Panzer, Ulf; Xie, Jingyuan; Chen, Nan; Tesar, Vladimir; Narita, Ichiei; Berthoux, Francois; Floege, Jürgen; Stengel, Benedicte; Zhang, Hong; Lifton, Richard P.; Gharavi, Ali G.

In: PLoS Genetics, Vol. 8, No. 6, e1002765, 06.2012.

Research output: Contribution to journalArticle

Kiryluk, K, Li, Y, Sanna-Cherchi, S, Rohanizadegan, M, Suzuki, H, Eitner, F, Snyder, HJ, Choi, M, Hou, P, Scolari, F, Izzi, C, Gigante, M, Gesualdo, L, Savoldi, S, Amoroso, A, Cusi, D, Zamboli, P, Julian, BA, Novak, J, Wyatt, RJ, Mucha, K, Perola, M, Kristiansson, K, Viktorin, A, Magnusson, PK, Thorleifsson, G, Thorsteinsdottir, U, Stefansson, K, Boland, A, Metzger, M, Thibaudin, L, Wanner, C, Jager, KJ, Goto, S, Maixnerova, D, Karnib, HH, Nagy, J, Panzer, U, Xie, J, Chen, N, Tesar, V, Narita, I, Berthoux, F, Floege, J, Stengel, B, Zhang, H, Lifton, RP & Gharavi, AG 2012, 'Geographic differences in genetic susceptibility to IgA nephropathy: GWAS replication study and geospatial risk analysis', PLoS Genetics, vol. 8, no. 6, e1002765. https://doi.org/10.1371/journal.pgen.1002765
Kiryluk, Krzysztof ; Li, Yifu ; Sanna-Cherchi, Simone ; Rohanizadegan, Mersedeh ; Suzuki, Hitoshi ; Eitner, Frank ; Snyder, Holly J. ; Choi, Murim ; Hou, Ping ; Scolari, Francesco ; Izzi, Claudia ; Gigante, Maddalena ; Gesualdo, Loreto ; Savoldi, Silvana ; Amoroso, Antonio ; Cusi, Daniele ; Zamboli, Pasquale ; Julian, Bruce A. ; Novak, Jan ; Wyatt, Robert J. ; Mucha, Krzysztof ; Perola, Markus ; Kristiansson, Kati ; Viktorin, Alexander ; Magnusson, Patrik K. ; Thorleifsson, Gudmar ; Thorsteinsdottir, Unnur ; Stefansson, Kari ; Boland, Anne ; Metzger, Marie ; Thibaudin, Lise ; Wanner, Christoph ; Jager, Kitty J. ; Goto, Shin ; Maixnerova, Dita ; Karnib, Hussein H. ; Nagy, J. ; Panzer, Ulf ; Xie, Jingyuan ; Chen, Nan ; Tesar, Vladimir ; Narita, Ichiei ; Berthoux, Francois ; Floege, Jürgen ; Stengel, Benedicte ; Zhang, Hong ; Lifton, Richard P. ; Gharavi, Ali G. / Geographic differences in genetic susceptibility to IgA nephropathy : GWAS replication study and geospatial risk analysis. In: PLoS Genetics. 2012 ; Vol. 8, No. 6.
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abstract = "IgA nephropathy (IgAN), major cause of kidney failure worldwide, is common in Asians, moderately prevalent in Europeans, and rare in Africans. It is not known if these differences represent variation in genes, environment, or ascertainment. In a recent GWAS, we localized five IgAN susceptibility loci on Chr.6p21 (HLA-DQB1/DRB1, PSMB9/TAP1, and DPA1/DPB2 loci), Chr.1q32 (CFHR3/R1 locus), and Chr.22q12 (HORMAD2 locus). These IgAN loci are associated with risk of other immune-mediated disorders such as type I diabetes, multiple sclerosis, or inflammatory bowel disease. We tested association of these loci in eight new independent cohorts of Asian, European, and African-American ancestry (N = 4,789), followed by meta-analysis with risk-score modeling in 12 cohorts (N = 10,755) and geospatial analysis in 85 world populations. Four susceptibility loci robustly replicated and all five loci were genome-wide significant in the combined cohort (P = 5×10-32-3×10-10), with heterogeneity detected only at the PSMB9/TAP1 locus (I2 = 0.60). Conditional analyses identified two new independent risk alleles within the HLA-DQB1/DRB1 locus, defining multiple risk and protective haplotypes within this interval. We also detected a significant genetic interaction, whereby the odds ratio for the HORMAD2 protective allele was reversed in homozygotes for a CFHR3/R1 deletion (P = 2.5×10-4). A seven-SNP genetic risk score, which explained 4.7{\%} of overall IgAN risk, increased sharply with Eastward and Northward distance from Africa (r = 0.30, P = 3×10-128). This model paralleled the known East-West gradient in disease risk. Moreover, the prediction of a South-North axis was confirmed by registry data showing that the prevalence of IgAN-attributable kidney failure is increased in Northern Europe, similar to multiple sclerosis and type I diabetes. Variation at IgAN susceptibility loci correlates with differences in disease prevalence among world populations. These findings inform genetic, biological, and epidemiological investigations of IgAN and permit cross-comparison with other complex traits that share genetic risk loci and geographic patterns with IgAN.",
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TY - JOUR

T1 - Geographic differences in genetic susceptibility to IgA nephropathy

T2 - GWAS replication study and geospatial risk analysis

AU - Kiryluk, Krzysztof

AU - Li, Yifu

AU - Sanna-Cherchi, Simone

AU - Rohanizadegan, Mersedeh

AU - Suzuki, Hitoshi

AU - Eitner, Frank

AU - Snyder, Holly J.

AU - Choi, Murim

AU - Hou, Ping

AU - Scolari, Francesco

AU - Izzi, Claudia

AU - Gigante, Maddalena

AU - Gesualdo, Loreto

AU - Savoldi, Silvana

AU - Amoroso, Antonio

AU - Cusi, Daniele

AU - Zamboli, Pasquale

AU - Julian, Bruce A.

AU - Novak, Jan

AU - Wyatt, Robert J.

AU - Mucha, Krzysztof

AU - Perola, Markus

AU - Kristiansson, Kati

AU - Viktorin, Alexander

AU - Magnusson, Patrik K.

AU - Thorleifsson, Gudmar

AU - Thorsteinsdottir, Unnur

AU - Stefansson, Kari

AU - Boland, Anne

AU - Metzger, Marie

AU - Thibaudin, Lise

AU - Wanner, Christoph

AU - Jager, Kitty J.

AU - Goto, Shin

AU - Maixnerova, Dita

AU - Karnib, Hussein H.

AU - Nagy, J.

AU - Panzer, Ulf

AU - Xie, Jingyuan

AU - Chen, Nan

AU - Tesar, Vladimir

AU - Narita, Ichiei

AU - Berthoux, Francois

AU - Floege, Jürgen

AU - Stengel, Benedicte

AU - Zhang, Hong

AU - Lifton, Richard P.

AU - Gharavi, Ali G.

PY - 2012/6

Y1 - 2012/6

N2 - IgA nephropathy (IgAN), major cause of kidney failure worldwide, is common in Asians, moderately prevalent in Europeans, and rare in Africans. It is not known if these differences represent variation in genes, environment, or ascertainment. In a recent GWAS, we localized five IgAN susceptibility loci on Chr.6p21 (HLA-DQB1/DRB1, PSMB9/TAP1, and DPA1/DPB2 loci), Chr.1q32 (CFHR3/R1 locus), and Chr.22q12 (HORMAD2 locus). These IgAN loci are associated with risk of other immune-mediated disorders such as type I diabetes, multiple sclerosis, or inflammatory bowel disease. We tested association of these loci in eight new independent cohorts of Asian, European, and African-American ancestry (N = 4,789), followed by meta-analysis with risk-score modeling in 12 cohorts (N = 10,755) and geospatial analysis in 85 world populations. Four susceptibility loci robustly replicated and all five loci were genome-wide significant in the combined cohort (P = 5×10-32-3×10-10), with heterogeneity detected only at the PSMB9/TAP1 locus (I2 = 0.60). Conditional analyses identified two new independent risk alleles within the HLA-DQB1/DRB1 locus, defining multiple risk and protective haplotypes within this interval. We also detected a significant genetic interaction, whereby the odds ratio for the HORMAD2 protective allele was reversed in homozygotes for a CFHR3/R1 deletion (P = 2.5×10-4). A seven-SNP genetic risk score, which explained 4.7% of overall IgAN risk, increased sharply with Eastward and Northward distance from Africa (r = 0.30, P = 3×10-128). This model paralleled the known East-West gradient in disease risk. Moreover, the prediction of a South-North axis was confirmed by registry data showing that the prevalence of IgAN-attributable kidney failure is increased in Northern Europe, similar to multiple sclerosis and type I diabetes. Variation at IgAN susceptibility loci correlates with differences in disease prevalence among world populations. These findings inform genetic, biological, and epidemiological investigations of IgAN and permit cross-comparison with other complex traits that share genetic risk loci and geographic patterns with IgAN.

AB - IgA nephropathy (IgAN), major cause of kidney failure worldwide, is common in Asians, moderately prevalent in Europeans, and rare in Africans. It is not known if these differences represent variation in genes, environment, or ascertainment. In a recent GWAS, we localized five IgAN susceptibility loci on Chr.6p21 (HLA-DQB1/DRB1, PSMB9/TAP1, and DPA1/DPB2 loci), Chr.1q32 (CFHR3/R1 locus), and Chr.22q12 (HORMAD2 locus). These IgAN loci are associated with risk of other immune-mediated disorders such as type I diabetes, multiple sclerosis, or inflammatory bowel disease. We tested association of these loci in eight new independent cohorts of Asian, European, and African-American ancestry (N = 4,789), followed by meta-analysis with risk-score modeling in 12 cohorts (N = 10,755) and geospatial analysis in 85 world populations. Four susceptibility loci robustly replicated and all five loci were genome-wide significant in the combined cohort (P = 5×10-32-3×10-10), with heterogeneity detected only at the PSMB9/TAP1 locus (I2 = 0.60). Conditional analyses identified two new independent risk alleles within the HLA-DQB1/DRB1 locus, defining multiple risk and protective haplotypes within this interval. We also detected a significant genetic interaction, whereby the odds ratio for the HORMAD2 protective allele was reversed in homozygotes for a CFHR3/R1 deletion (P = 2.5×10-4). A seven-SNP genetic risk score, which explained 4.7% of overall IgAN risk, increased sharply with Eastward and Northward distance from Africa (r = 0.30, P = 3×10-128). This model paralleled the known East-West gradient in disease risk. Moreover, the prediction of a South-North axis was confirmed by registry data showing that the prevalence of IgAN-attributable kidney failure is increased in Northern Europe, similar to multiple sclerosis and type I diabetes. Variation at IgAN susceptibility loci correlates with differences in disease prevalence among world populations. These findings inform genetic, biological, and epidemiological investigations of IgAN and permit cross-comparison with other complex traits that share genetic risk loci and geographic patterns with IgAN.

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