Geographic differences in genetic susceptibility to IgA nephropathy: GWAS replication study and geospatial risk analysis
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 loc...
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| creator | 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, Judit Panzer, Ulf Xie, Jingyuan Chen, Nan Tesar, Vladimir Narita, Ichiei Berthoux, Francois Floege, Jürgen Stengel, Benedicte Zhang, Hong Lifton, Richard P Gharavi, Ali G |
| description | 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. |
| doi_str_mv | 10.1371/journal.pgen.1002765 |
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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.</description><identifier>ISSN: 1553-7404</identifier><identifier>ISSN: 1553-7390</identifier><identifier>EISSN: 1553-7404</identifier><identifier>DOI: 10.1371/journal.pgen.1002765</identifier><identifier>PMID: 22737082</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Africa ; African Americans - genetics ; Alleles ; Asia ; Asian Continental Ancestry Group - genetics ; Biogeography ; Blood Proteins - genetics ; Chronic kidney failure ; Cohort Studies ; Cysteine Endopeptidases - genetics ; Development and progression ; Diabetes ; Diabetes Mellitus, Type 1 - genetics ; Disease ; Disease susceptibility ; Europe ; European Continental Ancestry Group - genetics ; Genealogy ; Genetic aspects ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Genomes ; Geospatial data ; Glomerulonephritis, IGA - genetics ; Haplotypes ; Health risk assessment ; HLA-DQ beta-Chains - genetics ; Humans ; Linkage Disequilibrium ; Medicine ; Multiple sclerosis ; Multiple Sclerosis - genetics ; Physiological aspects ; Prevalence studies (Epidemiology) ; Risk Factors</subject><ispartof>PLoS genetics, 2012-06, Vol.8 (6), p.e1002765-e1002765</ispartof><rights>COPYRIGHT 2012 Public Library of Science</rights><rights>2012 Kiryluk et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Kiryluk K, Li Y, Sanna-Cherchi S, Rohanizadegan M, Suzuki H, et al. (2012) Geographic Differences in Genetic Susceptibility to IgA Nephropathy: GWAS Replication Study and Geospatial Risk Analysis. PLoS Genet 8(6): e1002765. doi:10.1371/journal.pgen.1002765</rights><rights>Kiryluk et al. 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c830t-7f1ddbbba4ff7fb1f358ee5a6d9ebbcf1205d3190aab428fa0b1c59134d21e5a3</citedby><cites>FETCH-LOGICAL-c830t-7f1ddbbba4ff7fb1f358ee5a6d9ebbcf1205d3190aab428fa0b1c59134d21e5a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3380840/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3380840/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,550,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22737082$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttp://kipublications.ki.se/Default.aspx?queryparsed=id:124891607$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><contributor>McCarthy, Mark I.</contributor><creatorcontrib>Kiryluk, Krzysztof</creatorcontrib><creatorcontrib>Li, Yifu</creatorcontrib><creatorcontrib>Sanna-Cherchi, Simone</creatorcontrib><creatorcontrib>Rohanizadegan, Mersedeh</creatorcontrib><creatorcontrib>Suzuki, Hitoshi</creatorcontrib><creatorcontrib>Eitner, Frank</creatorcontrib><creatorcontrib>Snyder, Holly J</creatorcontrib><creatorcontrib>Choi, Murim</creatorcontrib><creatorcontrib>Hou, Ping</creatorcontrib><creatorcontrib>Scolari, Francesco</creatorcontrib><creatorcontrib>Izzi, Claudia</creatorcontrib><creatorcontrib>Gigante, Maddalena</creatorcontrib><creatorcontrib>Gesualdo, Loreto</creatorcontrib><creatorcontrib>Savoldi, Silvana</creatorcontrib><creatorcontrib>Amoroso, Antonio</creatorcontrib><creatorcontrib>Cusi, Daniele</creatorcontrib><creatorcontrib>Zamboli, Pasquale</creatorcontrib><creatorcontrib>Julian, Bruce A</creatorcontrib><creatorcontrib>Novak, Jan</creatorcontrib><creatorcontrib>Wyatt, Robert J</creatorcontrib><creatorcontrib>Mucha, Krzysztof</creatorcontrib><creatorcontrib>Perola, Markus</creatorcontrib><creatorcontrib>Kristiansson, Kati</creatorcontrib><creatorcontrib>Viktorin, Alexander</creatorcontrib><creatorcontrib>Magnusson, Patrik K</creatorcontrib><creatorcontrib>Thorleifsson, Gudmar</creatorcontrib><creatorcontrib>Thorsteinsdottir, Unnur</creatorcontrib><creatorcontrib>Stefansson, Kari</creatorcontrib><creatorcontrib>Boland, Anne</creatorcontrib><creatorcontrib>Metzger, Marie</creatorcontrib><creatorcontrib>Thibaudin, Lise</creatorcontrib><creatorcontrib>Wanner, Christoph</creatorcontrib><creatorcontrib>Jager, Kitty J</creatorcontrib><creatorcontrib>Goto, Shin</creatorcontrib><creatorcontrib>Maixnerova, Dita</creatorcontrib><creatorcontrib>Karnib, Hussein H</creatorcontrib><creatorcontrib>Nagy, Judit</creatorcontrib><creatorcontrib>Panzer, Ulf</creatorcontrib><creatorcontrib>Xie, Jingyuan</creatorcontrib><creatorcontrib>Chen, Nan</creatorcontrib><creatorcontrib>Tesar, Vladimir</creatorcontrib><creatorcontrib>Narita, Ichiei</creatorcontrib><creatorcontrib>Berthoux, Francois</creatorcontrib><creatorcontrib>Floege, Jürgen</creatorcontrib><creatorcontrib>Stengel, Benedicte</creatorcontrib><creatorcontrib>Zhang, Hong</creatorcontrib><creatorcontrib>Lifton, Richard P</creatorcontrib><creatorcontrib>Gharavi, Ali G</creatorcontrib><title>Geographic differences in genetic susceptibility to IgA nephropathy: GWAS replication study and geospatial risk analysis</title><title>PLoS genetics</title><addtitle>PLoS Genet</addtitle><description>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.</description><subject>Africa</subject><subject>African Americans - genetics</subject><subject>Alleles</subject><subject>Asia</subject><subject>Asian Continental Ancestry Group - genetics</subject><subject>Biogeography</subject><subject>Blood Proteins - genetics</subject><subject>Chronic kidney failure</subject><subject>Cohort Studies</subject><subject>Cysteine Endopeptidases - genetics</subject><subject>Development and progression</subject><subject>Diabetes</subject><subject>Diabetes Mellitus, Type 1 - genetics</subject><subject>Disease</subject><subject>Disease susceptibility</subject><subject>Europe</subject><subject>European Continental Ancestry Group - genetics</subject><subject>Genealogy</subject><subject>Genetic aspects</subject><subject>Genetic Predisposition to Disease</subject><subject>Genome-Wide Association Study</subject><subject>Genomes</subject><subject>Geospatial data</subject><subject>Glomerulonephritis, IGA - genetics</subject><subject>Haplotypes</subject><subject>Health risk assessment</subject><subject>HLA-DQ beta-Chains - genetics</subject><subject>Humans</subject><subject>Linkage Disequilibrium</subject><subject>Medicine</subject><subject>Multiple sclerosis</subject><subject>Multiple Sclerosis - genetics</subject><subject>Physiological aspects</subject><subject>Prevalence studies (Epidemiology)</subject><subject>Risk 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differences in genetic susceptibility to IgA nephropathy: GWAS replication study and geospatial risk analysis</title><author>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, Judit ; Panzer, Ulf ; Xie, Jingyuan ; Chen, Nan ; Tesar, Vladimir ; Narita, Ichiei ; Berthoux, Francois ; Floege, Jürgen ; Stengel, Benedicte ; Zhang, Hong ; Lifton, Richard P ; Gharavi, Ali G</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c830t-7f1ddbbba4ff7fb1f358ee5a6d9ebbcf1205d3190aab428fa0b1c59134d21e5a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Africa</topic><topic>African Americans - genetics</topic><topic>Alleles</topic><topic>Asia</topic><topic>Asian Continental Ancestry Group - genetics</topic><topic>Biogeography</topic><topic>Blood Proteins - genetics</topic><topic>Chronic kidney failure</topic><topic>Cohort Studies</topic><topic>Cysteine Endopeptidases - genetics</topic><topic>Development and progression</topic><topic>Diabetes</topic><topic>Diabetes Mellitus, Type 1 - genetics</topic><topic>Disease</topic><topic>Disease susceptibility</topic><topic>Europe</topic><topic>European Continental Ancestry Group - genetics</topic><topic>Genealogy</topic><topic>Genetic aspects</topic><topic>Genetic Predisposition to Disease</topic><topic>Genome-Wide Association Study</topic><topic>Genomes</topic><topic>Geospatial data</topic><topic>Glomerulonephritis, IGA - genetics</topic><topic>Haplotypes</topic><topic>Health risk assessment</topic><topic>HLA-DQ beta-Chains - genetics</topic><topic>Humans</topic><topic>Linkage Disequilibrium</topic><topic>Medicine</topic><topic>Multiple sclerosis</topic><topic>Multiple Sclerosis - genetics</topic><topic>Physiological aspects</topic><topic>Prevalence studies (Epidemiology)</topic><topic>Risk Factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kiryluk, Krzysztof</creatorcontrib><creatorcontrib>Li, Yifu</creatorcontrib><creatorcontrib>Sanna-Cherchi, Simone</creatorcontrib><creatorcontrib>Rohanizadegan, Mersedeh</creatorcontrib><creatorcontrib>Suzuki, Hitoshi</creatorcontrib><creatorcontrib>Eitner, Frank</creatorcontrib><creatorcontrib>Snyder, Holly J</creatorcontrib><creatorcontrib>Choi, Murim</creatorcontrib><creatorcontrib>Hou, Ping</creatorcontrib><creatorcontrib>Scolari, Francesco</creatorcontrib><creatorcontrib>Izzi, Claudia</creatorcontrib><creatorcontrib>Gigante, Maddalena</creatorcontrib><creatorcontrib>Gesualdo, Loreto</creatorcontrib><creatorcontrib>Savoldi, Silvana</creatorcontrib><creatorcontrib>Amoroso, Antonio</creatorcontrib><creatorcontrib>Cusi, Daniele</creatorcontrib><creatorcontrib>Zamboli, Pasquale</creatorcontrib><creatorcontrib>Julian, Bruce A</creatorcontrib><creatorcontrib>Novak, Jan</creatorcontrib><creatorcontrib>Wyatt, Robert J</creatorcontrib><creatorcontrib>Mucha, Krzysztof</creatorcontrib><creatorcontrib>Perola, Markus</creatorcontrib><creatorcontrib>Kristiansson, Kati</creatorcontrib><creatorcontrib>Viktorin, Alexander</creatorcontrib><creatorcontrib>Magnusson, Patrik K</creatorcontrib><creatorcontrib>Thorleifsson, Gudmar</creatorcontrib><creatorcontrib>Thorsteinsdottir, Unnur</creatorcontrib><creatorcontrib>Stefansson, Kari</creatorcontrib><creatorcontrib>Boland, Anne</creatorcontrib><creatorcontrib>Metzger, Marie</creatorcontrib><creatorcontrib>Thibaudin, Lise</creatorcontrib><creatorcontrib>Wanner, Christoph</creatorcontrib><creatorcontrib>Jager, Kitty J</creatorcontrib><creatorcontrib>Goto, Shin</creatorcontrib><creatorcontrib>Maixnerova, Dita</creatorcontrib><creatorcontrib>Karnib, Hussein H</creatorcontrib><creatorcontrib>Nagy, Judit</creatorcontrib><creatorcontrib>Panzer, Ulf</creatorcontrib><creatorcontrib>Xie, Jingyuan</creatorcontrib><creatorcontrib>Chen, Nan</creatorcontrib><creatorcontrib>Tesar, Vladimir</creatorcontrib><creatorcontrib>Narita, Ichiei</creatorcontrib><creatorcontrib>Berthoux, Francois</creatorcontrib><creatorcontrib>Floege, Jürgen</creatorcontrib><creatorcontrib>Stengel, Benedicte</creatorcontrib><creatorcontrib>Zhang, Hong</creatorcontrib><creatorcontrib>Lifton, Richard P</creatorcontrib><creatorcontrib>Gharavi, Ali G</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Canada</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Technology Research 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Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>SwePub</collection><collection>SwePub Articles</collection><collection>SWEPUB Freely available online</collection><collection>SwePub Articles full text</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PLoS genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kiryluk, Krzysztof</au><au>Li, Yifu</au><au>Sanna-Cherchi, Simone</au><au>Rohanizadegan, Mersedeh</au><au>Suzuki, Hitoshi</au><au>Eitner, Frank</au><au>Snyder, Holly J</au><au>Choi, Murim</au><au>Hou, Ping</au><au>Scolari, Francesco</au><au>Izzi, Claudia</au><au>Gigante, Maddalena</au><au>Gesualdo, Loreto</au><au>Savoldi, Silvana</au><au>Amoroso, Antonio</au><au>Cusi, Daniele</au><au>Zamboli, Pasquale</au><au>Julian, Bruce A</au><au>Novak, Jan</au><au>Wyatt, Robert J</au><au>Mucha, Krzysztof</au><au>Perola, Markus</au><au>Kristiansson, Kati</au><au>Viktorin, Alexander</au><au>Magnusson, Patrik K</au><au>Thorleifsson, Gudmar</au><au>Thorsteinsdottir, Unnur</au><au>Stefansson, Kari</au><au>Boland, Anne</au><au>Metzger, Marie</au><au>Thibaudin, Lise</au><au>Wanner, Christoph</au><au>Jager, Kitty J</au><au>Goto, Shin</au><au>Maixnerova, Dita</au><au>Karnib, Hussein H</au><au>Nagy, Judit</au><au>Panzer, Ulf</au><au>Xie, Jingyuan</au><au>Chen, Nan</au><au>Tesar, Vladimir</au><au>Narita, Ichiei</au><au>Berthoux, Francois</au><au>Floege, Jürgen</au><au>Stengel, Benedicte</au><au>Zhang, Hong</au><au>Lifton, Richard P</au><au>Gharavi, Ali G</au><au>McCarthy, Mark I.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Geographic differences in genetic susceptibility to IgA nephropathy: GWAS replication study and geospatial risk analysis</atitle><jtitle>PLoS genetics</jtitle><addtitle>PLoS Genet</addtitle><date>2012-06-01</date><risdate>2012</risdate><volume>8</volume><issue>6</issue><spage>e1002765</spage><epage>e1002765</epage><pages>e1002765-e1002765</pages><issn>1553-7404</issn><issn>1553-7390</issn><eissn>1553-7404</eissn><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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>22737082</pmid><doi>10.1371/journal.pgen.1002765</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1553-7404 |
| ispartof | PLoS genetics, 2012-06, Vol.8 (6), p.e1002765-e1002765 |
| issn | 1553-7404 1553-7390 1553-7404 |
| language | eng |
| recordid | cdi_plos_journals_1313548880 |
| source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; SWEPUB Freely available online |
| subjects | Africa African Americans - genetics Alleles Asia Asian Continental Ancestry Group - genetics Biogeography Blood Proteins - genetics Chronic kidney failure Cohort Studies Cysteine Endopeptidases - genetics Development and progression Diabetes Diabetes Mellitus, Type 1 - genetics Disease Disease susceptibility Europe European Continental Ancestry Group - genetics Genealogy Genetic aspects Genetic Predisposition to Disease Genome-Wide Association Study Genomes Geospatial data Glomerulonephritis, IGA - genetics Haplotypes Health risk assessment HLA-DQ beta-Chains - genetics Humans Linkage Disequilibrium Medicine Multiple sclerosis Multiple Sclerosis - genetics Physiological aspects Prevalence studies (Epidemiology) Risk Factors |
| title | Geographic differences in genetic susceptibility to IgA nephropathy: GWAS replication study and geospatial risk analysis |
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