A novel rare CUBN variant and three additional genes identified in Europeans with and without diabetes : results from an exome-wide association study of albuminuria
Aims/hypothesisIdentifying rare coding variants associated with albuminuria may open new avenues for preventing chronic kidney disease and end-stage renal disease, which are highly prevalent in individuals with diabetes. Efforts to identify genetic susceptibility variants for albuminuria have so far...
Published in: | Diabetologia |
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Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Format: | Article in Journal/Newspaper |
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2019
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Online Access: | http://hdl.handle.net/10138/298740 |
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ftunivhelsihelda:oai:helda.helsinki.fi:10138/298740 |
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HELDA – University of Helsinki Open Repository |
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ftunivhelsihelda |
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English |
topic |
Albuminuria Diabetes DKD Exome chip Genetics Genome-wide association study Kidney disease GWAS Rare variant SKAT Type 2 diabetes GENOME-WIDE KIDNEY-DISEASE RISK REVEALS LOCI METAANALYSIS PROTECTION RECEPTORS DISCOVERY FRAMEWORK 3121 General medicine internal medicine and other clinical medicine 3111 Biomedicine 1184 Genetics developmental biology physiology |
spellingShingle |
Albuminuria Diabetes DKD Exome chip Genetics Genome-wide association study Kidney disease GWAS Rare variant SKAT Type 2 diabetes GENOME-WIDE KIDNEY-DISEASE RISK REVEALS LOCI METAANALYSIS PROTECTION RECEPTORS DISCOVERY FRAMEWORK 3121 General medicine internal medicine and other clinical medicine 3111 Biomedicine 1184 Genetics developmental biology physiology Ahluwalia, Tarunveer S. Schulz, Christina-Alexandra Waage, Johannes Skaaby, Tea Sandholm, Niina van Zuydam, Natalie Charmet, Romain Bork-Jensen, Jette Almgren, Peter Thuesen, Betina H. Bedin, Mathilda Brandslund, Ivan Christensen, Cramer K. Linneberg, Allan Ahlqvist, Emma Groop, Per-Henrik Hadjadj, Samy Tregouet, David-Alexandre Jorgensen, Marit E. Grarup, Niels Pedersen, Oluf Simons, Matias Groop, Leif Orho-Melander, Marju McCarthy, Mark I. Melander, Olle Rossing, Peter Kilpeläinen, Tuomas O. Hansen, Torben A novel rare CUBN variant and three additional genes identified in Europeans with and without diabetes : results from an exome-wide association study of albuminuria |
topic_facet |
Albuminuria Diabetes DKD Exome chip Genetics Genome-wide association study Kidney disease GWAS Rare variant SKAT Type 2 diabetes GENOME-WIDE KIDNEY-DISEASE RISK REVEALS LOCI METAANALYSIS PROTECTION RECEPTORS DISCOVERY FRAMEWORK 3121 General medicine internal medicine and other clinical medicine 3111 Biomedicine 1184 Genetics developmental biology physiology |
description |
Aims/hypothesisIdentifying rare coding variants associated with albuminuria may open new avenues for preventing chronic kidney disease and end-stage renal disease, which are highly prevalent in individuals with diabetes. Efforts to identify genetic susceptibility variants for albuminuria have so far been limited, with the majority of studies focusing on common variants.MethodsWe performed an exome-wide association study to identify coding variants in a two-stage (discovery and replication) approach. Data from 33,985 individuals of European ancestry (15,872 with and 18,113 without diabetes) and 2605 Greenlanders were included.ResultsWe identified a rare (minor allele frequency [MAF]: 0.8%) missense (A1690V) variant in CUBN (rs141640975, =0.27, p=1.3x10(-11)) associated with albuminuria as a continuous measure in the combined European meta-analysis. The presence of each rare allele of the variant was associated with a 6.4% increase in albuminuria. The rare CUBN variant had an effect that was three times stronger in individuals with type 2 diabetes compared with those without (p(interaction)=7.0x10(-4), with diabetes=0.69, without diabetes=0.20) in the discovery meta-analysis. Gene-aggregate tests based on rare and common variants identified three additional genes associated with albuminuria (HES1, CDC73 and GRM5) after multiple testing correction (p(Bonferroni) Peer reviewed |
author2 |
Clinicum Research Programs Unit Nefrologian yksikkö Diabetes and Obesity Research Program Department of Medicine Per Henrik Groop / Principal Investigator Centre of Excellence in Complex Disease Genetics Institute for Molecular Medicine Finland University of Helsinki HUS Abdominal Center |
format |
Article in Journal/Newspaper |
author |
Ahluwalia, Tarunveer S. Schulz, Christina-Alexandra Waage, Johannes Skaaby, Tea Sandholm, Niina van Zuydam, Natalie Charmet, Romain Bork-Jensen, Jette Almgren, Peter Thuesen, Betina H. Bedin, Mathilda Brandslund, Ivan Christensen, Cramer K. Linneberg, Allan Ahlqvist, Emma Groop, Per-Henrik Hadjadj, Samy Tregouet, David-Alexandre Jorgensen, Marit E. Grarup, Niels Pedersen, Oluf Simons, Matias Groop, Leif Orho-Melander, Marju McCarthy, Mark I. Melander, Olle Rossing, Peter Kilpeläinen, Tuomas O. Hansen, Torben |
author_facet |
Ahluwalia, Tarunveer S. Schulz, Christina-Alexandra Waage, Johannes Skaaby, Tea Sandholm, Niina van Zuydam, Natalie Charmet, Romain Bork-Jensen, Jette Almgren, Peter Thuesen, Betina H. Bedin, Mathilda Brandslund, Ivan Christensen, Cramer K. Linneberg, Allan Ahlqvist, Emma Groop, Per-Henrik Hadjadj, Samy Tregouet, David-Alexandre Jorgensen, Marit E. Grarup, Niels Pedersen, Oluf Simons, Matias Groop, Leif Orho-Melander, Marju McCarthy, Mark I. Melander, Olle Rossing, Peter Kilpeläinen, Tuomas O. Hansen, Torben |
author_sort |
Ahluwalia, Tarunveer S. |
title |
A novel rare CUBN variant and three additional genes identified in Europeans with and without diabetes : results from an exome-wide association study of albuminuria |
title_short |
A novel rare CUBN variant and three additional genes identified in Europeans with and without diabetes : results from an exome-wide association study of albuminuria |
title_full |
A novel rare CUBN variant and three additional genes identified in Europeans with and without diabetes : results from an exome-wide association study of albuminuria |
title_fullStr |
A novel rare CUBN variant and three additional genes identified in Europeans with and without diabetes : results from an exome-wide association study of albuminuria |
title_full_unstemmed |
A novel rare CUBN variant and three additional genes identified in Europeans with and without diabetes : results from an exome-wide association study of albuminuria |
title_sort |
novel rare cubn variant and three additional genes identified in europeans with and without diabetes : results from an exome-wide association study of albuminuria |
publisher |
Springer |
publishDate |
2019 |
url |
http://hdl.handle.net/10138/298740 |
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ENVELOPE(147.222,147.222,59.340,59.340) |
geographic |
Skat |
geographic_facet |
Skat |
genre |
greenlander* |
genre_facet |
greenlander* |
op_relation |
10.1007/s00125-018-4783-z TSA was supported by Lundbeck Foundation travel grant (reference 2013-14471). This study was partially funded by the Immunometabolism grant from the Novo Nordisk Foundation (NNF15CC0018486). Study-specific funding details are shown in ESM Table 11. Ahluwalia , T S , Schulz , C-A , Waage , J , Skaaby , T , Sandholm , N , van Zuydam , N , Charmet , R , Bork-Jensen , J , Almgren , P , Thuesen , B H , Bedin , M , Brandslund , I , Christensen , C K , Linneberg , A , Ahlqvist , E , Groop , P-H , Hadjadj , S , Tregouet , D-A , Jorgensen , M E , Grarup , N , Pedersen , O , Simons , M , Groop , L , Orho-Melander , M , McCarthy , M I , Melander , O , Rossing , P , Kilpeläinen , T O & Hansen , T 2019 , ' A novel rare CUBN variant and three additional genes identified in Europeans with and without diabetes : results from an exome-wide association study of albuminuria ' , Diabetologia , vol. 62 , no. 2 , pp. 292-305 . https://doi.org/10.1007/s00125-018-4783-z ORCID: /0000-0003-4322-6942/work/53827463 85058467890 130d1b77-a988-40b7-9b18-d1f11c24def8 http://hdl.handle.net/10138/298740 000455114700011 |
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cc_by openAccess info:eu-repo/semantics/openAccess |
container_title |
Diabetologia |
container_volume |
62 |
container_issue |
2 |
container_start_page |
292 |
op_container_end_page |
305 |
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1787424988536504320 |
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ftunivhelsihelda:oai:helda.helsinki.fi:10138/298740 2024-01-07T09:43:42+01:00 A novel rare CUBN variant and three additional genes identified in Europeans with and without diabetes : results from an exome-wide association study of albuminuria Ahluwalia, Tarunveer S. Schulz, Christina-Alexandra Waage, Johannes Skaaby, Tea Sandholm, Niina van Zuydam, Natalie Charmet, Romain Bork-Jensen, Jette Almgren, Peter Thuesen, Betina H. Bedin, Mathilda Brandslund, Ivan Christensen, Cramer K. Linneberg, Allan Ahlqvist, Emma Groop, Per-Henrik Hadjadj, Samy Tregouet, David-Alexandre Jorgensen, Marit E. Grarup, Niels Pedersen, Oluf Simons, Matias Groop, Leif Orho-Melander, Marju McCarthy, Mark I. Melander, Olle Rossing, Peter Kilpeläinen, Tuomas O. Hansen, Torben Clinicum Research Programs Unit Nefrologian yksikkö Diabetes and Obesity Research Program Department of Medicine Per Henrik Groop / Principal Investigator Centre of Excellence in Complex Disease Genetics Institute for Molecular Medicine Finland University of Helsinki HUS Abdominal Center 2019-02-06T13:35:01Z 14 application/pdf http://hdl.handle.net/10138/298740 eng eng Springer 10.1007/s00125-018-4783-z TSA was supported by Lundbeck Foundation travel grant (reference 2013-14471). This study was partially funded by the Immunometabolism grant from the Novo Nordisk Foundation (NNF15CC0018486). Study-specific funding details are shown in ESM Table 11. Ahluwalia , T S , Schulz , C-A , Waage , J , Skaaby , T , Sandholm , N , van Zuydam , N , Charmet , R , Bork-Jensen , J , Almgren , P , Thuesen , B H , Bedin , M , Brandslund , I , Christensen , C K , Linneberg , A , Ahlqvist , E , Groop , P-H , Hadjadj , S , Tregouet , D-A , Jorgensen , M E , Grarup , N , Pedersen , O , Simons , M , Groop , L , Orho-Melander , M , McCarthy , M I , Melander , O , Rossing , P , Kilpeläinen , T O & Hansen , T 2019 , ' A novel rare CUBN variant and three additional genes identified in Europeans with and without diabetes : results from an exome-wide association study of albuminuria ' , Diabetologia , vol. 62 , no. 2 , pp. 292-305 . https://doi.org/10.1007/s00125-018-4783-z ORCID: /0000-0003-4322-6942/work/53827463 85058467890 130d1b77-a988-40b7-9b18-d1f11c24def8 http://hdl.handle.net/10138/298740 000455114700011 cc_by openAccess info:eu-repo/semantics/openAccess Albuminuria Diabetes DKD Exome chip Genetics Genome-wide association study Kidney disease GWAS Rare variant SKAT Type 2 diabetes GENOME-WIDE KIDNEY-DISEASE RISK REVEALS LOCI METAANALYSIS PROTECTION RECEPTORS DISCOVERY FRAMEWORK 3121 General medicine internal medicine and other clinical medicine 3111 Biomedicine 1184 Genetics developmental biology physiology Article publishedVersion 2019 ftunivhelsihelda 2023-12-14T00:10:36Z Aims/hypothesisIdentifying rare coding variants associated with albuminuria may open new avenues for preventing chronic kidney disease and end-stage renal disease, which are highly prevalent in individuals with diabetes. Efforts to identify genetic susceptibility variants for albuminuria have so far been limited, with the majority of studies focusing on common variants.MethodsWe performed an exome-wide association study to identify coding variants in a two-stage (discovery and replication) approach. Data from 33,985 individuals of European ancestry (15,872 with and 18,113 without diabetes) and 2605 Greenlanders were included.ResultsWe identified a rare (minor allele frequency [MAF]: 0.8%) missense (A1690V) variant in CUBN (rs141640975, =0.27, p=1.3x10(-11)) associated with albuminuria as a continuous measure in the combined European meta-analysis. The presence of each rare allele of the variant was associated with a 6.4% increase in albuminuria. The rare CUBN variant had an effect that was three times stronger in individuals with type 2 diabetes compared with those without (p(interaction)=7.0x10(-4), with diabetes=0.69, without diabetes=0.20) in the discovery meta-analysis. Gene-aggregate tests based on rare and common variants identified three additional genes associated with albuminuria (HES1, CDC73 and GRM5) after multiple testing correction (p(Bonferroni) Peer reviewed Article in Journal/Newspaper greenlander* HELDA – University of Helsinki Open Repository Skat ENVELOPE(147.222,147.222,59.340,59.340) Diabetologia 62 2 292 305 |