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

Tarunveer S Ahluwalia, Christina-Alexandra Schulz, Johannes Waage, Tea Skaaby, Niina Sandholm, Natalie van Zuydam, Romain Charmet, Jette Bork-Jensen, Peter Almgren, Betina H Thuesen, Mathilda Bedin, Ivan Brandslund, Cramer K Christensen, Allan Linneberg, Emma Ahlqvist, Per-Henrik Groop, Samy Hadjadj, David-Alexandre Tregouet, Marit E Jørgensen, Niels Grarup & 9 others Oluf Pedersen, Matias Simons, Leif Groop, Marju Orho-Melander, Mark I McCarthy, Olle Melander, Peter Rossing, Tuomas O Kilpeläinen, Torben Hansen

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Abstract

AIMS/HYPOTHESIS: Identifying 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.

METHODS: We 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.

RESULTS: We identified a rare (minor allele frequency [MAF]: 0.8%) missense (A1690V) variant in CUBN (rs141640975, β = 0.27, p = 1.3 × 10-11) 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 (pinteraction = 7.0 × 10-4, β with diabetes = 0.69, β 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 (pBonferroni < 2.7 × 10-6).

CONCLUSIONS/INTERPRETATION: The current study identifies a rare coding variant in the CUBN locus and other potential genes associated with albuminuria in individuals with and without diabetes. These genes have been implicated in renal and cardiovascular dysfunction. The findings provide new insights into the genetic architecture of albuminuria and highlight target genes and pathways for the prevention of diabetes-related kidney disease.

Original languageEnglish
JournalDiabetologia
Volume62
Issue number2
Pages (from-to)292-305
ISSN0012-186X
DOIs
Publication statusPublished - Feb 2019

Fingerprint

Exome
Albuminuria
Meta-Analysis
Kidney Diseases
Type 2 Diabetes Mellitus
Alleles
Kidney

Keywords

  • Albuminuria
  • DKD
  • Diabetes
  • Exome chip
  • GWAS
  • Genetics
  • Genome-wide association study
  • Kidney disease
  • Rare variant
  • SKAT
  • Type 2 diabetes

Cite this

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 ; Jørgensen, 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. In: Diabetologia. 2019 ; Vol. 62, No. 2. pp. 292-305.
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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",
abstract = "AIMS/HYPOTHESIS: Identifying 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.METHODS: We 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.RESULTS: We identified a rare (minor allele frequency [MAF]: 0.8{\%}) missense (A1690V) variant in CUBN (rs141640975, β = 0.27, p = 1.3 × 10-11) 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 (pinteraction = 7.0 × 10-4, β with diabetes = 0.69, β 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 (pBonferroni < 2.7 × 10-6).CONCLUSIONS/INTERPRETATION: The current study identifies a rare coding variant in the CUBN locus and other potential genes associated with albuminuria in individuals with and without diabetes. These genes have been implicated in renal and cardiovascular dysfunction. The findings provide new insights into the genetic architecture of albuminuria and highlight target genes and pathways for the prevention of diabetes-related kidney disease.",
keywords = "Albuminuria, DKD, Diabetes, Exome chip, GWAS, Genetics, Genome-wide association study, Kidney disease, Rare variant, SKAT, Type 2 diabetes",
author = "Ahluwalia, {Tarunveer S} and Christina-Alexandra Schulz and Johannes Waage and Tea Skaaby and Niina Sandholm and {van Zuydam}, Natalie and Romain Charmet and Jette Bork-Jensen and Peter Almgren and Thuesen, {Betina H} and Mathilda Bedin and Ivan Brandslund and Christensen, {Cramer K} and Allan Linneberg and Emma Ahlqvist and Per-Henrik Groop and Samy Hadjadj and David-Alexandre Tregouet and J{\o}rgensen, {Marit E} and Niels Grarup and Oluf Pedersen and Matias Simons and Leif Groop and Marju Orho-Melander and McCarthy, {Mark I} and Olle Melander and Peter Rossing and Kilpel{\"a}inen, {Tuomas O} and Torben Hansen",
year = "2019",
month = "2",
doi = "10.1007/s00125-018-4783-z",
language = "English",
volume = "62",
pages = "292--305",
journal = "Diabetologia",
issn = "0012-186X",
publisher = "Heinemann",
number = "2",

}

Ahluwalia, TS, Schulz, C-A, Waage, J, Skaaby, T, Sandholm, N, van Zuydam, N, Charmet, R, Bork-Jensen, J, Almgren, P, Thuesen, BH, Bedin, M, Brandslund, I, Christensen, CK, Linneberg, A, Ahlqvist, E, Groop, P-H, Hadjadj, S, Tregouet, D-A, Jørgensen, ME, Grarup, N, Pedersen, O, Simons, M, Groop, L, Orho-Melander, M, McCarthy, MI, Melander, O, Rossing, P, Kilpeläinen, TO & 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

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; Jørgensen, 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.

In: Diabetologia, Vol. 62, No. 2, 02.2019, p. 292-305.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - A novel rare CUBN variant and three additional genes identified in Europeans with and without diabetes

T2 - results from an exome-wide association study of albuminuria

AU - Ahluwalia, Tarunveer S

AU - Schulz, Christina-Alexandra

AU - Waage, Johannes

AU - Skaaby, Tea

AU - Sandholm, Niina

AU - van Zuydam, Natalie

AU - Charmet, Romain

AU - Bork-Jensen, Jette

AU - Almgren, Peter

AU - Thuesen, Betina H

AU - Bedin, Mathilda

AU - Brandslund, Ivan

AU - Christensen, Cramer K

AU - Linneberg, Allan

AU - Ahlqvist, Emma

AU - Groop, Per-Henrik

AU - Hadjadj, Samy

AU - Tregouet, David-Alexandre

AU - Jørgensen, Marit E

AU - Grarup, Niels

AU - Pedersen, Oluf

AU - Simons, Matias

AU - Groop, Leif

AU - Orho-Melander, Marju

AU - McCarthy, Mark I

AU - Melander, Olle

AU - Rossing, Peter

AU - Kilpeläinen, Tuomas O

AU - Hansen, Torben

PY - 2019/2

Y1 - 2019/2

N2 - AIMS/HYPOTHESIS: Identifying 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.METHODS: We 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.RESULTS: We identified a rare (minor allele frequency [MAF]: 0.8%) missense (A1690V) variant in CUBN (rs141640975, β = 0.27, p = 1.3 × 10-11) 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 (pinteraction = 7.0 × 10-4, β with diabetes = 0.69, β 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 (pBonferroni < 2.7 × 10-6).CONCLUSIONS/INTERPRETATION: The current study identifies a rare coding variant in the CUBN locus and other potential genes associated with albuminuria in individuals with and without diabetes. These genes have been implicated in renal and cardiovascular dysfunction. The findings provide new insights into the genetic architecture of albuminuria and highlight target genes and pathways for the prevention of diabetes-related kidney disease.

AB - AIMS/HYPOTHESIS: Identifying 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.METHODS: We 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.RESULTS: We identified a rare (minor allele frequency [MAF]: 0.8%) missense (A1690V) variant in CUBN (rs141640975, β = 0.27, p = 1.3 × 10-11) 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 (pinteraction = 7.0 × 10-4, β with diabetes = 0.69, β 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 (pBonferroni < 2.7 × 10-6).CONCLUSIONS/INTERPRETATION: The current study identifies a rare coding variant in the CUBN locus and other potential genes associated with albuminuria in individuals with and without diabetes. These genes have been implicated in renal and cardiovascular dysfunction. The findings provide new insights into the genetic architecture of albuminuria and highlight target genes and pathways for the prevention of diabetes-related kidney disease.

KW - Albuminuria

KW - DKD

KW - Diabetes

KW - Exome chip

KW - GWAS

KW - Genetics

KW - Genome-wide association study

KW - Kidney disease

KW - Rare variant

KW - SKAT

KW - Type 2 diabetes

U2 - 10.1007/s00125-018-4783-z

DO - 10.1007/s00125-018-4783-z

M3 - Journal article

VL - 62

SP - 292

EP - 305

JO - Diabetologia

JF - Diabetologia

SN - 0012-186X

IS - 2

ER -