Advanced

A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes

van Zuydam, Natalie R; Ahlqvist, Emma LU ; Ladenvall, Claes LU ; Almgren, Peter LU ; Schulz, Christina-Alexandra LU ; Orho-Melander, Marju LU ; Melander, Olle LU ; Lyssenko, Valeriya LU ; Tuomi, Tiinamaija LU and Groop, Leif C LU , et al. (2018) In Diabetes 67(7). p.1414-1427
Abstract

Identification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific... (More)

Identification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 × 10-8) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.

(Less)
Please use this url to cite or link to this publication:
author
, et al. (More)
(Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Adult, Aged, Aged, 80 and over, Case-Control Studies, Diabetes Mellitus, Type 2/complications, Diabetic Nephropathies/epidemiology, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Kidney Failure, Chronic/complications, Male, Middle Aged, Polymorphism, Single Nucleotide, Renal Insufficiency, Chronic/complications
in
Diabetes
volume
67
issue
7
pages
1414 - 1427
publisher
American Diabetes Association Inc.
external identifiers
  • scopus:85048828771
ISSN
1939-327X
DOI
10.2337/db17-0914
language
English
LU publication?
yes
id
e3c96975-5e0d-4cbe-a251-eb7c1473bb53
date added to LUP
2019-01-21 10:27:26
date last changed
2019-03-19 04:04:25
@article{e3c96975-5e0d-4cbe-a251-eb7c1473bb53,
  abstract     = {<p>Identification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 × 10-8) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.</p>},
  author       = {van Zuydam, Natalie R and Ahlqvist, Emma and Ladenvall, Claes and Almgren, Peter and Schulz, Christina-Alexandra and Orho-Melander, Marju and Melander, Olle and Lyssenko, Valeriya and Tuomi, Tiinamaija and Groop, Leif C and McCarthy, Mark I and ,  and ,  and ,  and ,  and , },
  issn         = {1939-327X},
  keyword      = {Adult,Aged,Aged, 80 and over,Case-Control Studies,Diabetes Mellitus, Type 2/complications,Diabetic Nephropathies/epidemiology,Female,Genetic Predisposition to Disease,Genome-Wide Association Study,Humans,Kidney Failure, Chronic/complications,Male,Middle Aged,Polymorphism, Single Nucleotide,Renal Insufficiency, Chronic/complications},
  language     = {eng},
  number       = {7},
  pages        = {1414--1427},
  publisher    = {American Diabetes Association Inc.},
  series       = {Diabetes},
  title        = {A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes},
  url          = {http://dx.doi.org/10.2337/db17-0914},
  volume       = {67},
  year         = {2018},
}