A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes.
Natalie R van ZuydamEmma AhlqvistErkka ValoHarshal DeshmukhN William RaynerMoustafa AbdallaClaes LadenvallDaniel ZiemekEric FaumanNeil R RobertsonPaul M McKeigueErkka ValoCarol ForsblomValma Harjutsalonull nullAnnalisa PernaErica RuraliM Loredana MarcovecchioRobert P IgoRany M SalemNorberto PericoMaria LajerAnnemari KäräjämäkiMinako ImamuraMichiaki KuboAtsushi TakahashiXueling SimJianjun LiuRob M van DamGuozhi JiangClaudia H T TamAndrea O Y LukHeung Man LeeCadmon K P LimCheuk Chun SzetoWing Yee SoJuliana C N Channull nullSu Fen AngRajkumar DorajooLing WangTan Si Hua ClaraAmy-Jayne McKnightSeamus Duffynull nullMarcus G Pezzolesinull nullMichel MarreBeata GyorgySamy HadjadjLinda T Hirakinull nullTarunveer S AhluwaliaPeter AlmgrenChristina-Alexandra SchulzMarju Orho-MelanderAllan LinnebergCramer ChristensenDaniel R WitteNiels GrarupIvan BrandslundOlle MelanderAndrew D PatersonDavid TregouetAlexander P MaxwellSu Chi LimRonald C W MaE Shyong TaiShiro MaedaValeriya LyssenkoTiinamaija TuomiAndrzej S KrolewskiStephen S RichJoel N HirschhornJose C FlorezProfessor David DungerOluf PedersenTorben HansenPeter RossingGiuseppe Remuzzinull nullMary Julia BrosnanColin N A PalmerPer-Henrik GroopHelen Martina ColhounLeif C GroopMark I McCarthyPublished in: Diabetes (2018)
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.