title: Genome-Wide Association and Trans-ethnic Meta-Analysis for Advanced Diabetic Kidney Disease: Family Investigation of Nephropathy and Diabetes (FIND).
abstract: Diabetic kidney disease (DKD) is the most common etiology of chronic kidney disease (CKD) in the industrialized world and accounts for much of the excess mortality in patients with diabetes mellitus. Approximately 45% of U.S. patients with incident end-stage kidney disease (ESKD) have DKD. Independent of glycemic control, DKD aggregates in families and has higher incidence rates in African, Mexican, and American Indian ancestral groups relative to European populations. The Family Investigation of Nephropathy and Diabetes (FIND) performed a genome-wide association study (GWAS) contrasting 6,197 unrelated individuals with advanced DKD with healthy and diabetic individuals lacking nephropathy of European American, African American, Mexican American, or American Indian ancestry. A large-scale replication and trans-ethnic meta-analysis included 7,539 additional European American, African American and American Indian DKD cases and non-nephropathy controls. Within ethnic group meta-analysis of discovery GWAS and replication set results identified genome-wide significant evidence for association between DKD and rs12523822 on chromosome 6q25.2 in American Indians (P = 5.74x10-9). The strongest signal of association in the trans-ethnic meta-analysis was with a SNP in strong linkage disequilibrium with rs12523822 (rs955333; P = 1.31x10-8), with directionally consistent results across ethnic groups. These 6q25.2 SNPs are located between the SCAF8 and CNKSR3 genes, a region with DKD relevant changes in gene expression and an eQTL with IPCEF1, a gene co-translated with CNKSR3. Several other SNPs demonstrated suggestive evidence of association with DKD, within and across populations. These data identify a novel DKD susceptibility locus with consistent directions of effect across diverse ancestral groups and provide insight into the genetic architecture of DKD.
authors: Department of Epidemiology & Biostatistics, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors: Sudha K
authors: SK
authors: Iyengar
authors: Departments of Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America; Departments of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors: John R
authors: JR
authors: Sedor
authors: Department of Internal Medicine, Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
authors: Barry I
authors: BI
authors: Freedman
authors: Department of Epidemiology and Medicine, John Hopkins University, Baltimore, Maryland, United States of America.
authors: W H Linda
authors: WH
authors: Kao
authors: Department of Internal Medicine/Nephrology, University of Michigan, Ann Arbor, Michigan, United States of America.
authors: Matthias
authors: M
authors: Kretzler
authors: Department of Internal Medicine/Nephrology, University of Michigan, Ann Arbor, Michigan, United States of America.
authors: Benjamin J
authors: BJ
authors: Keller
authors: Department of Medicine/Nephrology, The University of Texas Health Science Center, San Antonio, Texas, United States of America.
authors: Hanna E
authors: HE
authors: Abboud
authors: Department of Medicine, Division of Nephrology and Hypertension, Harbor-UCLA Medical Center, Torrance, California, United States of America.
authors: Sharon G
authors: SG
authors: Adler
authors: Missouri Breaks Industries Research, Timber Lake, South Dakota, United States of America.
authors: Lyle G
authors: LG
authors: Best
authors: Department of Biochemistry, Center for Human Genomics, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
authors: Donald W
authors: DW
authors: Bowden
authors: Department of Internal Medicine/Nephrology, University of Michigan, Ann Arbor, Michigan, United States of America.
authors: Allison
authors: A
authors: Burlock
authors: The Institute for Translational Genomics and Population Sciences, Harbor-UCLA Medical Center, Torrance, California, United States of America.
authors: Yii-Der Ida
authors: YD
authors: Chen
authors: Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas, United States of America.
authors: Shelley A
authors: SA
authors: Cole
authors: Center for Public Health Genomics and Department of Biostatistical Sciences, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, United States of America.
authors: Mary E
authors: ME
authors: Comeau
authors: National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona, United States of America.
authors: Jeffrey M
authors: JM
authors: Curtis
authors: Center for Public Health Genomics and Department of Biostatistical Sciences, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, United States of America.
authors: Jasmin
authors: J
authors: Divers
authors: University Hospital Würzburg, Renal Division and Comprehensive Heart Failure Center, Würzburg, Germany.
authors: Christiane
authors: C
authors: Drechsler
authors: Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas, United States of America.
authors: Ravi
authors: R
authors: Duggirala
authors: Department of Epidemiology & Biostatistics, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors: Robert C
authors: RC
authors: Elston
authors: The Institute for Translational Genomics and Population Sciences, Harbor-UCLA Medical Center, Torrance, California, United States of America.
authors: Xiuqing
authors: X
authors: Guo
authors: Department of Ecology and Evolutionary Biology, University of Michigan, Ann Arbor, Michigan, United States of America.
authors: Huateng
authors: H
authors: Huang
authors: Department of Clinical Chemistry, University Medical Center, Freiburg, Germany.
authors: Michael Marcus
authors: MM
authors: Hoffmann
authors: MedStar Health Research Institute, Hyattsville, Maryland, United States of America.
authors: Barbara V
authors: BV
authors: Howard
authors: Department of Medicine, Section of Diabetes and Metabolism, Harbor-UCLA Medical Center, Torrance, California, United States of America.
authors: Eli
authors: E
authors: Ipp
authors: Division of Kidney, Urologic, and Hematologic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States of America.
authors: Paul L
authors: PL
authors: Kimmel
authors: Johns Hopkins Bloomberg School of Public Health, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America.
authors: Michael J
authors: MJ
authors: Klag
authors: National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona, United States of America.
authors: William C
authors: WC
authors: Knowler
authors: Department of Medicine, University of Chicago Medicine, Chicago, Illinois, United States of America.
authors: Orly F
authors: OF
authors: Kohn
authors: Department of Internal Medicine/Nephrology, University of Michigan, Ann Arbor, Michigan, United States of America.
authors: Tennille S
authors: TS
authors: Leak
authors: Department of Medicine, Loyola School of Medicine, Maywood, Illinois, United States of America.
authors: David J
authors: DJ
authors: Leehey
authors: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
authors: Man
authors: M
authors: Li
authors: National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona, United States of America.
authors: Alka
authors: A
authors: Malhotra
authors: Heidelberg University and Synlab Academy, University of Graz, Graz, Austria.
authors: Winfried
authors: W
authors: März
authors: Department of Internal Medicine/Nephrology, University of Michigan, Ann Arbor, Michigan, United States of America.
authors: Viji
authors: V
authors: Nair
authors: National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona, United States of America.
authors: Robert G
authors: RG
authors: Nelson
authors: Department of Medicine, University of California, Los Angeles, Los Angeles, California, United States of America.
authors: Susanne B
authors: SB
authors: Nicholas
authors: Theodosius Dobzhansky Center for Genome Bioinformatics, St. Petersburg, Russia, and Oceanographic Center, Nova Southeastern University, Ft. Lauderdale, Florida, United States of America.
authors: Stephen J
authors: SJ
authors: O'Brien
authors: Department of Medicine, University of California, Irvine, Irvine, California, United States of America.
authors: Madeleine V
authors: MV
authors: Pahl
authors: Departments of Paediatrics and Medicine, Hospital for Sick Children, University Health Network and the University of Toronto, Toronto, Ontario, Canada.
authors: Rulan S
authors: RS
authors: Parekh
authors: Department of Medicine, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, United States of America.
authors: Marcus G
authors: MG
authors: Pezzolesi
authors: National Institute of Diabetes and Digestive Disease, National Institutes of Health, Bethesda, Maryland, United States of America.
authors: Rebekah S
authors: RS
authors: Rasooly
authors: Center for Research on Genomics and Global Health, Bethesda, Maryland, United States of America.
authors: Charles N
authors: CN
authors: Rotimi
authors: The Institute for Translational Genomics and Population Sciences, Harbor-UCLA Medical Center, Torrance, California, United States of America.
authors: Jerome I
authors: JI
authors: Rotter
authors: Departments of Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors: Jeffrey R
authors: JR
authors: Schelling
authors: Department of Biochemistry and Molecular Medicine, UC Davis School of Medicine, Davis, California, United States of America.
authors: Michael F
authors: MF
authors: Seldin
authors: Department of Biochemistry & Molecular Biology, University of New Mexico, Albuquerque, New Mexico, United States of America.
authors: Vallabh O
authors: VO
authors: Shah
authors: Joslin Diabetes Center, Section on Genetics and Epidemiology, Boston, Massachusetts, United States of America.
authors: Adam M
authors: AM
authors: Smiles
authors: National Human Genome Research Institute, Rockville, Maryland, United States of America.
authors: Michael W
authors: MW
authors: Smith
authors: The Institute for Translational Genomics and Population Sciences, Harbor-UCLA Medical Center, Torrance, California, United States of America.
authors: Kent D
authors: KD
authors: Taylor
authors: Department of Medicine, The University of Texas Health Science Center, San Antonio, Texas, United States of America.
authors: Farook
authors: F
authors: Thameem
authors: Nephrology, University of Alabama Birmingham, Birmingham, Alabama, United States of America.
authors: Denyse P
authors: DP
authors: Thornley-Brown
authors: Department of Epidemiology & Biostatistics, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors: Barbara J
authors: BJ
authors: Truitt
authors: Department of Medicine, Division of Nephrology, University Hospital Würzburg, Würzburg, Germany.
authors: Christoph
authors: C
authors: Wanner
authors: National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona, United States of America.
authors: E Jennifer
authors: EJ
authors: Weil
authors: Center for Cancer Research, National Cancer Institute, Frederick, Maryland, United States of America.
authors: Cheryl A
authors: CA
authors: Winkler
authors: Department of Internal Medicine, University of New Mexico, Albuquerque, New Mexico, United States of America.
authors: Philip G
authors: PG
authors: Zager
authors: Department of Epidemiology & Biostatistics, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors: Robert P
authors: RP
authors: Igo
authors: National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona, United States of America.
authors: Robert L
authors: RL
authors: Hanson
authors: The Institute for Translational Genomics and Population Sciences, Harbor-UCLA Medical Center, Torrance, California, United States of America.
authors: Carl D
authors: CD
authors: Langefeld
mesh_terms: D001741:Black or African American / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000235:genetics*; D003928:Diabetic Nephropathies / Q000208:ethnology / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006630:Hispanic or Latino / Q000235:genetics; D006801:Humans; D007198:Indians, North American / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics; D014481:United States; D044465:White People / Q000235:genetics
chemical_list: D016601:RNA-Binding Proteins; C531982:SCAF8 protein, human