Identification of HKDC1 and BACE2 as Genes Influencing Glycemic Traits During Pregnancy Through Genome-Wide Association Studies
- M. Geoffrey Hayes1⇑,
- Margrit Urbanek1,
- Marie-France Hivert2,3,
- Loren L. Armstrong1,
- Jean Morrison4,
- Cong Guo12,
- Lynn P. Lowe6,
- Douglas A. Scheftner1,
- Anna Pluzhnikov4,
- David M. Levine7,
- Caitlin P. McHugh7,
- Christine M. Ackerman1,
- Luigi Bouchard8,9,
- Diane Brisson9,
- Brian T. Layden1,13,
- Daniel Mirel10,
- Kimberly F. Doheny11,
- Marysa V. Leya1,
- Rachel N. Lown-Hecht1,
- Alan R. Dyer6,
- Boyd E. Metzger1,
- Timothy E. Reddy5,12,
- Nancy J. Cox4,
- William L. Lowe Jr.1,
- for the HAPO Study Cooperative Research Group
- 1Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
- 2Department of Medicine, Division of Endocrinology, Université de Sherbrooke, Sherbrooke, Quebec, Canada
- 3General Medicine Division, Massachusetts General Hospital, Boston, Massachusetts
- 4Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, Illinois
- 5Department of Biostatistics & Bioinformatics, Duke University Medical Center, Durham, North Carolina
- 6Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
- 7Department of Biostatistics, University of Washington, Seattle, Washington
- 8Department of Biochemistry, Université de Sherbrooke, Sherbrooke, Quebec, Canada
- 9ECOGENE-21 and Lipid Clinic, Chicoutimi Hospital, Saguenay, Quebec, Canada
- 10The Broad Institute, Cambridge, Massachusetts
- 11Center for Inherited Disease Research, Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland
- 12Institute for Genome Sciences & Policy, Duke University, Durham, North Carolina
- 13Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois.
- Corresponding author: M. Geoffrey Hayes, .
Maternal metabolism during pregnancy impacts the developing fetus, affecting offspring birth weight and adiposity. This has important implications for metabolic health later in life (e.g., offspring of mothers with pre-existing or gestational diabetes mellitus have an increased risk of metabolic disorders in childhood). To identify genetic loci associated with measures of maternal metabolism obtained during an oral glucose tolerance test at ∼28 weeks’ gestation, we performed a genome-wide association study of 4,437 pregnant mothers of European (n = 1,367), Thai (n = 1,178), Afro-Caribbean (n = 1,075), and Hispanic (n = 817) ancestry, along with replication of top signals in three additional European ancestry cohorts. In addition to identifying associations with genes previously implicated with measures of glucose metabolism in nonpregnant populations, we identified two novel genome-wide significant associations: 2-h plasma glucose and HKDC1, and fasting C-peptide and BACE2. These results suggest that the genetic architecture underlying glucose metabolism may differ, in part, in pregnancy.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db12-1692/-/DC1.
- Received December 6, 2012.
- Accepted May 5, 2013.
- © 2013 by the American Diabetes Association.
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