title: Meta-GWAS and Meta-Analysis of Exome Array Studies Do Not Reveal Genetic Determinants of Serum Hepcidin.
abstract: Serum hepcidin concentration is regulated by iron status, inflammation, erythropoiesis and numerous other factors, but underlying processes are incompletely understood. We studied the association of common and rare single nucleotide variants (SNVs) with serum hepcidin in one Italian study and two large Dutch population-based studies. We genotyped common SNVs with genome-wide association study (GWAS) arrays and subsequently performed imputation using the 1000 Genomes reference panel. Cohort-specific GWAS were performed for log-transformed serum hepcidin, adjusted for age and gender, and results were combined in a fixed-effects meta-analysis (total N 6,096). Six top SNVs (p<5x10-6) were genotyped in 3,821 additional samples, but associations were not replicated. Furthermore, we meta-analyzed cohort-specific exome array association results of rare SNVs with serum hepcidin that were available for two of the three cohorts (total N 3,226), but no exome-wide significant signal (p<1.4x10-6) was identified. Gene-based meta-analyses revealed 19 genes that showed significant association with hepcidin. Our results suggest the absence of common SNVs and rare exonic SNVs explaining a large proportion of phenotypic variation in serum hepcidin. We recommend extension of our study once additional substantial cohorts with hepcidin measurements, GWAS and/or exome array data become available in order to increase power to identify variants that explain a smaller proportion of hepcidin variation. In addition, we encourage follow-up of the potentially interesting genes that resulted from the gene-based analysis of low-frequency and rare variants.
authors.affiliation: Radboud university medical center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands.
authors.forename: Tessel E
authors.initials: TE
authors.lastname: Galesloot
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Cardiology, Groningen, The Netherlands.
authors.forename: Niek
authors.initials: N
authors.lastname: Verweij
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milano, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Traglia
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milano, Italy.|Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Barbieri
authors.affiliation: University of Groningen, University Medical Center Groningen, Genomics Coordination Center, Groningen, The Netherlands.|University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.
authors.forename: Freerk
authors.initials: F
authors.lastname: van Dijk
authors.affiliation: Radboud university medical center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.|Hepcidinanalysis.com, Department of Laboratory Medicine, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: Anneke J
authors.initials: AJ
authors.lastname: Geurts-Moespot
authors.affiliation: Department of Medicine, Section of Internal Medicine, University of Verona, Verona, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Girelli
authors.affiliation: Radboud university medical center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands.
authors.forename: Lambertus A L M
authors.initials: LA
authors.lastname: Kiemeney
authors.affiliation: Radboud university medical center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands.
authors.forename: Fred C G J
authors.initials: FC
authors.lastname: Sweep
authors.affiliation: University of Groningen, University Medical Center Groningen, Genomics Coordination Center, Groningen, The Netherlands.|University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.
authors.forename: Morris A
authors.initials: MA
authors.lastname: Swertz
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Cardiology, Groningen, The Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: van der Meer
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milano, Italy.|Vita-Salute University, Milan, Italy.
authors.forename: Clara
authors.initials: C
authors.lastname: Camaschella
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milano, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Toniolo
authors.affiliation: Radboud university medical center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands.
authors.forename: Sita H
authors.initials: SH
authors.lastname: Vermeulen
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Cardiology, Groningen, The Netherlands.|University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.
authors.forename: Pim
authors.initials: P
authors.lastname: van der Harst
authors.affiliation: Radboud university medical center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.|Hepcidinanalysis.com, Department of Laboratory Medicine, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: Dorine W
authors.initials: DW
authors.lastname: Swinkels
mesh_terms: D004920:Erythropoiesis / Q000235:genetics; D059472:Exome / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D064451:Hepcidins / Q000097:blood / Q000235:genetics*; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000235:genetics* / Q000473:pathology; D007501:Iron / Q000097:blood*; D008297:Male; D020641:Polymorphism, Single Nucleotide
chemical_list: D064451:Hepcidins; D007501:Iron