title: Genomic architecture of sickle cell disease in West African children.
abstract: Sickle cell disease (SCD) is a congenital blood disease, affecting predominantly children from sub-Saharan Africa, but also populations world-wide. Although the causal mutation of SCD is known, the sources of clinical variability of SCD remain poorly understood, with only a few highly heritable traits associated with SCD having been identified. Phenotypic heterogeneity in the clinical expression of SCD is problematic for follow-up (FU), management, and treatment of patients. Here we used the joint analysis of gene expression and whole genome genotyping data to identify the genetic regulatory effects contributing to gene expression variation among groups of patients exhibiting clinical variability, as well as unaffected siblings, in Benin, West Africa. We characterized and replicated patterns of whole blood gene expression variation within and between SCD patients at entry to clinic, as well as in follow-up programs. We present a global map of genes involved in the disease through analysis of whole blood sampled from the cohort. Genome-wide association mapping of gene expression revealed 390 peak genome-wide significant expression SNPs (eSNPs) and 6 significant eSNP-by-clinical status interaction effects. The strong modulation of the transcriptome implicates pathways affecting core circulating cell functions and shows how genotypic regulatory variation likely contributes to the clinical variation observed in SCD.
authors.affiliation: Department of Social and Preventive Medicine, Faculty of Medicine, School of Public Health, University of Montreal Montreal, QC, Canada ; Department of Pediatrics, Faculty of Medicine, Sainte-Justine Research Center, University of Montreal Montreal, QC, Canada.
authors.forename: Jacklyn
authors.initials: J
authors.lastname: Quinlan
authors.affiliation: Department of Pediatrics, Faculty of Medicine, Sainte-Justine Research Center, University of Montreal Montreal, QC, Canada ; Biology, Division of Science and Mathematics, New York University Abu Dhabi Abu Dhabi, United Arab Emirates.
authors.forename: Youssef
authors.initials: Y
authors.lastname: Idaghdour
authors.affiliation: Department of Pediatrics, Faculty of Medicine, Sainte-Justine Research Center, University of Montreal Montreal, QC, Canada.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Goulet
authors.affiliation: Department of Pediatrics, Faculty of Medicine, Sainte-Justine Research Center, University of Montreal Montreal, QC, Canada.
authors.forename: Elias
authors.initials: E
authors.lastname: Gbeha
authors.affiliation: Department of Pediatrics, Faculty of Medicine, Sainte-Justine Research Center, University of Montreal Montreal, QC, Canada.
authors.forename: Thibault
authors.initials: T
authors.lastname: de Malliard
authors.affiliation: Department of Pediatrics, Faculty of Medicine, Sainte-Justine Research Center, University of Montreal Montreal, QC, Canada.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Bruat
authors.affiliation: Department of Pediatrics, Faculty of Medicine, Sainte-Justine Research Center, University of Montreal Montreal, QC, Canada.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Grenier
authors.affiliation: Laboratoire de Biochimie et Biologie Moléculaire, Faculté des Sciences et Techniques, Université d'Abomey-Calavi Cotonou, Benin.
authors.forename: Selma
authors.initials: S
authors.lastname: Gomez
authors.affiliation: Laboratoire de Biochimie et Biologie Moléculaire, Faculté des Sciences et Techniques, Université d'Abomey-Calavi Cotonou, Benin.
authors.forename: Ambaliou
authors.initials: A
authors.lastname: Sanni
authors.affiliation: Faculté des Sciences de la Santé, Centre de Prise en charge Médicale Intégrée du Nourrisson et de la Femme Enceinte atteints de Drépanocytose, Université d'Abomey-Calavi Cotonou, Benin.
authors.forename: Mohamed C
authors.initials: MC
authors.lastname: Rahimy
authors.affiliation: Department of Pediatrics, Faculty of Medicine, Sainte-Justine Research Center, University of Montreal Montreal, QC, Canada.
authors.forename: Philip
authors.initials: P
authors.lastname: Awadalla
keywords: eSNP mapping; gene-by-environment interactions; genomics; sickle cell disease; transcriptome