title: Contribution of rare and common variants determine complex diseases-Hirschsprung disease as a model.
abstract: Finding genes for complex diseases has been the goal of many genetic studies. Most of these studies have been successful by searching for genes and mutations in rare familial cases, by screening candidate genes and by performing genome wide association studies. However, only a small fraction of the total genetic risk for these complex genetic diseases can be explained by the identified mutations and associated genetic loci. In this review we focus on Hirschsprung disease (HSCR) as an example of a complex genetic disorder. We describe the genes identified in this congenital malformation and postulate that both common 'low penetrant' variants in combination with rare or private 'high penetrant' variants determine the risk on HSCR, and likely, on other complex diseases. We also discuss how new technological advances can be used to gain further insights in the genetic background of complex diseases. Finally, we outline a few steps to develop functional assays in order to determine the involvement of these variants in disease development.
authors.affiliation: Department of Clinical Genetics, Dr. Molewaterplein, 50, Rotterdam, The Netherlands. Electronic address: m.alves@erasmusmc.nl.
authors.forename: Maria M
authors.initials: MM
authors.lastname: Alves
authors.forename: Yunia
authors.initials: Y
authors.lastname: Sribudiani
authors.forename: Rutger W W
authors.initials: RW
authors.lastname: Brouwer
authors.forename: Jeanne
authors.initials: J
authors.lastname: Amiel
authors.forename: Guillermo
authors.initials: G
authors.lastname: Antiñolo
authors.forename: Salud
authors.initials: S
authors.lastname: Borrego
authors.forename: Isabella
authors.initials: I
authors.lastname: Ceccherini
authors.forename: Aravinda
authors.initials: A
authors.lastname: Chakravarti
authors.forename: Raquel M
authors.initials: RM
authors.lastname: Fernández
authors.forename: Maria-Mercè
authors.initials: MM
authors.lastname: Garcia-Barcelo
authors.forename: Paola
authors.initials: P
authors.lastname: Griseri
authors.forename: Stanislas
authors.initials: S
authors.lastname: Lyonnet
authors.forename: Paul K
authors.initials: PK
authors.lastname: Tam
authors.forename: Wilfred F J
authors.initials: WF
authors.lastname: van Ijcken
authors.forename: Bart J L
authors.initials: BJ
authors.lastname: Eggen
authors.forename: Gerard J
authors.initials: GJ
authors.lastname: te Meerman
authors.forename: Robert M W
authors.initials: RM
authors.lastname: Hofstra
mesh_terms: D000818:Animals; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006627:Hirschsprung Disease / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008954:Models, Biological
keywords: Functional assays; GWAS; Hirschsprung disease; Next generation sequencing; Rare variants; Systems biology