title: Low-density lipoprotein receptor mutations generate synthetic genome-wide associations.
abstract: Genome-wide association (GWA) studies have discovered multiple common genetic risk variants related to common diseases. It has been proposed that a number of these signals of common polymorphisms are based on synthetic associations that are generated by rare causative variants. We investigated if mutations in the low-density lipoprotein receptor (LDLR) gene causing familial hypercholesterolemia (FH, OMIM #143890) produce such signals. We genotyped 480 254 polymorphisms in 464 FH patients and in 5945 subjects from the general population. A total of 28 polymorphisms located up to 2.4 Mb from the LDLR gene were genome-wide significantly associated with FH (P<10(-8)). We replicated the 10 top signals in 2189 patients with a clinical diagnosis of FH and in 2157 subjects of a second sample of the general population (P<0.000087). Our findings confirm that rare variants are able to cause synthetic genome-wide significant associations, and that they exert this effect at relatively large distances from the causal mutation.
authors.affiliation: Department of Internal Medicine-D435, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Daniëlla M
authors.initials: DM
authors.lastname: Oosterveer
authors.forename: Jorie
authors.initials: J
authors.lastname: Versmissen
authors.forename: Joep C
authors.initials: JC
authors.lastname: Defesche
authors.forename: Suthesh
authors.initials: S
authors.lastname: Sivapalaratnam
authors.forename: Mojgan
authors.initials: M
authors.lastname: Yazdanpanah
authors.forename: Monique
authors.initials: M
authors.lastname: Mulder
authors.forename: Leonie
authors.initials: L
authors.lastname: van der Zee
authors.forename: André G
authors.initials: AG
authors.lastname: Uitterlinden
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.forename: John J P
authors.initials: JJ
authors.lastname: Kastelein
authors.forename: Yurii S
authors.initials: YS
authors.lastname: Aulchenko
authors.forename: Eric J G
authors.initials: EJ
authors.lastname: Sijbrands
mesh_terms: D015331:Cohort Studies; D055106:Genome-Wide Association Study; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011973:Receptors, LDL / Q000235:genetics*
chemical_list: D011973:Receptors, LDL