TY - JOUR
T1 - Low-density lipoprotein receptor mutations generate synthetic genome-wide associations
AU - Oosterveer, Daniëlla M.
AU - Versmissen, Jorie
AU - Defesche, Joep C.
AU - Sivapalaratnam, Suthesh
AU - Yazdanpanah, Mojgan
AU - Mulder, Monique
AU - van der Zee, Leonie
AU - Uitterlinden, André G.
AU - van Duijn, Cornelia M.
AU - Hofman, Albert
AU - Kastelein, John J. P.
AU - Aulchenko, Yurii S.
AU - Sijbrands, Eric J. G.
PY - 2013
Y1 - 2013
N2 - 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
AB - 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
U2 - https://doi.org/10.1038/ejhg.2012.207
DO - https://doi.org/10.1038/ejhg.2012.207
M3 - Article
C2 - 22968135
SN - 1018-4813
VL - 21
SP - 563
EP - 566
JO - European journal of human genetics
JF - European journal of human genetics
IS - 5
ER -