Low-density lipoprotein receptor mutations generate synthetic genome-wide associations.
Oosterveer DM., Versmissen J., Defesche JC., Sivapalaratnam S., Yazdanpanah M., Mulder M., van der Zee L., Uitterlinden AG., van Duijn CM., Hofman A., Kastelein JJP., Aulchenko YS., Sijbrands EJG.
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.