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.
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Authors | Daniëlla M Oosterveer, Jorie Versmissen, Joep C Defesche, Suthesh Sivapalaratnam, Mojgan Yazdanpanah, Monique Mulder, Leonie van der Zee, André G Uitterlinden, Cornelia M van Duijn, Albert Hofman, John J P Kastelein, Yurii S Aulchenko, Eric J G Sijbrands |
Journal | European journal of human genetics : EJHG
(Eur J Hum Genet)
Vol. 21
Issue 5
Pg. 563-6
(May 2013)
ISSN: 1476-5438 [Electronic] England |
PMID | 22968135
(Publication Type: Journal Article)
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Chemical References |
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Topics |
- Cohort Studies
- Genome-Wide Association Study
- Genotype
- Haplotypes
(genetics)
- Humans
- Hyperlipoproteinemia Type II
(genetics)
- Mutation
(genetics)
- Oligonucleotide Array Sequence Analysis
- Polymorphism, Single Nucleotide
(genetics)
- Receptors, LDL
(genetics)
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