title: Regional heritability mapping method helps explain missing heritability of blood lipid traits in isolated populations.
abstract: Single single-nucleotide polymorphism (SNP) genome-wide association studies (SSGWAS) may fail to identify loci with modest effects on a trait. The recently developed regional heritability mapping (RHM) method can potentially identify such loci. In this study, RHM was compared with the SSGWAS for blood lipid traits (high-density lipoprotein (HDL), low-density lipoprotein (LDL), plasma concentrations of total cholesterol (TC) and triglycerides (TG)). Data comprised 2246 adults from isolated populations genotyped using ∼300 000 SNP arrays. The results were compared with large meta-analyses of these traits for validation. Using RHM, two significant regions affecting HDL on chromosomes 15 and 16 and one affecting LDL on chromosome 19 were identified. These regions covered the most significant SNPs associated with HDL and LDL from the meta-analysis. The chromosome 19 region was identified in our data despite the fact that the most significant SNP in the meta-analysis (or any SNP tagging it) was not genotyped in our SNP array. The SSGWAS identified one SNP associated with HDL on chromosome 16 (the top meta-analysis SNP) and one on chromosome 10 (not reported by RHM or in the meta-analysis and hence possibly a false positive association). The results further confirm that RHM can have better power than SSGWAS in detecting causal regions including regions containing crucial ungenotyped variants. This study suggests that RHM can be a useful tool to explain some of the 'missing heritability' of complex trait variation.
authors.affiliation: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
authors.forename: M
authors.initials: M
authors.lastname: Shirali
authors.affiliation: Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Midlothian, UK.
authors.forename: R
authors.initials: R
authors.lastname: Pong-Wong
authors.affiliation: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
authors.forename: P
authors.identifier: http://orcid.org/0000-0001-5576-8584
authors.initials: P
authors.lastname: Navarro
authors.affiliation: Institute of Evolutionary Biology, University of Edinburgh, Edinburgh, UK.
authors.forename: S
authors.initials: S
authors.lastname: Knott
authors.affiliation: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
authors.forename: C
authors.initials: C
authors.lastname: Hayward
authors.affiliation: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
authors.forename: V
authors.initials: V
authors.lastname: Vitart
authors.affiliation: Croatian Centre for Global Health, Faculty of Medicine, University of Split, Split, Croatia.|Centre for Population Health sciences, University of Edinburgh, Edinburgh, UK.
authors.forename: I
authors.identifier: http://orcid.org/0000-0001-6993-6884
authors.initials: I
authors.lastname: Rudan
authors.affiliation: Centre for Population Health sciences, University of Edinburgh, Edinburgh, UK.
authors.forename: H
authors.initials: H
authors.lastname: Campbell
authors.affiliation: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
authors.forename: N D
authors.initials: ND
authors.lastname: Hastie
authors.affiliation: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
authors.forename: A F
authors.initials: AF
authors.lastname: Wright
authors.affiliation: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.|Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Midlothian, UK.
authors.forename: C S
authors.initials: CS
authors.lastname: Haley
mesh_terms: D008076:Cholesterol, HDL / Q000097:blood / Q000235:genetics*; D008078:Cholesterol, LDL / Q000097:blood / Q000235:genetics*; D002874:Chromosome Mapping / Q000379:methods; D017523:Croatia; D005828:Genetics, Population; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D040582:Inheritance Patterns; D008957:Models, Genetic; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D014280:Triglycerides / Q000097:blood / Q000235:genetics*
chemical_list: D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D014280:Triglycerides