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Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High- Density Imputation
- Source :
- PLoS genetics, vol 11, iss 7, PLoS Genet. 11:e1005230 (2015), PLoS Genetics, 11(7):e1005230. Public Library of Science, Plos Genetics, 11(7):e1005230. Public Library of Science, PLoS Genetics, Vol 11, Iss 7, p e1005230 (2015), PLoS Genetics, 11(7), PLoS Genetics (print), 11(7). Public Library of Science, PLoS Genetics, 11(7):e1005230, Horikoshi, M, Mägi, R, van de Bunt, M, Surakka, I, Sarin, A-P, Mahajan, A, Marullo, L, Thorleifsson, G, Hägg, S, Hottenga, J J, Ladenvall, C, Ried, J S, Winkler, T W, Willems, S M, Pervjakova, N, Esko, T, Beekman, M, Nelson, C P, Willenborg, C, Wiltshire, S, Ferreira, T, Fernandez, J, Gaulton, K J, Steinthorsdottir, V, Hamsten, A, Magnusson, P K E, Willemsen, G, Milaneschi, Y, Robertson, N R, Groves, C J, Bennett, A J, Lehtimäki, T, Viikari, J S, Rung, J, Lyssenko, V, Perola, M, Heid, I M, Herder, C, Grallert, H, Müller-Nurasyid, M, Roden, M, Hypponen, E, Isaacs, A, van Leeuwen, E M, Karssen, L C, Mihailov, E, Houwing-Duistermaat, J J, de Craen, A J, Deelen, J, Havulinna, A S, Blades, M, Hengstenberg, C, Erdmann, J, Schunkert, H, Kaprio, J, Tobin, M D, Samani, N J, Lind, L, Salomaa, V, Lindgren, C M, Slagboom, P E, Metspalu, A, van Duijn, C M, Eriksson, J G, Peters, A, Gieger, C, Jula, A, Groop, L, Raitakari, O T, Power, C, Penninx, B W J H, de Geus, E J C, Smit, J H, Boomsma, D I, Pedersen, N L, Ingelsson, E, Thorsteinsdottir, U, Stefansson, K, Ripatti, S, Prokopenko, I, McCarthy, M I & Morris, A P 2015, ' Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High-Density Imputation ', PLoS Genetics, vol. 11, no. 7, e1005230 . https://doi.org/10.1371/journal.pgen.1005230, PLoS Genetics, PLoS Genetics; 11(7), no e1005230 (2015), PLoS Genet
- Publication Year :
- 2015
- Publisher :
- Public Library of Science, 2015.
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Abstract
- Reference panels from the 1000 Genomes (1000G) Project Consortium provide near complete coverage of common and low-frequency genetic variation with minor allele frequency ≥0.5% across European ancestry populations. Within the European Network for Genetic and Genomic Epidemiology (ENGAGE) Consortium, we have undertaken the first large-scale meta-analysis of genome-wide association studies (GWAS), supplemented by 1000G imputation, for four quantitative glycaemic and obesity-related traits, in up to 87,048 individuals of European ancestry. We identified two loci for body mass index (BMI) at genome-wide significance, and two for fasting glucose (FG), none of which has been previously reported in larger meta-analysis efforts to combine GWAS of European ancestry. Through conditional analysis, we also detected multiple distinct signals of association mapping to established loci for waist-hip ratio adjusted for BMI (RSPO3) and FG (GCK and G6PC2). The index variant for one association signal at the G6PC2 locus is a low-frequency coding allele, H177Y, which has recently been demonstrated to have a functional role in glucose regulation. Fine-mapping analyses revealed that the non-coding variants most likely to drive association signals at established and novel loci were enriched for overlap with enhancer elements, which for FG mapped to promoter and transcription factor binding sites in pancreatic islets, in particular. Our study demonstrates that 1000G imputation and genetic fine-mapping of common and low-frequency variant association signals at GWAS loci, integrated with genomic annotation in relevant tissues, can provide insight into the functional and regulatory mechanisms through which their effects on glycaemic and obesity-related traits are mediated.<br />Author Summary Human genetic studies have demonstrated that quantitative human anthropometric and metabolic traits, including body mass index, waist-hip ratio, and plasma concentrations of glucose and insulin, are highly heritable, and are established risk factors for type 2 diabetes and cardiovascular diseases. Although many regions of the genome have been associated with these traits, the specific genes responsible have not yet been identified. By making use of advanced statistical “imputation” techniques applied to more than 87,000 individuals of European ancestry, and publicly available “reference panels” of more than 37 million genetic variants, we have been able to identify novel regions of the genome associated with these glycaemic and obesity-related traits and localise genes within these regions that are most likely to be causal. This improved understanding of the biological mechanisms underlying glycaemic and obesity-related traits is extremely important because it may advance drug development for downstream disease endpoints, ultimately leading to public health benefits.
- Subjects :
- Netherlands Twin Register (NTR)
Cancer Research
RARE GENETIC-VARIATION
Obesity/genetics
Genome-wide association study
Body Mass Index
Germinal Center Kinases
0302 clinical medicine
quantitative trait locus
Gene Frequency
genetic variability
2.1 Biological and endogenous factors
Aetiology
Association mapping
Genetics (clinical)
2. Zero hunger
Genetics
G6PC2 gene
Genetics & Heredity
0303 health sciences
INSULIN-RESISTANCE
Glycemic Index/genetics
Chromosome Mapping
Single Nucleotide
ENGAGE Consortium
Protein-Serine-Threonine Kinases
Polymorphism, Single Nucleotide/genetics
ddc
3. Good health
fine-mapping
Gene Frequency/genetics
Glucose-6-Phosphatase
LOW-FREQUENCY
RSPO3 gene
Life Sciences & Biomedicine
Single Nucleotide/genetics
Medical Genetics
Research Article
Biotechnology
lcsh:QH426-470
Protein-Serine-Threonine Kinases/genetics
Thrombospondins/genetics
Quantitative Trait Loci
Locus (genetics)
Biology
Endocrinology and Diabetes
Protein Serine-Threonine Kinases
GENOTYPE IMPUTATION
Polymorphism, Single Nucleotide
ASIAN POPULATIONS
03 medical and health sciences
SDG 3 - Good Health and Well-being
Humans
Genetic Predisposition to Disease
Obesity
1000 Genomes Project
GENOME-WIDE ASSOCIATION
Polymorphism
Molecular Biology
Allele frequency
Ecology, Evolution, Behavior and Systematics
Metabolic and endocrine
030304 developmental biology
Genetic association
Medicinsk genetik
Nutrition
Science & Technology
Body mass index
Molecular genetics
Quantitative trait loci
Genome-wide association studies
Quality control
Genomic signal processing
Meta-analysis
Human Genome
gene mapping
ta3121
Minor allele frequency
BODY-MASS INDEX
lcsh:Genetics
Glucose-6-Phosphatase/genetics
Glycemic Index
glycemic control
TYPE-2 DIABETES RISK
3111 Biomedicine
GCK gene
WAIST-HIP RATIO
Quantitative Trait Loci/genetics
Thrombospondins
030217 neurology & neurosurgery
Imputation (genetics)
FASTING GLUCOSE
Genome-Wide Association Study
Developmental Biology
Subjects
Details
- Language :
- English
- ISSN :
- 15537404 and 15537390
- Volume :
- 11
- Issue :
- 7
- Database :
- OpenAIRE
- Journal :
- PLoS Genetics
- Accession number :
- edsair.doi.dedup.....c40aa44cb832bdce71a21e12d966f5d0