| 1. |
- Heid, Iris M, et al.
(författare)
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Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 949-960
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Tidskriftsartikel (refereegranskat)abstract
- Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.
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| 2. |
- Speliotes, Elizabeth K., et al.
(författare)
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Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 937-948
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ~2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10−8), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
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| 3. |
- Lango Allen, Hana, et al.
(författare)
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Hundreds of variants clustered in genomic loci and biological pathways affect human height.
- 2010
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 467:7317, s. 832-8
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Tidskriftsartikel (refereegranskat)abstract
- Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P<0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.
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| 4. |
- Middeldorp, Christel M., et al.
(författare)
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The Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia : design, results and future prospects
- 2019
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Ingår i: European Journal of Epidemiology. - : Springer Science and Business Media LLC. - 0393-2990 .- 1573-7284. ; 34:3, s. 279-300
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Tidskriftsartikel (refereegranskat)abstract
- The impact of many unfavorable childhood traits or diseases, such as low birth weight and mental disorders, is not limited to childhood and adolescence, as they are also associated with poor outcomes in adulthood, such as cardiovascular disease. Insight into the genetic etiology of childhood and adolescent traits and disorders may therefore provide new perspectives, not only on how to improve wellbeing during childhood, but also how to prevent later adverse outcomes. To achieve the sample sizes required for genetic research, the Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia were established. The majority of the participating cohorts are longitudinal population-based samples, but other cohorts with data on early childhood phenotypes are also involved. Cohorts often have a broad focus and collect(ed) data on various somatic and psychiatric traits as well as environmental factors. Genetic variants have been successfully identified for multiple traits, for example, birth weight, atopic dermatitis, childhood BMI, allergic sensitization, and pubertal growth. Furthermore, the results have shown that genetic factors also partly underlie the association with adult traits. As sample sizes are still increasing, it is expected that future analyses will identify additional variants. This, in combination with the development of innovative statistical methods, will provide detailed insight on the mechanisms underlying the transition from childhood to adult disorders. Both consortia welcome new collaborations. Policies and contact details are available from the corresponding authors of this manuscript and/or the consortium websites.
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| 5. |
- Fernandez, Celine, et al.
(författare)
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Plasma Lipid Composition and Risk of Developing Cardiovascular Disease
- 2013
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 8:8
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Tidskriftsartikel (refereegranskat)abstract
- Aims: We tested whether characteristic changes of the plasma lipidome in individuals with comparable total lipids level associate with future cardiovascular disease (CVD) outcome and whether 23 validated gene variants associated with coronary artery disease (CAD) affect CVD associated lipid species. Methods and Results: Screening of the fasted plasma lipidome was performed by top-down shotgun analysis and lipidome compositions compared between incident CVD cases (n = 211) and controls (n = 216) from the prospective population-based MDC study using logistic regression adjusting for Framingham risk factors. Associations with incident CVD were seen for eight lipid species (0.21 <= q <= 0.23). Each standard deviation unit higher baseline levels of two lysophosphatidylcholine species (LPC), LPC16:0 and LPC20:4, was associated with a decreased risk for CVD (P=0.024-0.028). Sphingomyelin (SM) 38: 2 was associated with increased odds of CVD (P=0.057). Five triglyceride (TAG) species were associated with protection (P=0.031-0.049). LPC16:0 was negatively correlated with the carotid intima-media thickness (P=0.010) and with HbA1c (P=0.012) whereas SM38:2 was positively correlated with LDL-cholesterol (P=0.0*10(-6)) and the q-values were good (q <= 0.03). The risk allele of 8 CAD-associated gene variants showed significant association with the plasma level of several lipid species. However, the q-values were high for many of the associations (0.015 <= q <= 0.75). Risk allele carriers of 3 CAD-loci had reduced level of LPC16:0 and/or LPC 20:4 (P <= 0.056). Conclusion: Our study suggests that CVD development is preceded by reduced levels of LPC16: 0, LPC20: 4 and some specific TAG species and by increased levels of SM38:2. It also indicates that certain lipid species are intermediate phenotypes between genetic susceptibility and overt CVD. But it is a preliminary study that awaits replication in a larger population because statistical significance was lost for the associations between lipid species and future cardiovascular events when correcting for multiple testing.
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| 6. |
- Ling, Charlotte, et al.
(författare)
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Genetic and epigenetic factors are associated with expression of respiratory chain component NDUFB6 in human skeletal muscle.
- 2007
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Ingår i: The Journal of clinical investigation. - 0021-9738. ; 117:11, s. 3427-35
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Tidskriftsartikel (refereegranskat)abstract
- Insulin resistance and type 2 diabetes are associated with decreased expression of genes that regulate oxidative phosphorylation in skeletal muscle. To determine whether this defect might be inherited or acquired, we investigated the association of genetic, epigenetic, and nongenetic factors with expression of NDUFB6, a component of the respiratory chain that is decreased in muscle from diabetic patients. Expression of NDUFB6 was influenced by age, with lower gene expression in muscle of elderly subjects. Heritability of NDUFB6 expression in muscle was estimated to be approximately 60% in twins. A polymorphism in the NDUFB6 promoter region that creates a possible DNA methylation site (rs629566, A/G) was associated with a decline in muscle NDUFB6 expression with age. Although young subjects with the rs629566 G/G genotype exhibited higher muscle NDUFB6 expression, this genotype was associated with reduced expression in elderly subjects. This was subsequently explained by the finding of increased DNA methylation in the promoter of elderly, but not young, subjects carrying the rs629566 G/G genotype. Furthermore, the degree of DNA methylation correlated negatively with muscle NDUFB6 expression, which in turn was associated with insulin sensitivity. Our results demonstrate that genetic, epigenetic, and nongenetic factors associate with NDUFB6 expression in human muscle and suggest that genetic and epigenetic factors may interact to increase age-dependent susceptibility to insulin resistance.
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| 7. |
- Chen, X., et al.
(författare)
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A genome-wide association study of IgM antibody against phosphorylcholine: shared genetics and phenotypic relationship to chronic lymphocytic leukemia
- 2018
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 27:10, s. 1809-1818
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Tidskriftsartikel (refereegranskat)abstract
- Phosphorylcholine (PC) is an epitope on oxidized low-density lipoprotein (oxLDL), apoptotic cells and several pathogens like Streptococcus pneumoniae. Immunoglobulin M against PC (IgM anti-PC) has the ability to inhibit uptake of oxLDL by macrophages and increase clearance of apoptotic cells. From our genome-wide association studies (GWASs) in four European-ancestry cohorts, six single nucleotide polymorphisms (SNPs) in 11q24.1 were discovered (in 3002 individuals) and replicated (in 646 individuals) to be associated with serum level of IgM anti-PC (the leading SNP rs35923643-G, combined beta = 0.19, 95% confidence interval 0.13-0.24, P = 4.3 x 10-11). The haplotype tagged by rs35923643-G (or its proxy SNP rs735665-A) is also known as the top risk allele for chronic lymphocytic leukemia (CLL), and a main increasing allele for general IgM. By using summary GWAS results of IgM anti-PC and CLL in the polygenic risk score (PRS) analysis, PRS on the basis of IgM anti-PC risk alleles positively associated with CLL risk (explained 0.6% of CLL variance, P = 1.2 x 10-15). Functional prediction suggested that rs35923643-G might impede the binding of Runt-related transcription factor 3, a tumor suppressor playing a central role in the immune regulation of cancers. Contrary to the expectations from the shared genetics between IgM anti-PC and CLL, an inverse relationship at the phenotypic level was found in a nested case-control study (30 CLL cases with 90 age- and sex-matched controls), potentially reflecting reverse causation. The suggested function of the top variant as well as the phenotypic association between IgM anti-PC and CLL risk needs replication and motivates further studies.
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| 8. |
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| 9. |
- Fredriksson, Jenny, et al.
(författare)
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Variation in GYS1 Interacts with Exercise and Gender to Predict Cardiovascular Mortality
- 2007
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 2:3
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Tidskriftsartikel (refereegranskat)abstract
- Background. The muscle glycogen synthase gene (GYS1) has been associated with type 2 diabetes (T2D), the metabolic syndrome (MetS), male myocardial infarction and a defective increase in muscle glycogen synthase protein in response to exercise. We addressed the questions whether polymorphism in GYS1 can predict cardiovascular (CV) mortality in a high-risk population, if this risk is influenced by gender or physical activity, and if the association is independent of genetic variation in nearby apolipoprotein E gene (APOE). Methodology/Principal Findings. Polymorphisms in GYS1 (XbaIC>T) and APOE (-219G>T, epsilon 2/epsilon 3/epsilon 4) were genotyped in 4,654 subjects participating in the Botnia T2D-family study and followed for a median of eight years. Mortality analyses were performed using Cox proportional-hazards regression. During the follow-up period, 749 individuals died, 409 due to CV causes. In males the GYS1 XbaI T-allele (hazard ratio (HR) 1.9 [1.2-2.9]), T2D (2.5 [1.7-3.8]), earlier CV events (1.7 [1.2-2.5]), physical inactivity (1.9 [1.2-2.9]) and smoking (1.5 [1.0-2.3]) predicted CV mortality. The GYS1 XbaI T-allele predicted CV mortality particularly in physically active males (HR 1.7 [1.3-2.0]). Association of GYS1 with CV mortality was independent of APOE (219TT/epsilon 4), which by its own exerted an effect on CV mortality risk in females (2.9 [1.9-4.4]). Other independent predictors of CV mortality in females were fasting plasma glucose (1.2 [1.1-1.2]), high body mass index (BMI) (1.0 [1.0-1.1]), hypertension (1.9 [1.2-3.1]), earlier CV events (1.9 [1.3-2.8]) and physical inactivity (1.9 [1.2-2.8]). Conclusions/Significance. Polymorphisms in GYS1 and APOE predict CV mortality in T2D families in a gender-specific fashion and independently of each other. Physical exercise seems to unmask the effect associated with the GYS1 polymorphism, rendering carriers of the variant allele less susceptible to the protective effect of exercise on the risk of CV death, which finding could be compatible with a previous demonstration of defective increase in the glycogen synthase protein in carriers of this polymorphism.
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| 10. |
- Glad, Camilla A M, 1981, et al.
(författare)
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The GH receptor exon 3 deleted/full-length polymorphism is associated with central adiposity in the general population.
- 2015
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Ingår i: European journal of endocrinology / European Federation of Endocrine Societies. - 1479-683X .- 0804-4643. ; 172:2, s. 123-128
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To test the hypothesis that the growth hormone (GH) receptor (GHR) d3/fl polymorphism influences anthropometry and body composition in the general population. Design and Setting: The Swedish Obese Subjects (SOS) reference study is a cross-sectional population-based study, randomly selected from a population registry. A sub-group of the population-based Malmö Diet and Cancer Study (MDC-CC) was used as a replication cohort. Methods: The SOS reference study comprises 1135 subjects (46.2% men), with an average age of 49.5 yrs. The MDC-CC includes 5451 successfully genotyped subjects (41.5% men), with an average age of 57.5 yrs. GHR d3/fl genotypes were determined using tagSNP rs6873545. Linear regression analyses were used to test for genotype - phenotype associations. Results: In the SOS reference study, subjects homozygous for the d3-GHR weighed approximately four kilos more (p=0.011), had larger waist-to-hip ratio (WHR, p=0.036), waist circumference (p=0.016) and more fat free mass estimated from total body potassium (TBK, p=0.026) than grouped fl/d3 and fl/fl subjects (d3-recessive genetic model). The association with WHR was replicated in the MDC-CC (p=0.002), but not those with other anthropometric traits. Conclusions: In this population-based study the GHR d3/fl polymorphism was found to be of functional relevance and associated with central adiposity, such that subjects homozygous for the d3-GHR showed an increased abdominal obesity.
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