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Sökning: WFRF:(James P) > Salomaa Veikko > Peltonen Leena > Uppsala universitet > Jula Antti

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1.
  • Heid, Iris M., et al. (författare)
  • Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution.
  • 2010
  • Ingår i: Nature genetics. - 1546-1718. ; 42:11, s. 949
  • 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 x 10(-9) to P = 1.8 x 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 x 10(-3) to P = 1.2 x 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.
  • Lango Allen, Hana, et al. (författare)
  • Hundreds of variants clustered in genomic loci and biological pathways affect human height.
  • 2010
  • Ingår i: Nature. - 1476-4687. ; 467:7317, s. 832
  • 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(1), 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(2,3). 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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3.
  • Dupuis, Josee, et al. (författare)
  • New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk
  • 2010
  • Ingår i: Nature Genetics. - 1061-4036. ; 42:2, s. 105-116
  • Tidskriftsartikel (refereegranskat)abstract
    • Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.
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4.
  • Manning, Alisa K., et al. (författare)
  • A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance
  • 2012
  • Ingår i: Nature Genetics. - New York : Nature Publishing Group. - 1061-4036. ; 44:6, s. 659-669
  • Tidskriftsartikel (refereegranskat)abstract
    • Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and beta-cell dysfunction but have contributed little to the understanding of the genetic basis of insulin resistance. We hypothesized that genes implicated in insulin resistance pathways might be uncovered by accounting for differences in body mass index (BMI) and potential interactions between BMI and genetic variants. We applied a joint meta-analysis approach to test associations with fasting insulin and glucose on a genome-wide scale. We present six previously unknown loci associated with fasting insulin at P < 5 x 10(-8) in combined discovery and follow-up analyses of 52 studies comprising up to 96,496 non-diabetic individuals. Risk variants were associated with higher triglyceride and lower high-density lipoprotein (HDL) cholesterol levels, suggesting a role for these loci in insulin resistance pathways. The discovery of these loci will aid further characterization of the role of insulin resistance in T2D pathophysiology.
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5.
  • Surakka, Ida, et al. (författare)
  • A Genome-Wide Screen for Interactions Reveals a New Locus on 4p15 Modifying the Effect of Waist-to-Hip Ratio on Total Cholesterol
  • 2011
  • Ingår i: PLoS Genetics. - 1553-7390. ; 7:10, s. e1002333
  • Tidskriftsartikel (refereegranskat)abstract
    • Recent genome-wide association (GWA) studies described 95 loci controlling serum lipid levels. These common variants explain similar to 25% of the heritability of the phenotypes. To date, no unbiased screen for gene-environment interactions for circulating lipids has been reported. We screened for variants that modify the relationship between known epidemiological risk factors and circulating lipid levels in a meta-analysis of genome-wide association (GWA) data from 18 population-based cohorts with European ancestry (maximum N = 32,225). We collected 8 further cohorts (N = 17,102) for replication, and rs6448771 on 4p15 demonstrated genome-wide significant interaction with waist-to-hip-ratio (WHR) on total cholesterol (TC) with a combined P-value of 4.79 x 10(-9). There were two potential candidate genes in the region, PCDH7 and CCKAR, with differential expression levels for rs6448771 genotypes in adipose tissue. The effect of WHR on TC was strongest for individuals carrying two copies of G allele, for whom a one standard deviation (sd) difference in WHR corresponds to 0.19 sd difference in TC concentration, while for A allele homozygous the difference was 0.12 sd. Our findings may open up possibilities for targeted intervention strategies for people characterized by specific genomic profiles. However, more refined measures of both body-fat distribution and metabolic measures are needed to understand how their joint dynamics are modified by the newly found locus.
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6.
  • Kilpeläinen, Tuomas O, et al. (författare)
  • Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile.
  • 2011
  • Ingår i: Nature genetics. - 1546-1718. ; 43:8, s. 753
  • Tidskriftsartikel (refereegranskat)abstract
    • Genome-wide association studies have identified 32 loci influencing body mass index, but this measure does not distinguish lean from fat mass. To identify adiposity loci, we meta-analyzed associations between similar to 2.5 million SNPs and body fat percentage from 36,626 individuals and followed up the 14 most significant (P < 10(-6)) independent loci in 39,576 individuals. We confirmed a previously established adiposity locus in FTO (P = 3 x 10(-26)) and identified two new loci associated with body fat percentage, one near IRS1 (P = 4 x 10(-11)) and one near SPRY2 (P = 3 x 10(-8)). Both loci contain genes with potential links to adipocyte physiology. Notably, the body-fat-decreasing allele near IRS1 is associated with decreased IRS1 expression and with an impaired metabolic profile, including an increased visceral to subcutaneous fat ratio, insulin resistance, dyslipidemia, risk of diabetes and coronary artery disease and decreased adiponectin levels. Our findings provide new insights into adiposity and insulin resistance.
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