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Sökning: WFRF:(Kajantie Eero)

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1.
  • Ried, Janina S., et al. (författare)
  • A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape
  • 2016
  • Ingår i: Nature Communications. - Nature Publishing Group. - 2041-1723. ; 7
  • Tidskriftsartikel (refereegranskat)abstract
    • Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.
2.
  • Allen, Hana Lango, 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. 832-8
  • 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.
  • Barban, Nicola, et al. (författare)
  • Genome-wide analysis identifies 12 loci influencing human reproductive behavior
  • 2016
  • Ingår i: Nature Genetics. - 1061-4036 .- 1546-1718. ; 48:12, s. 1462-1472
  • Tidskriftsartikel (refereegranskat)abstract
    • The genetic architecture of human reproductive behavior age at first birth (AFB) and number of children ever born (NEB) has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified, and the underlying mechanisms of AFB and NEB are poorly understood. We report a large genome-wide association study of both sexes including 251,151 individuals for AFB and 343,072 individuals for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study and 4 additional loci associated in a gene-based effort. These loci harbor genes that are likely to have a role, either directly or by affecting non-local gene expression, in human reproduction and infertility, thereby increasing understanding of these complex traits.
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4.
  • Bolton, Jennifer L., et al. (författare)
  • Genome Wide Association Identifies Common Variants at the SERPINA6/SERPINA1 Locus Influencing Plasma Cortisol and Corticosteroid Binding Globulin.
  • 2014
  • Ingår i: PLoS genetics. - 1553-7404. ; 10:7
  • Tidskriftsartikel (refereegranskat)abstract
    • Variation in plasma levels of cortisol, an essential hormone in the stress response, is associated in population-based studies with cardio-metabolic, inflammatory and neuro-cognitive traits and diseases. Heritability of plasma cortisol is estimated at 30-60% but no common genetic contribution has been identified. The CORtisol NETwork (CORNET) consortium undertook genome wide association meta-analysis for plasma cortisol in 12,597 Caucasian participants, replicated in 2,795 participants. The results indicate that <1% of variance in plasma cortisol is accounted for by genetic variation in a single region of chromosome 14. This locus spans SERPINA6, encoding corticosteroid binding globulin (CBG, the major cortisol-binding protein in plasma), and SERPINA1, encoding alpha 1-antitrypsin (which inhibits cleavage of the reactive centre loop that releases cortisol from CBG). Three partially independent signals were identified within the region, represented by common SNPs; detailed biochemical investigation in a nested sub-cohort showed all these SNPs were associated with variation in total cortisol binding activity in plasma, but some variants influenced total CBG concentrations while the top hit (rs12589136) influenced the immunoreactivity of the reactive centre loop of CBG. Exome chip and 1000 Genomes imputation analysis of this locus in the CROATIA-Korcula cohort identified missense mutations in SERPINA6 and SERPINA1 that did not account for the effects of common variants. These findings reveal a novel common genetic source of variation in binding of cortisol by CBG, and reinforce the key role of CBG in determining plasma cortisol levels. In turn this genetic variation may contribute to cortisol-associated degenerative diseases.
5.
  • Goodman, Anna, et al. (författare)
  • The relationship between umbilical cord length and chronic rheumatic heart disease : a prospective cohort study
  • 2015
  • Ingår i: European Journal of Preventive Cardiology. - 2047-4873. ; 22:9, s. 1154-1160
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: One previous, preliminary study reported that the length of the umbilical cord at birth is related to the risk of developing chronic rheumatic heart disease in later life. We sought to replicate this finding.DESIGN: Prospective, population-based birth cohort.METHODS: We traced 11,580 individuals born between 1915 and 1929 in Uppsala, Sweden. We identified cases with a main or secondary diagnosis of chronic rheumatic heart disease in the Swedish national inpatient, outpatient or death registers. Archived obstetric records provided data on umbilical cord length, gestational age, birthweight and placental weight.RESULTS: There were 136 patients with chronic rheumatic heart disease (72 men and 64 women) with a mean age at first hospital admission of 68 years (range 36-92). There was evidence of a positive association between umbilical cord length and risk of subsequent chronic rheumatic heart disease. The overall hazard ratio in the Swedish study (1.13, 95% confidence interval 1.01 to 1.27) was similar to that of the previous study, with some suggestion of larger effect in men than in women. No other birth characteristics were predictive except for weak evidence of a protective effect of higher birthweight in men.CONCLUSIONS: People with longer umbilical cords at birth are more likely to develop chronic rheumatic heart disease in later life. As longer umbilical cords have more spiral arteries and a higher vascular resistance, we hypothesize that the increased pressure load on the heart leads to changes in endothelial biology and increased vulnerability to the autoimmune process initiated by infection with β-haemolytic streptococci.
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6.
  • 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. 949-60
  • 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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7.
  • Johnson, Linda, et al. (författare)
  • Early Life Risk Factors for Incident Atrial Fibrillation in the Helsinki Birth Cohort Study
  • 2017
  • Ingår i: Journal of the American Heart Association. - Wiley-Blackwell. - 2047-9980. ; 6:6
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Early life risk factors are associated with cardiometabolic disease, but have not been fully studied in atrial fibrillation (AF). There are discordant results from existing studies of birth weight and AF, and the impact of maternal body size, gestational age, placental size, and birth length is unknown.METHODS AND RESULTS: The Helsinki Birth Cohort Study includes 13 345 people born as singletons in Helsinki in the years 1934-1944. Follow-up was through national registries, and ended on December 31, 2013, with 907 incident cases. Cox regression analyses stratified on year of birth were constructed for perinatal variables and incident AF, adjusting for offspring sex, gestational age, and socioeconomic status at birth. There was a significant U-shaped association between birth weight and AF (P for quadratic term=0.01). The lowest risk of AF was found among those with a birth weight of 3.4 kg (3.8 kg for women [85th percentile] and 3.0 kg for men [17th percentile]). High maternal body mass index (≥30 kg/m(2)) predicted offspring AF; hazard ratio 1.36 (95% CI 1.07-1.74, P=0.01) compared with normal body mass index (<25 kg/m(2)). Maternal height was associated with early-onset AF (<65.3 years), hazard ratio 1.47 (95% CI 1.24-1.74, P<0.0001), but not with later onset AF. Results were independent of incident coronary artery disease, hypertension, or diabetes mellitus.CONCLUSIONS: High maternal body mass index during pregnancy and maternal height are previously undescribed predictors of offspring AF. Efforts to prevent maternal obesity might reduce later AF in offspring. Birth weight has a U-shaped relation to incident AF independent of other perinatal variables.
8.
  • Kalapotharakos, Grigorios, et al. (författare)
  • Plasma Heme Scavengers Alpha-1-Microglobulin and Hemopexin as Biomarkers in High-Risk Pregnancies
  • 2019
  • Ingår i: Frontiers in Physiology. - Frontiers. - 1664-042X. ; 10
  • Tidskriftsartikel (refereegranskat)abstract
    • Women with established preeclampsia (PE) have increased plasma concentration of free fetal hemoglobin. We measured two hemoglobin scavenger system proteins, hemopexin (Hpx) and alpha-1-microglobulin (A1M) in maternal plasma using enzyme-linked immunosorbent assay during the late second trimester of pregnancy in women with high and low risk of developing PE. In total 142 women were included in nested case-control study: 42 women diagnosed with PE and 100 controls (49 randomly selected high-risk and 51 low-risk controls). The concentration of plasma A1M in high-risk controls was higher compared to low-risk controls. Women with severe PE had higher plasma A1M levels compared to women with non-severe PE. In conclusion, the concentration of plasma A1M is increased in the late second trimester in high-risk controls, suggesting activation of endogenous protective system against oxidative stress.
9.
  • Kilpeläinen, Tuomas O, et al. (författare)
  • Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels
  • 2016
  • Ingår i: Nature Communications. - 2041-1723. ; 7
  • Tidskriftsartikel (refereegranskat)abstract
    • Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P &lt; 10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P &lt; 5 x 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.
10.
  • Ligthart, Symen, et al. (författare)
  • Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders
  • 2018
  • Ingår i: American Journal of Human Genetics. ; 103:5, s. 691-706
  • Tidskriftsartikel (refereegranskat)abstract
    • C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p &lt; 5 × 10-8). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.
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