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Sökning: WFRF:(Räikkönen Katri)

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1.
  • 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 .- 1553-7390. ; 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 α1-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.
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3.
  • Tuomi, Tiinamaija, et al. (författare)
  • Increased Melatonin Signaling Is a Risk Factor for Type 2 Diabetes
  • Ingår i: Cell Metabolism. - : Cell Press. - 1550-4131 .- 1932-7420. ; 23:6, s. 1067-1077
  • Tidskriftsartikel (refereegranskat)abstract
    • Type 2 diabetes (T2D) is a global pandemic. Genome-wide association studies (GWASs) have identified >100 genetic variants associated with the disease, including a common variant in the melatonin receptor 1 b gene (MTNR1B). Here, we demonstrate increased MTNR1B expression in human islets from risk G-allele carriers, which likely leads to a reduction in insulin release, increasing T2D risk. Accordingly, in insulin-secreting cells, melatonin reduced cAMP levels, and MTNR1B overexpression exaggerated the inhibition of insulin release exerted by melatonin. Conversely, mice with a disruption of the receptor secreted more insulin. Melatonin treatment in a human recall-by-genotype study reduced insulin secretion and raised glucose levels more extensively in risk G-allele carriers. Thus, our data support a model where enhanced melatonin signaling in islets reduces insulin secretion, leading to hyperglycemia and greater future risk of T2D. The findings also imply that melatonin physiologically serves to inhibit nocturnal insulin release.
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4.
  • Davies, G., et al. (författare)
  • Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function
  • 2018
  • Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723 .- 2041-1723. ; 9:1
  • Tidskriftsartikel (refereegranskat)abstract
    • General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 × 10-8) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.
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5.
  • Haljas, Kadri, et al. (författare)
  • Bivariate genome-wide association study of depressive symptoms with type 2 diabetes and quantitative glycemic traits
  • 2018
  • Ingår i: Psychosomatic Medicine. - : Lippincott Williams and Wilkins. - 0033-3174. ; 80:3, s. 242-251
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: Shared genetic background may explain phenotypic associations between depression and Type 2 diabetes (T2D). We aimed to study, on a genome-wide level, if genetic correlation and pleiotropic loci exist between depressive symptoms and T2D or glycemic traits. Methods: We estimated single-nucleotide polymorphism (SNP)-based heritability and analyzed genetic correlation between depressive symptoms and T2D and glycemic traits with the linkage disequilibrium score regression by combining summary statistics of previously conducted meta-analyses for depressive symptoms by CHARGE consortium (N = 51,258), T2D by DIAGRAM consortium (N = 34,840 patients and 114,981 controls), fasting glucose, fasting insulin, and homeostatic model assessment of β-cell function and insulin resistance by MAGIC consortium (N = 58,074). Finally, we investigated pleiotropic loci using a bivariate genome-wide association study approach with summary statistics from genome-wide association study meta-analyses and reported loci with genome-wide significant bivariate association p value (p < 5 10−8). Biological annotation and function of significant pleiotropic SNPs were assessed in several databases. Results: The SNP-based heritability ranged from 0.04 to 0.10 in each individual trait. In the linkage disequilibrium score regression analyses, depressive symptoms showed no significant genetic correlation with T2D or glycemic traits (p > 0.37). However, we identified pleiotropic genetic variations for depressive symptoms and T2D (in the IGF2BP2, CDKAL1, CDKN2B-AS, and PLEKHA1 genes), and fasting glucose (in the MADD, CDKN2B-AS, PEX16, and MTNR1B genes). Conclusions: We found no significant overall genetic correlations between depressive symptoms, T2D, or glycemic traits suggesting major differences in underlying biology of these traits. However, several potential pleiotropic loci were identified between depressive symptoms, T2D, and fasting glucose, suggesting that previously established phenotypic associations may be partly explained by genetic variation in these specific loci.
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6.
  • Haljas, Kadri, et al. (författare)
  • Melatonin receptor 1B gene rs10830963 polymorphism, depressive symptoms and glycaemic traits
  • Ingår i: Annals of Medicine. - : Informa Healthcare. - 0785-3890. ; 50:8, s. 704-712
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: The association between depression and type 2 diabetes is bidirectional. Underlying biological determinants remain elusive. We examined whether a common melatonin receptor 1B gene diabetes risk variant rs10830963 influenced the associations between depressive symptoms and glycaemic traits. Materials: The Prevalence, Prediction and Prevention of Diabetes-Botnia Study participants (n = 4,455) with no diabetes who underwent an oral glucose tolerance test were genotyped for rs10830963 and completed the Mental Health Inventory on depressive symptoms. Results: The rs10830963 did not influence significantly the associations between depressive symptoms and glycaemic traits. Yet, the addition of each copy of the minor G allele of the rs1080963 and higher depressive symptoms were both, independent of each other, associated significantly with higher glucose response (glucose area under the curve), higher insulin resistance (Insulin Sensitivity Index) and lower insulin secretion (Disposition Index). Depressive symptoms, but not rs1080963, were also significantly associated with higher fasting insulin, insulin area under the curve and insulin resistance (Homeostasis Model Assessment, Homeostasis Model Assessment-2); rs1080963, but not depressive symptoms, was significantly associated with higher fasting glucose and lower Corrected Insulin Response. Conclusions: Our study shows that the diabetes risk variant rs10830963 does not contribute to the known comorbidity between depression and type 2 diabetes.Key messages The association between depression and type 2 diabetes is bidirectional. We tested whether a common variant rs10830963 in the gene encoding Melatonin Receptor 1B influences the known association between depressive symptoms and glycaemic traits in a population-based sample from Western Finland. The MTNR1B genetic diabetes risk variant rs10830963 does not contribute to the known comorbidity between depression and type 2 diabetes. Depressive symptoms and rs10830963 are associated with a worse glycaemic profile independently of each other.
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7.
  • Haljas, Kadri, et al. (författare)
  • The associations of daylight and melatonin receptor 1B gene rs10830963 variant with glycemic traits : the prospective PPP-Botnia study
  • Ingår i: Annals of Medicine. - : Informa Healthcare. - 0785-3890. ; 51:1, s. 58-67
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Seasonal variation in glucose metabolism might be driven by changes in daylight. Melatonin entrains circadian regulation and is directly associated with daylight. The relationship between melatonin receptor 1B gene variants with glycemic traits and type 2 diabetes is well established. We studied if daylight length was associated with glycemic traits and if it modified the relationship between melatonin receptor 1B gene rs10830963 variant and glycemic traits. Materials: A population-based sample of 3422 18–78-year-old individuals without diabetes underwent an oral glucose tolerance test twice, an average 6.8 years (SD = 0.9) apart and were genotyped for rs10830963. Daylight data was obtained from the Finnish Meteorological Institute. Results: Cross-sectionally, more daylight was associated with lower fasting glucose, but worse insulin sensitivity and secretion at follow-up. Longitudinally, individuals studied on lighter days at follow-up than at baseline showed higher glucose values during the oral glucose tolerance test and lower Corrected Insulin Response at follow-up. GG genotype carriers in the rs10830963 became more insulin resistant during follow-up if daylight length was shorter at follow-up than at baseline. Conclusions: Our study shows that individual glycemic profiles may vary according to daylight, MTNR1B genotype and their interaction. Future studies may consider taking daylight length into account.Key messages In Western Finland, the amount daylight follows an extensive annual variation ranging from 4 h 44 min to 20 h 17 min, making it ideal to study the associations between daylight and glycemic traits. Moreover, this allows researchers to explore if the relationship between the melatonin receptor 1B gene rs10830963 variant and glycemic traits is modified by the amount of daylight both cross-sectionally and longitudinally. This study shows that individuals, who participated in the study on lighter days at the follow-up than at the baseline, displayed to a greater extent worse glycemic profiles across the follow-up. Novel findings from the current study show that in the longitudinal analyses, each addition of the minor G allele of the melatonin receptor 1B gene rs10830963 was associated with worsening of fasting glucose values and insulin secretion across the 6.8-year follow-up. Importantly, this study shows that in those with the rs10830963 GG genotype, insulin sensitivity deteriorated the most significantly across the 6.8-year follow-up if the daylight length on the oral glucose tolerance testing date at the follow-up was shorter than at the baseline. Taken together, the current findings suggest that the amount of daylight may affect glycemic traits, especially fasting glucose and insulin secretion even though the effect size is small. The association can very according to the rs10830963 risk variant. Further research is needed to elucidate the mechanisms behind these associations.
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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 Media S. A.. - 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.
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9.
  • Maddock, Jane, et al. (författare)
  • Vitamin D and cognitive function : A Mendelian randomisation study.
  • 2017
  • Ingår i: Scientific Reports. - 2045-2322 .- 2045-2322. ; 7
  • Tidskriftsartikel (refereegranskat)abstract
    • The causal nature of the association between hypovitaminosis D and poor cognitive function in mid- to later-life is uncertain. Using a Mendelian randomisation(MR) approach, we examined the causal relationship between 25(OH)D and cognitive function. Data came from 172,349 participants from 17 cohorts. DHCR7(rs12785878), CYP2R1 rs12794714) and their combined synthesis score were chosen to proxy 25(OH)D. Cognitive tests were standardised into global and memory scores. Analyses were stratified by 25(OH)D tertiles, sex and age. Random effects meta-analyses assessed associations between 25(OH)D and cognitive function. Associations of serum 25(OH)D with global and memory-related cognitive function were non-linear (lower cognitive scores for both low and high 25(OH)D, p curvature ≤ 0.006), with much of the curvature attributed to a single study. DHCR7, CYP2R1, and the synthesis score were associated with small reductions in 25(OH)D per vitamin D-decreasing allele. However, coefficients for associations with global or memory-related cognitive function were non-significant and in opposing directions for DHCR7 and CYP2R1, with no overall association observed for the synthesis score. Coefficients for the synthesis score and global and memory cognition were similar when stratified by 25(OH)D tertiles, sex and age. We found no evidence for serum 25(OH)D concentration as a causal factor for cognitive performance in mid- to later life.
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10.
  • McQuillan, Ruth, et al. (författare)
  • Evidence of Inbreeding Depression on Human Height
  • 2012
  • Ingår i: PLOS Genetics. - 1553-7404. ; 8:7, s. e1002655-
  • Tidskriftsartikel (refereegranskat)abstract
    • Stature is a classical and highly heritable complex trait, with 80%–90% of variation explained by genetic factors. In recent years, genome-wide association studies (GWAS) have successfully identified many common additive variants influencing human height; however, little attention has been given to the potential role of recessive genetic effects. Here, we investigated genome-wide recessive effects by an analysis of inbreeding depression on adult height in over 35,000 people from 21 different population samples. We found a highly significant inverse association between height and genome-wide homozygosity, equivalent to a height reduction of up to 3 cm in the offspring of first cousins compared with the offspring of unrelated individuals, an effect which remained after controlling for the effects of socio-economic status, an important confounder (χ2 = 83.89, df = 1; p = 5.2×10−20). There was, however, a high degree of heterogeneity among populations: whereas the direction of the effect was consistent across most population samples, the effect size differed significantly among populations. It is likely that this reflects true biological heterogeneity: whether or not an effect can be observed will depend on both the variance in homozygosity in the population and the chance inheritance of individual recessive genotypes. These results predict that multiple, rare, recessive variants influence human height. Although this exploratory work focuses on height alone, the methodology developed is generally applicable to heritable quantitative traits (QT), paving the way for an investigation into inbreeding effects, and therefore genetic architecture, on a range of QT of biomedical importance.
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