| 1. |
- Ried, Janina S., et al.
(författare)
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A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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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.
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| 2. |
- Beaumont, Robin N, et al.
(författare)
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Genome-wide association study of placental weight identifies distinct and shared genetic influences between placental and fetal growth.
- 2023
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Ingår i: Nature genetics. - 1546-1718 .- 1061-4036. ; 55:11, s. 1807-19
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Tidskriftsartikel (refereegranskat)abstract
- A well-functioning placenta is essential for fetal and maternal health throughout pregnancy. Using placental weight as a proxy for placental growth, we report genome-wide association analyses in the fetal (n=65,405), maternal (n=61,228) and paternal (n=52,392) genomes, yielding 40 independent association signals. Twenty-six signals are classified as fetal, four maternal and three fetal and maternal. A maternal parent-of-origin effect is seen near KCNQ1. Genetic correlation and colocalization analyses reveal overlap with birth weight genetics, but 12 loci are classified as predominantly or only affecting placental weight, with connections to placental development and morphology, and transport of antibodies and amino acids. Mendelian randomization analyses indicate that fetal genetically mediated higher placental weight is causally associated with preeclampsia risk and shorter gestational duration. Moreover, these analyses support the role of fetal insulin in regulating placental weight, providing a key link between fetal and placental growth.
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| 3. |
- Broadaway, K Alaine, et al.
(författare)
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Loci for insulin processing and secretion provide insight into type 2 diabetes risk.
- 2023
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Ingår i: American Journal of Human Genetics. - : Elsevier. - 0002-9297 .- 1537-6605. ; 110:2, s. 284-299
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Tidskriftsartikel (refereegranskat)abstract
- Insulin secretion is critical for glucose homeostasis, and increased levels of the precursor proinsulin relative to insulin indicate pancreatic islet beta-cell stress and insufficient insulin secretory capacity in the setting of insulin resistance. We conducted meta-analyses of genome-wide association results for fasting proinsulin from 16 European-ancestry studies in 45,861 individuals. We found 36 independent signals at 30 loci (p value < 5 × 10-8), which validated 12 previously reported loci for proinsulin and ten additional loci previously identified for another glycemic trait. Half of the alleles associated with higher proinsulin showed higher rather than lower effects on glucose levels, corresponding to different mechanisms. Proinsulin loci included genes that affect prohormone convertases, beta-cell dysfunction, vesicle trafficking, beta-cell transcriptional regulation, and lysosomes/autophagy processes. We colocalized 11 proinsulin signals with islet expression quantitative trait locus (eQTL) data, suggesting candidate genes, including ARSG, WIPI1, SLC7A14, and SIX3. The NKX6-3/ANK1 proinsulin signal colocalized with a T2D signal and an adipose ANK1 eQTL signal but not the islet NKX6-3 eQTL. Signals were enriched for islet enhancers, and we showed a plausible islet regulatory mechanism for the lead signal in the MADD locus. These results show how detailed genetic studies of an intermediate phenotype can elucidate mechanisms that may predispose one to disease.
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| 4. |
- Frazier-Wood, Alexis C., et al.
(författare)
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Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses
- 2016
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Ingår i: Nature Genetics. - : Nature Research (part of Springer Nature). - 1061-4036 .- 1546-1718. ; 48, s. 624-
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Tidskriftsartikel (refereegranskat)abstract
- Very few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data. We conducted genome-wide association studies of three phenotypes: subjective well-being (n = 298,420), depressive symptoms (n = 161,460), and neuroticism (n = 170,911). We identify 3 variants associated with subjective well-being, 2 variants associated with depressive symptoms, and 11 variants associated with neuroticism, including 2 inversion polymorphisms. The two loci associated with depressive symptoms replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (vertical bar(p) over cap vertical bar approximate to 0.8) strengthen the overall credibility of the findings and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal or pancreas tissues are strongly enriched for association.
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| 5. |
- Goodman, Anna, et al.
(författare)
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The relationship between umbilical cord length and chronic rheumatic heart disease : a prospective cohort study
- 2015
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Ingår i: European Journal of Preventive Cardiology. - : Oxford University Press (OUP). - 2047-4873 .- 2047-4881. ; 22:9, s. 1154-1160
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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. |
- Haapanen, Markus J., et al.
(författare)
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Early growth, stress, and socioeconomic factors as predictors of the rate of multimorbidity accumulation across the life course : a longitudinal birth cohort study
- 2024
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Ingår i: Lancet healthy longevity. - 2666-7568. ; 5:1, s. e56-e65
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Tidskriftsartikel (refereegranskat)abstract
- Background: Early growth, stress, and socioeconomic factors are associated with future risk of individual chronic diseases. It is uncertain whether they also affect the rate of multimorbidity accumulation later in life. This study aimed to explore whether early life factors are associated with the rate at which chronic diseases are accumulated across older age.Methods: In this national birth cohort study, we studied people born at Helsinki University Central Hospital, Helsinki, Finland between Jan 1, 1934, and Dec 31, 1944, who attended child welfare clinics in the city, and were living in Finland in 1971. Individuals who had died or emigrated from Finland before 1987 were excluded, alongside participants without any registry data and who died before the end of the registry follow-up on Dec 31, 2017. Early anthropometry, growth, wartime parental separation, and socioeconomic factors were recorded from birth, child welfare clinic, or school health-care records, and Finnish National Archives. International Classification of Diseases codes of diagnoses for chronic diseases were obtained from the Care Register for Health Care starting from 1987 (when participants were aged 42-53 years) until 2017. Linear mixed models were used to study the association between early-life factors and the rate of change in the number of chronic diseases over 10-year periods.Findings: From Jan 1, 1934, to Dec 31, 2017, 11 689 people (6064 [51 center dot 9%] men and 5625 [48 center dot 1%] women) were included in the study. Individuals born to mothers younger than 25 years (beta 0 center dot 09; 95% CI 0 center dot 06-0 center dot 12), mothers with a BMI of 25-30 kg/m2 (0 center dot 08; 0 center dot 05-0 center dot 10), and mothers with a BMI more than 30 kg/m2 (0 center dot 26; 0 center dot 21-0 center dot 31) in late pregnancy accumulated chronic diseases faster than those born to older mothers (25-30 years) and those with a BMI of less than 25 kg/m2. Individuals with a birthweight less than 2 center dot 5 kg (0 center dot 17; 0 center dot 10-0 center dot 25) and those with a rapid growth in height and weight from birth until age 11 years accumulated chronic diseases faster during their life course. Additionally, paternal occupational class (manual workers vs upper-middle class 0 center dot 27; 0 center dot 23-0 center dot 30) and wartime parental separation (0 center dot 24; 0 center dot 19-0 center dot 29 for boys; 0 center dot 31; 0 center dot 25-0 center dot 36 for girls) were associated with a faster rate of chronic disease accumulation. Interpretation Our findings suggest that the foundation for accumulating chronic diseases is established early in life. Early interventions might be needed for vulnerable populations, including war evacuee children and children with lower socioeconomic status.
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| 7. |
- 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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| 8. |
- Islam, Mohammad Redwanul, et al.
(författare)
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Accelerometer-Measured Physical Activity, Fitness and Indicators of Cardiometabolic Risk among Rural Adolescents: A Cross-Sectional Study at 15-Year Follow-up of the MINIMat Cohort
- 2024
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Ingår i: JOURNAL OF EPIDEMIOLOGY AND GLOBAL HEALTH. - : SPRINGERNATURE. - 2210-6006.
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Tidskriftsartikel (refereegranskat)abstract
- Background Little is known about the relationship of physical activity (PA) and fitness with cardiometabolic risk among rural adolescents in low- and middle-income countries. Thus, we examined the associations of PA and fitness with selected cardiometabolic indicators along with potential gender-based differences in a birth cohort of rural adolescents from southeast Bangladesh.Methods We utilized data from the 15-year follow-up of Maternal and Infant Nutrition Interventions in Matlab (MINIMat) cohort (n = 2253). Wrist-worn ActiGraph wGT3x-BT accelerometers were used to estimate sedentary time (ST) and PA. Fitness was assessed using: handgrip strength, standing long jump, and Chester Step Test. Anthropometric parameters, systolic blood pressure (SBP), and fasting lipid, insulin and glucose levels were measured. We calculated insulin resistance using the Homeostasis Model Assessment equation (HOMA-IR). Linear regression and isotemporal substitution models were fitted.Results The adolescents spent 64 min/day (inter-quartile range: 50-81) in moderate-to-vigorous physical activity (MVPA). A 10-minute-per-day higher vigorous PA (VPA) was associated with: 4.9% (95% confidence interval (CI): 2.9-6.8%) lower waist circumference (WC), 3.2 mmHg (95% CI: 1.5-4.8) lower SBP, 10.4% (95% CI: 2.9-17.3%) lower TG, and 24.4% (95% CI: 11.3-34.9%) lower HOMA-IR. MVPA showed similar associations of notably smaller magnitude. Except for WC, the associations were more pronounced among the boys. Substituting ST with VPA of equal duration was associated with lower WC, SBP, triglyceride and HOMA-IR. Grip strength was favorably associated with all indicators, displaying considerably large effect sizes.Conclusion Our findings indicated beneficial roles of PA- particularly VPA- and muscular fitness in shaping cardiometabolic profile in mid-adolescence. VPA and grip strength may represent potential targets for preventive strategies tailored to adolescents in resource-limited settings.
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| 9. |
- Islam, Mohammad Redwanul, 1986-, et al.
(författare)
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Dietary patterns and indicators of cardiometabolic risk among rural adolescents : A cross-sectional study at 15-year follow-up of the MINIMat cohort
- 2023
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Ingår i: Frontiers in Nutrition. - : Frontiers Media S.A.. - 2296-861X. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Background: Diet being a modifiable factor, its relationship with cardiometabolicrisk is of public health interest. The vast majority of studies on associations ofdietary patterns with cardiometabolic risk indicators among adolescents are fromhigh-income countries and urban settings. We sought to describe dietary patternsand examine their associations with selected cardiometabolic risk indicators–waist circumference (WC), systolic blood pressure, fasting lipid profile and insulinresistance–along with its gender stratification among adolescents in a low-income,rural setting.Methods: This cross-sectional study utilized data from the 15-year follow-up ofthe Maternal and Infant Nutrition Interventions in Matlab (MINIMat) cohort insoutheast Bangladesh. The children who were born as singletons to the mothersrandomized in the MINIMat trial and had valid birth anthropometrics were eligiblefor the follow-up. We employed a single, qualitative 24-hour recall to assess diet.Dietary patterns were derived from simple K-means cluster analysis, and calculationof dietary diversity score (DDS) using a validated instrument. Anthropometricparameters and systolic blood pressure were recorded. Fasting plasma triglyceride,total cholesterol, low- and high-density lipoproteins, insulin and glucose levels weremeasured. We calculated insulin resistance using the Homeostasis Model Assessmentequation (HOMA-IR). Three right-skewed outcome variables were natural log (Ln)transformed: WC, triglyceride and HOMA-IR. Omnibus and gender-specific multiplelinear regression models were fitted.Results: Among 2,253 adolescents (52.1% girls, 7.1% overweight/obese), we identifiedfour diet clusters: Traditional, Fish-dominant, Meat-dominant, and High-variety.No significant associations were found between the clusters and indicators. Ongender-stratification, triglyceride levels were lower among boys in the Fish-dominant (Ln-triglyceride βadjusted: −0.09; 95% confidence interval (CI): −0.15, −0.02) andMeat-dominant (Ln-triglyceride βadjusted: −0.08; 95% CI: −0.15, −0.004) clusters thanamong boys in the Traditional cluster. Compared to boys in the bottom quartile of DDS, boys in the top quartile had 2.1 mm of Hg (95% CI: 0.5, 3.6) higher systolic bloodpressure and 1.9% (95% CI: 0.01–3.8%) higher WC.Conclusion: While statistically significant, the gender-specific differences intriglyceride, systolic blood pressure, and waist circumference across dietarypatterns were small. Associations between dietary patterns and cardiometabolic riskindicators may require a time lag beyond mid-adolescence to manifest in a ruralsetting. Prospective studies are warranted to delineate the magnitude and directionof those associations.
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| 10. |
- Johnson, Linda, et al.
(författare)
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Early Life Risk Factors for Incident Atrial Fibrillation in the Helsinki Birth Cohort Study
- 2017
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Ingår i: Journal of the American Heart Association. - 2047-9980. ; 6:6
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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.
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| 11. |
- Kalapotharakos, Grigorios, et al.
(författare)
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Plasma Heme Scavengers Alpha-1-Microglobulin and Hemopexin as Biomarkers in High-Risk Pregnancies
- 2019
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Ingår i: Frontiers in Physiology. - : Frontiers Media SA. - 1664-042X. ; 10
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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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| 12. |
- Kilpeläinen, Tuomas O, et al.
(författare)
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Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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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<10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 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.
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| 13. |
- 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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| 14. |
- Lind, Lars, et al.
(författare)
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Genome Wide Association Identifies Common Variants at the SERPINA6/SERPINA1 Locus Influencing Plasma Cortisol and Corticosteroid Binding Globulin.
- 2014
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Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 10:7
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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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| 15. |
- Lu, Yingchang, et al.
(författare)
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New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P<5 × 10(-8)), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk.
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| 16. |
- Murtoniemi, Katja, et al.
(författare)
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Longitudinal changes in plasma hemopexin and alpha-1-microglobulin concentrations in women with and without clinical risk factors for pre-eclampsia
- 2019
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 14:12
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Tidskriftsartikel (refereegranskat)abstract
- Recent studies have shown increased concentration of fetal hemoglobin (HbF) in pre-eclamptic women. Plasma hemopexin (Hpx) and alpha-1-microglobulin (A1M) are hemoglobin scavenger proteins that protect against toxic effects of free heme released in the hemoglobin degradation process. We used an enzyme-linked immunosorbent assay to analyze maternal plasma Hpx and A1M concentrations at 12–14, 18–20 and 26–28 weeks of gestation in three groups: 1) 51 women with a low risk for pre-eclampsia (LRW), 2) 49 women with a high risk for pre-eclampsia (PE) who did not develop PE (HRW) and 3) 42 women with a high risk for PE who developed PE (HRPE). The study had three aims: 1) to investigate whether longitudinal differences exist between study groups, 2) to examine if Hpx and A1M concentrations develop differently in pre-eclamptic women with small for gestational age (SGA) fetuses vs. pre-eclamptic women with appropriate for gestational age fetuses, and 3) to examine if longitudinal Hpx and A1M profiles differ by PE subtype (early-onset vs. late-onset and severe vs. non-severe PE). Repeated measures analysis of variance was used to analyze differences in Hpx and A1M concentrations between the groups. We found that the differences in longitudinal plasma Hpx and A1M concentrations in HRW compared to HRPE and to LRW may be associated with reduced risk of PE regardless of clinical risk factors. In women who developed PE, a high A1M concentration from midgestation to late second trimester was associated with SGA. There were no differences in longitudinal Hpx and A1M concentrations from first to late second trimester in high-risk women who developed early-onset or. late-onset PE or in women who developed severe or. non-severe PE.
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| 17. |
- Pervjakova, Natalia, et al.
(författare)
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Multi-ancestry genome-wide association study of gestational diabetes mellitus highlights genetic links with type 2 diabetes
- 2022
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 31:19, s. 3377-3391
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Tidskriftsartikel (refereegranskat)abstract
- Gestational diabetes mellitus (GDM) is associated with increased risk of pregnancy complications and adverse perinatal outcomes. GDM often reoccurs and is associated with increased risk of subsequent diagnosis of type 2 diabetes (T2D). To improve our understanding of the aetiological factors and molecular processes driving the occurrence of GDM, including the extent to which these overlap with T2D pathophysiology, the GENetics of Diabetes In Pregnancy (GenDIP) Consortium assembled genome-wide association studies (GWAS) of diverse ancestry in a total of 5485 women with GDM and 347 856 without GDM. Through multi-ancestry meta-analysis, we identified five loci with genome-wide significant association (p < 5x10-8) with GDM, mapping to/near MTNR1B (p = 4.3x10-54), TCF7L2 (p = 4.0x10-16), CDKAL1 (p = 1.6 × 10-14), CDKN2A-CDKN2B (p = 4.1x10-9) and HKDC1 (p = 2.9x10-8). Multiple lines of evidence pointed to the shared pathophysiology of GDM and T2D: (i) four of the five GDM loci (not HKDC1) have been previously reported at genome-wide significance for T2D; (ii) significant enrichment for associations with GDM at previously reported T2D loci; (iii) strong genetic correlation between GDM and T2D; and (iv) enrichment of GDM associations mapping to genomic annotations in diabetes-relevant tissues and transcription factor binding sites. Mendelian randomisation analyses demonstrated significant causal association (5% false discovery rate) of higher body mass index on increased GDM risk. Our results provide support for the hypothesis that GDM and T2D are part of the same underlying pathology but that, as exemplified by the HKDC1 locus, there are genetic determinants of GDM that are specific to glucose regulation in pregnancy.
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| 18. |
- Ronkainen, Justiina, et al.
(författare)
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LongITools: Dynamic longitudinal exposome trajectories in cardiovascular and metabolic noncommunicable diseases
- 2022
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Ingår i: Environmental Epidemiology. - 2474-7882. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- The current epidemics of cardiovascular and metabolic noncommunicable diseases have emerged alongside dramatic modifications in lifestyle and living environments. These correspond to changes in our "modern" postwar societies globally characterized by rural-to-urban migration, modernization of agricultural practices, and transportation, climate change, and aging. Evidence suggests that these changes are related to each other, although the social and biological mechanisms as well as their interactions have yet to be uncovered. LongITools, as one of the 9 projects included in the European Human Exposome Network, will tackle this environmental health equation linking multidimensional environmental exposures to the occurrence of cardiovascular and metabolic noncommunicable diseases.
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| 19. |
- Räikkönen, Katri, et al.
(författare)
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Insulin, Glucose, and the Metabolic Syndrome in Cardiovascular Behavioral Medicine
- 2022
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Ingår i: Handbook of Cardiovascular Behavioral Medicine. - New York, NY : Springer New York. - 9780387859606 - 9780387859590 ; , s. 809-831
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- It has been known for decades that risk factors for diabetes and cardiovascular disease (CVD) tend to cluster. Metabolic syndrome refers to this risk factor clustering for some of the more well-established and dangerous risk factors. This chapter provides a historical overview on the concept of the metabolic syndrome; describes the clinical criteria used in the definition of the metabolic syndrome and how to measure components of the metabolic syndrome, emphasizing measurements related to insulin and glucose; provides a brief overview of the genetic, endocrine, and early life determinants of the metabolic syndrome; and presents findings from studies that have focused on psychological correlates, determinants, and consequences of the metabolic syndrome, focusing in particular on psychosocial stress and depression.
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| 20. |
- 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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| 21. |
- Surendran, Praveen, et al.
(författare)
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Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals
- 2020
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 52:12, s. 1314-1332
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Tidskriftsartikel (refereegranskat)abstract
- Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to similar to 1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency <= 0.01) variant BP associations (P < 5 x 10(-8)), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were similar to 8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
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| 22. |
- Surendran, Praveen, et al.
(författare)
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Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension
- 2016
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 48:10, s. 1151-1161
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Tidskriftsartikel (refereegranskat)abstract
- High blood pressure is a major risk factor for cardiovascular disease and premature death. However, there is limited knowledge on specific causal genes and pathways. To better understand the genetics of blood pressure, we genotyped 242,296 rare, low-frequency and common genetic variants in up to 192,763 individuals and used -1/4155,063 samples for independent replication. We identified 30 new blood pressure- or hypertension-associated genetic regions in the general population, including 3 rare missense variants in RBM47, COL21A1 and RRAS with larger effects (>1.5 mm Hg/allele) than common variants. Multiple rare nonsense and missense variant associations were found in A2ML1, and a low-frequency nonsense variant in ENPEP was identified. Our data extend the spectrum of allelic variation underlying blood pressure traits and hypertension, provide new insights into the pathophysiology of hypertension and indicate new targets for clinical intervention.
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| 23. |
- Wedenoja, Satu, et al.
(författare)
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Fetal HLA-G mediated immune tolerance and interferon response in preeclampsia
- 2020
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Ingår i: EBioMedicine. - : Elsevier BV. - 2352-3964. ; 59
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Tidskriftsartikel (refereegranskat)abstract
- Background: Fetal immune tolerance is crucial for pregnancy success. We studied the link between preeclampsia, a severe pregnancy disorder with uncertain pathogenesis, and fetal human leukocyte antigen G (HLA-G) and other genes regulating maternal immune responses.Methods: We assessed sex ratios and regulatory HLA-G haplotypes in population cohorts and series of preeclampsia and stillbirth. We studied placental mRNA expression of 136 genes by sequencing and HLA-G and interferon alpha (IFNα) protein expression by immunohistochemistry.Findings: We found underrepresentation of males in preeclamptic births, especially those delivered preterm or small for gestational age. Balancing selection at HLA-G associated with the sex ratio, stillbirth, and preeclampsia. We observed downregulation of HLA-G, its receptors, and many other tolerogenic genes, and marked upregulation of IFNA1 in preeclamptic placentas.Interpretation: These findings indicate that an evolutionary trade-off between immune tolerance and protection against infections at the maternal-fetal interface promotes genetic diversity in fetal HLA-G, thereby affecting survival, preeclampsia, and sex ratio. We highlight IFNA1 as a potential mediator of preeclampsia and a target for therapeutic trials.
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| 24. |
- Yin, Weiyao, et al.
(författare)
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Association between parental psychiatric disorders and risk of offspring autism spectrum disorder: a Swedish and Finnish population-based cohort study
- 2024
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Ingår i: The Lancet Regional Health. - : ELSEVIER. - 2666-7762. ; 40
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Tidskriftsartikel (refereegranskat)abstract
- Background Roughly more than one in six adults worldwide suffer from psychiatric conditions. Sporadic studies have associated parental psychiatric disorders with autism spectrum disorder in offspring. Comprehensively examining the association between parental psychiatric disorders and offspring autism spectrum disorder is needed to guide health policies, and to inform etiologic studies. Methods We included all children born in Sweden and Finland 1997 - 2016. Diagnoses were clinically ascertained from National Registers through 2017. We calculated adjusted hazard ratios (aHRs) and 95% con fi dence intervals (CIs) for autism spectrum disorder in offspring of fathers and mothers with psychiatric disorders, in both parents jointly and across co-occurring conditions. Findings Among 2,505,842 children, 33,612 were diagnosed with autism spectrum disorder, of which 20% had a parent with psychiatric disorders. The risk of autism spectrum disorder was increased across all psychiatric disorders in fathers (Sweden: aHR = 2.02, 95% CI = 1.92 - 2.12; Finland: aHR = 1.63, 95% CI = 1.50 - 1.77), mothers (Sweden: aHR = 2.34, 95% CI = 2.24 - 2.43; Finland aHR = 2.12, 95% CI = 1.92 - 2.28), or both parents (Sweden: aHR = 3.76, 95% CI = 3.48 - 4.07; Finland aHR = 3.61, 95% CI = 3.20 - 4.07), compared to neither parents. Co -occurrence of parental psychiatric disorders further increased risk (e.g., Sweden: for one, two or >= three different diagnostic categories compared to no diagnosis, in fathers aHR = 1.81, 2.07, 2.52; in mothers aHR = 2.05, 2.63, 3.57). Interpretation Psychiatric disorders in both parents conveyed the highest risk of offspring autism spectrum disorder, followed by mothers and then fathers. The risk increased with number of co-occurring disorders. All parental psychiatric disorders were associated with increased the risk of autism spectrum disorder. To reliably assess the risk of autism spectrum disorder in children, a comprehensive history incorporating the full range of parental psychiatric disorders is needed beyond solely focusing on familial autism spectrum disorder.
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| 25. |
- Yin, Weiyao, et al.
(författare)
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Paternal and maternal psychiatric history and risk of preterm and early term birth: A nationwide study using Swedish registers
- 2023
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Ingår i: PLoS Medicine. - : PUBLIC LIBRARY SCIENCE. - 1549-1277 .- 1549-1676. ; 20:7
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundWomen with psychiatric diagnoses are at increased risk of preterm birth (PTB), with potential life-long impact on offspring health. Less is known about the risk of PTB in offspring of fathers with psychiatric diagnoses, and for couples where both parents were diagnosed. In a nationwide birth cohort, we examined the association between psychiatric history in fathers, mothers, and both parents and gestational age. Methods and findingsWe included all infants live-born to Nordic parents in 1997 to 2016 in Sweden. Psychiatric diagnoses were obtained from the National Patient Register. Data on gestational age were retrieved from the Medical Birth Register. Associations between parental psychiatric history and PTB were quantified by relative risk (RR) and two-sided 95% confidence intervals (CIs) from log-binomial regressions, by psychiatric disorders overall and by diagnostic categories. We extended the analysis beyond PTB by calculating risks over the whole distribution of gestational age, including "early term" (37 to 38 weeks).Among the 1,488,920 infants born throughout the study period, 1,268,507 were born to parents without a psychiatric diagnosis, of whom 73,094 (5.8%) were born preterm. 4,597 of 73,500 (6.3%) infants were born preterm to fathers with a psychiatric diagnosis, 8,917 of 122,611 (7.3%) infants were born preterm to mothers with a pscyhiatric diagnosis, and 2,026 of 24,302 (8.3%) infants were born preterm to both parents with a pscyhiatric diagnosis. We observed a shift towards earlier gestational age in offspring of parents with psychiatric history. The risks of PTB associated with paternal and maternal psychiatric diagnoses were similar for different psychiatric disorders. The risks for PTB were estimated at RR 1.12 (95% CI [1.08, 1.15] p < 0.001) for paternal diagnoses, at RR 1.31 (95% CI [1.28, 1.34] p < 0.001) for maternal diagnoses, and at RR 1.52 (95% CI [1.46, 1.59] p < 0.001) when both parents were diagnosed with any psychiatric disorder, compared to when neither parent had a psychiatric diagnosis. Stress-related disorders were associated with the highest risks of PTB with corresponding RRs estimated at 1.23 (95% CI [1.16, 1.31] p < 0.001) for a psychiatry history in fathers, at 1.47 (95% CI [1.42, 1.53] p < 0.001) for mothers, and at 1.90 (95% CI [1.64, 2.20] p < 0.001) for both parents. The risks for early term were similar to PTB. Co-occurring diagnoses from different diagnostic categories increased risk; for fathers: RR 1.10 (95% CI [1.07, 1.13] p < 0.001), 1.15 (95% CI [1.09, 1.21] p < 0.001), and 1.33 (95% CI [1.23, 1.43] p < 0.001), for diagnoses in 1, 2, and & GE;3 categories; for mothers: RR 1.25 (95% CI [1.22, 1.28] p < 0.001), 1.39 (95% CI [1.34, 1.44] p < 0.001) and 1.65 (95% CI [1.56, 1.74] p < 0.001). Despite the large sample size, statistical precision was limited in subgroups, mainly where both parents had specific psychiatric subtypes. Pathophysiology and genetics underlying different psychiatric diagnoses can be heterogeneous. ConclusionsPaternal and maternal psychiatric history were associated with a shift to earlier gestational age and increased risk of births before full term. The risk consistently increased when fathers had a positive history of different psychiatric disorders, increased further when mothers were diagnosed and was highest when both parents were diagnosed. Author summary Why was this study done? Women with psychiatric diagnoses are at increased risk of preterm birth (PTB). It is already known that PTB is associated with negative health consequences for the offspring.Less is known about the risk of PTB in offspring of fathers with psychiatric diagnoses and for couples where both parents had psychiatric diagnoses.Earlier studies have not thoroughly examined the full range of psychiatric disorders and gestational age. What did the researchers do and find? In a cohort of 1.5 million births, we observed a shift towards earlier gestational age in offspring of parents with a history with psychiatric disorders, particularly for preterm and early term births.The risk of PTB consistently increased when fathers were diagnosed with different psychiatric disorders (relative risk (RR) = 1.12, 95% confidence interval (CI) [1.08, 1.15]), increased further when mothers were diagnosed (RR = 1.31, 95% CI [1.28, 1.34]), and was highest when both parents were diagnosed (RR = 1.52, 95% CI [1.46, 1.59]).For both the father and the mother, the risk increased in parents diagnosed with several different psychiatric disorders.The increased risk was present not only for children born preterm, but also for the larger group of offspring born at early term (37 to 38 weeks), who represent approximately 20% of all births. What do these findings mean? These data suggest that the presence of psychiatric diagnoses in either one or both parents impacts gestational age at birth.Whether additional social and psychiatric support and prenatal care to families with a positive psychiatric history could mitigate against this warrants further investigation.
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