| 1. |
- Kanoni, Stavroula, et al.
(författare)
-
Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.
- 2022
-
Ingår i: Genome biology. - : Springer Science and Business Media LLC. - 1474-760X .- 1465-6906 .- 1474-7596. ; 23:1
-
Tidskriftsartikel (refereegranskat)abstract
- Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N=1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism.Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
|
|
| 2. |
- Locke, Adam E, et al.
(författare)
-
Genetic studies of body mass index yield new insights for obesity biology.
- 2015
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 197-401
-
Tidskriftsartikel (refereegranskat)abstract
- Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
|
|
| 3. |
- Shungin, Dmitry, et al.
(författare)
-
New genetic loci link adipose and insulin biology to body fat distribution.
- 2015
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 187-378
-
Tidskriftsartikel (refereegranskat)abstract
- Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
|
|
| 4. |
- Do, Ron, et al.
(författare)
-
Common variants associated with plasma triglycerides and risk for coronary artery disease
- 2013
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:11, s. 1345-
-
Tidskriftsartikel (refereegranskat)abstract
- Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 x 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.
|
|
| 5. |
- Willer, Cristen J., et al.
(författare)
-
Discovery and refinement of loci associated with lipid levels
- 2013
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:11, s. 1274-1283
-
Tidskriftsartikel (refereegranskat)abstract
- Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 x 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.
|
|
| 6. |
- Gielen, Marij, et al.
(författare)
-
Body mass index is negatively associated with telomere length : A collaborative cross-sectional meta-analysis of 87 observational studies
- 2018
-
Ingår i: American Journal of Clinical Nutrition. - : Elsevier BV. - 0002-9165. ; 108:3, s. 453-475
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Even before the onset of age-related diseases, obesity might be a contributing factor to the cumulative burden of oxidative stress and chronic inflammation throughout the life course. Obesity may therefore contribute to accelerated shortening of telomeres. Consequently, obese persons are more likely to have shorter telomeres, but the association between body mass index (BMI) and leukocyte telomere length (TL) might differ across the life span and between ethnicities and sexes. Objective: A collaborative cross-sectionalmeta-analysis of observational studies was conducted to investigate the associations between BMI and TL across the life span. Design: Eighty-seven distinct study samples were included in the meta-analysis capturing data from 146,114 individuals. Studyspecific age- and sex-adjusted regression coefficients were combined by using a random-effects model in which absolute [base pairs (bp)] and relative telomere to single-copy gene ratio (T/S ratio) TLs were regressed against BMI. Stratified analysis was performed by 3 age categories ("young": 18-60 y; "middle": 61-75 y; and "old": >75 y), sex, and ethnicity. Results: Each unit increase in BMI corresponded to a-3.99 bp (95% CI: -5.17, -2.81 bp) difference in TL in the total pooled sample; among young adults, each unit increase in BMI corresponded to a -7.67 bp (95% CI:-10.03,-5.31 bp) difference. Each unit increase in BMI corresponded to a -1.58 × 10-3 unit T/S ratio (0.16% decrease; 95% CI: -2.14 × 10-3, -1.01 × 10-3) difference in ageand sex-adjusted relative TL in the total pooled sample; among young adults, each unit increase in BMI corresponded to a -2.58 × 10-3 unit T/S ratio (0.26% decrease; 95% CI: -3.92 × 10-3, -1.25 × 10-3). The associations were predominantly for the white pooled population. No sex differences were observed. Conclusions: A higher BMI is associated with shorter telomeres, especially in younger individuals. The presently observed difference is not negligible. Meta-analyses of longitudinal studies evaluating change in body weight alongside change in TL arewarranted.
|
|
| 7. |
|
|
| 8. |
- Hunt, Linda A
(författare)
-
Dementia and road performance
- 1991
-
Ingår i: Proceedings of Strategic Highway Research Program and Traffic Safety on Two Continents. Conference in Gothenburg, Sweden, September 18-20, 1991. - Linköping : Statens väg- och transportforskningsinstitut. ; , s. 135-147
-
Konferensbidrag (övrigt vetenskapligt/konstnärligt)
|
|
| 9. |
- Mlynczak, Martin G., et al.
(författare)
-
Atomic oxygen in the mesosphere and lower thermosphere derived from SABER : Algorithm theoretical basis and measurement uncertainty
- 2013
-
Ingår i: Journal of Geophysical Research - Atmospheres. - : American Geophysical Union (AGU). - 2169-897X .- 2169-8996. ; 118:11, s. 5724-5735
-
Tidskriftsartikel (refereegranskat)abstract
- Atomic oxygen (O) is a fundamental component in chemical aeronomy of Earth's mesosphere and lower thermosphere region extending from approximately 50 km to over 100 km in altitude. Atomic oxygen is notoriously difficult to measure, especially with remote sensing techniques from orbiting satellite sensors. It is typically inferred from measurements of the ozone concentration in the day or from measurements of the Meinel band emission of the hydroxyl radical (OH) at night. The Sounding of the Atmosphere using Broadband Emission Radiometry (SABER) instrument on the NASA Thermosphere-Ionosphere-Mesosphere Energetics and Dynamics (TIMED) satellite measures OH emission and ozone for the purpose of determining the O-atom concentration. In this paper, we present the algorithms used in the derivation of day and night atomic oxygen from these measurements. We find excellent consistency between the day and night O-atom concentrations from daily to annual time scales. We also examine in detail the collisional relaxation of the highly vibrationally excited OH molecule at night measured by SABER. Large rate coefficients for collisional removal of vibrationally excited OH molecules by atomic oxygen are consistent with the SABER observations if the deactivation of OH(9) proceeds solely by collisional quenching. An uncertainty analysis of the derived atomic oxygen is also given. Uncertainty in the rate coefficient for recombination of O and molecular oxygen is shown to be the largest source of uncertainty in the derivation of atomic oxygen day or night.
|
|
| 10. |
- Mlynczak, Martin G., et al.
(författare)
-
Observations of infrared radiative cooling in the thermosphere on daily to multiyear timescales from the TIMED/SABER instrument
- 2010
-
Ingår i: Journal of Geophysical Research - Space Physics. - 2169-9380 .- 2169-9402. ; 115:A3
-
Tidskriftsartikel (refereegranskat)abstract
- We present observations of the infrared radiative cooling by carbon dioxide (CO2) and nitric oxide (NO) in Earth's thermosphere. These data have been taken over a period of 7 years by the Sounding of the Atmosphere using Broadband Emission Radiometry (SABER) instrument on the NASA Thermosphere-Ionosphere-Mesosphere Energetics and Dynamics (TIMED) satellite and are the dominant radiative cooling mechanisms for the thermosphere. From the SABER observations we derive vertical profiles of radiative cooling rates (W m−3), radiative fluxes (W m−2), and radiated power (W). In the period from January 2002 through January 2009, we observe a large decrease in the cooling rates, fluxes, and power consistent with the declining phase of solar cycle 23. The power radiated by NO during 2008 when the Sun exhibited few sunspots was nearly one order of magnitude smaller than the peak power observed shortly after the mission began. Substantial short-term variability in the infrared emissions is also observed throughout the entire mission duration. Radiative cooling rates and radiative fluxes from NO exhibit fundamentally different latitude dependence than do those from CO2, with the NO fluxes and cooling rates being largest at high latitudes and polar regions. The cooling rates are shown to be derived relatively independent of the collisional and radiative processes that drive the departure from local thermodynamic equilibrium (LTE) in the CO2 15 μm and the NO 5.3 μm vibration-rotation bands. The observed NO and CO2 cooling rates have been compiled into a separate data set and represent a climate data record that is available for use in assessments of radiative cooling in upper atmosphere general circulation models.
|
|
