| 1. |
- Beecham, Ashley H, et al.
(författare)
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Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis.
- 2013
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 45:11, s. 1353-60
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Tidskriftsartikel (refereegranskat)abstract
- Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.
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| 2. |
- Locke, Adam E, et al.
(författare)
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Genetic studies of body mass index yield new insights for obesity biology.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 197-401
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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.
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| 3. |
- Anderson, Leif G., et al.
(författare)
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The effect of the Siberian tundra on the environment of the shelf seas and the Arctic Ocean
- 1999
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Ingår i: Ambio. - 0044-7447. ; 28:3, s. 270-280
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Tidskriftsartikel (refereegranskat)abstract
- The Tundra Ecology -94 expedition investigated inflow of inorganic and organic carbon to the shelf seas by river runoff, and its transformation by biochemical processes in seawater and sediment. In addition, anthropogenic radionuclides, 137Cs, 90Sr, and 239,240Pu, were studied in water and sediments. The distribution of dissolved inorganic carbon indicates that the majority of the Ob and Yenisey discharges flow into the Laptev Sea before entering the central Arctic Ocean. The sediment study shows that there is a marked difference in benthic oxygen uptake, efflux of dissolved inorganic carbon and nutrients between localities. 137Cs activity from the Chernobyl accident is 30% in the Barents, Kara, and Laptev Seas. 137Cs increased from 5-8 Bq m-3 in Barents Sea, 5-13 Bq m-3 in the Kara Sea to 8-15 Bq m-3 in the Laptev Sea, but with locally low concentrations at the river mouths. Corresponding values for 90Sr were 2.5, 3, and 4 Bq m-3, respectively.
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| 4. |
- Berndt, Sonja I., et al.
(författare)
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Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:5, s. 501-U69
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Tidskriftsartikel (refereegranskat)abstract
- Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
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| 5. |
- Bonaglia, Stefano, et al.
(författare)
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The fate of fixed nitrogen in marine sediments with low organic loading : an in situ study
- 2017
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Ingår i: Biogeosciences. - : Copernicus GmbH. - 1726-4170 .- 1726-4189. ; 14:2, s. 285-300
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Tidskriftsartikel (refereegranskat)abstract
- Over the last decades, the impact of human activities on the global nitrogen (N) cycle has drastically increased. Consequently, benthic N cycling has mainly been studied in anthropogenically impacted estuaries and coasts, while in oligotrophic systems its understanding is still scarce. Here we report on benthic solute fluxes and on rates of denitrification, anammox, and dissimilatory nitrate reduction to ammonium (DNRA) studied by in situ incubations with benthic chamber landers during two cruises to the Gulf of Bothnia (GOB), a cold, oligotrophic basin located in the northern part of the Baltic Sea. Rates of N burial were also inferred to investigate the fate of fixed N in these sediments. Most of the total dissolved fixed nitrogen (TDN) diffusing to the water column was composed of organic N. Average rates of dinitrogen (N-2) production by denitrification and anammox (range: 53-360 mu mol Nm(-2) day(-1)) were comparable to those from Arctic and subarctic sediments worldwide (range: 34-344 mu mol Nm(-2) day(-1)). Anammox accounted for 18-26% of the total N2 production. Absence of free hydrogen sulfide and low concentrations of dissolved iron in sediment pore water suggested that denitrification and DNRA were driven by organic matter oxidation rather than chemolithotrophy. DNRA was as important as denitrification at a shallow, coastal station situated in the northern Bothnian Bay. At this pristine and fully oxygenated site, ammonium regeneration through DNRA contributed more than one-third to the TDN efflux and accounted, on average, for 45% of total nitrate reduction. At the offshore stations, the proportion of DNRA in relation to denitrification was lower (0-16% of total nitrate reduction). Median value and range of benthic DNRA rates from the GOB were comparable to those from the southern and central eutrophic Baltic Sea and other temperate estuaries and coasts in Europe. Therefore, our results contrast with the view that DNRA is negligible in cold and well-oxygenated sediments with low organic carbon loading. However, the mechanisms behind the variability in DNRA rates between our sites were not resolved. The GOB sediments were a major source (237 kt yr(-1), which corresponds to 184% of the external N load) of fixed N to the water column through recycling mechanisms. To our knowledge, our study is the first to document the simultaneous contribution of denitrification, DNRA, anammox, and TDN recycling combined with in situ measurements.
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| 6. |
- 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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| 7. |
- Mälarstig, Anders, et al.
(författare)
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Evaluation of circulating plasma proteins in breast cancer using Mendelian randomisation
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Biomarkers for early detection of breast cancer may complement population screening approaches to enable earlier and more precise treatment. The blood proteome is an important source for biomarker discovery but so far, few proteins have been identified with breast cancer risk. Here, we measure 2929 unique proteins in plasma from 598 women selected from the Karolinska Mammography Project to explore the association between protein levels, clinical characteristics, and gene variants, and to identify proteins with a causal role in breast cancer. We present 812 cis-acting protein quantitative trait loci for 737 proteins which are used as instruments in Mendelian randomisation analyses of breast cancer risk. Of those, we present five proteins (CD160, DNPH1, LAYN, LRRC37A2 and TLR1) that show a potential causal role in breast cancer risk with confirmatory results in independent cohorts. Our study suggests that these proteins should be further explored as biomarkers and potential drug targets in breast cancer.
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| 8. |
- Nilsson, Madeleine, et al.
(författare)
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Particle shuttling and oxidation capacity of sedimentary organic carbon on the Baltic Sea system scale
- 2021
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Ingår i: Marine Chemistry. - : Elsevier BV. - 0304-4203. ; 232
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Tidskriftsartikel (refereegranskat)abstract
- Continental margin sediments receive most of the particulate organic carbon (POC) deposited on the global seafloor, making them crucial locations in the carbon cycle. However, the complex environments in coastal oceans make it challenging to predict the fate of sedimentary organic carbon (OC) in these areas. Here we use data from 21 sites in the Baltic Sea, representing different biological and physiochemical regimes, to explore controls on sedimentary OC cycling. To this end, we combine in situ measured benthic fluxes of dissolved inorganic carbon (DIC; proxy for OC oxidation) with data on sediment properties. In the Gulf of Bothnia, low sedimentary OC oxidation capacities (yearly DIC flux divided by sedimentary POC inventory) were likely caused by a large fraction of terrestrial material in the POC pool, indicated by low sedimentary chlorophyll a content and high (> 10) carbon:nitrogen ratios. The highest OC oxidation capacities were measured at shallow, permanently oxic sites in the Baltic Proper, where bioturbation likely stimulates OC oxidation. The other sites in the Baltic Proper and all stations in the Gulf of Finland displayed increasing OC oxidation capacities with increasing normalised water depth (station depth divided by maximal depth in the basin). This pattern suggests that substantial quantities of POC are shuttled, through repeated cycles of resuspension-redeposition, from shallow erosion-transport (ET) areas to deep accumulation (A) areas. This interpretation was supported by decreasing sediment age and increasing sedimentary inventories of POC and chlorophyll a with normalised water depth. Our calculations indicate that particle shuttling redistributes almost half of the deposited export production from ET areas to A areas in the Baltic Proper, and that substantial amounts of terrestrial organic material are transported through particle shuttling to the deeper parts of the Gulf of Finland and Gulf of Bothnia. Depositional setting and POC origin can thus be central factors in predicting the distribution and fate of OC in coastal and shelf sediments.
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| 9. |
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| 10. |
- Sawcer, Stephen, et al.
(författare)
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Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis
- 2011
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 476:7359, s. 214-219
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Tidskriftsartikel (refereegranskat)abstract
- Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
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