| 1. |
- Kiiskinen, Tuomo, et al.
(author)
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Genetic predictors of lifelong medication-use patterns in cardiometabolic diseases
- 2023
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In: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 29:1, s. 209-218
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Journal article (peer-reviewed)abstract
- Little is known about the genetic determinants of medication use in preventing cardiometabolic diseases. Using the Finnish nationwide drug purchase registry with follow-up since 1995, we performed genome-wide association analyses of longitudinal patterns of medication use in hyperlipidemia, hypertension and type 2 diabetes in up to 193,933 individuals (55% women) in the FinnGen study. In meta-analyses of up to 567,671 individuals combining FinnGen with the Estonian Biobank and the UK Biobank, we discovered 333 independent loci (P < 5 × 10–9) associated with medication use. Fine-mapping revealed 494 95% credible sets associated with the total number of medication purchases, changes in medication combinations or treatment discontinuation, including 46 credible sets in 40 loci not associated with the underlying treatment targets. The polygenic risk scores (PRS) for cardiometabolic risk factors were strongly associated with the medication-use behavior. A medication-use enhanced multitrait PRS for coronary artery disease matched the performance of a risk factor-based multitrait coronary artery disease PRS in an independent sample (UK Biobank, n = 343,676). In summary, we demonstrate medication-based strategies for identifying cardiometabolic risk loci and provide genome-wide tools for preventing cardiovascular diseases.
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| 2. |
- Bergvall, Ulrika A, et al.
(author)
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Associational effects of plant defences in relation to within- and between-patch food choice by a mammalian herbivore : neighbour contrast susceptibility and defence
- 2006
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In: Oecologia. - : Springer Science and Business Media LLC. - 0029-8549 .- 1432-1939. ; 147:2, s. 253-60
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Journal article (peer-reviewed)abstract
- A basic idea of plant defences is that a plant should gain protection from its own defence. In addition, there is evidence that defence traits of the neighbouring plants can influence the degree of protection of an individual plant. These associational effects depend in part on the spatial scale of herbivore selectivity. A strong between-patch selectivity together with a weak within-patch selectivity leads to a situation where a palatable plant could avoid being grazed by growing in a patch with unpalatable plants, which is referred to as associational defence. Quite different associational effects will come about if the herbivore instead is unselective between patches and selective within a patch. We studied these effects in a manipulative experiment where we followed the food choice of fallow deer when they encountered two patches of overall different quality. One of the two patches consisted of pellets with low-tannin concentration in seven out of eight buckets and with high concentration in the remaining bucket. The other patch instead had seven high- and one low-tannin bucket. We performed the experiment both with individuals one at a time and with a group of 16-17 deer. We found that the deer were unselective between patches, but selective within a patch, and that the single low-tannin bucket among seven high-tannin buckets was used more than a low-tannin bucket among other low-tannin buckets. This corresponds to a situation where a palatable plant that grows among unpalatable plants is attacked more than if it was growing among its own kind, and for this effect we suggest the term neighbour contrast susceptibility, which is the opposite of associational defence. We also found that the high-tannin bucket in the less defended patch was less used than the high-tannin buckets in the other patch, which corresponds to neighbour contrast defence. The neighbour contrast susceptibility was present both for individual and group foraging, but the strength of the effect was somewhat weaker for groups due to weaker within-patch selectivity.
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| 3. |
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| 4. |
- Bergvall, Ulrika A, et al.
(author)
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The effect of spatial scale on plant associational defences against mammalian herbivores
- 2008
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In: Ecoscience. - 1195-6860. ; 15, s. 343-348
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Journal article (peer-reviewed)abstract
- Intraspecific variation in plant toxins at different spatial scales can influence foraging decisions by wild herbivores. In order to investigate plant associational defences in relation to spatial scale, we performed an experiment with fallow deer encountering 2 patches of low- and high-tannin hazel branches. One patch was good, consisting of 7 low- and I high-tannin branch, and the other bad, with low- and 7 high-tannin branches. We kept the between-patch spatial scale constant and varied the within-patch spatial scale: the branches in a patch were either spread out or close together in a bundle. When the low-tannin branches were spread out, the deer showed a clear preference for low_tannin branches both patches and consumed similar amounts from low-tannin branches in the good and the bad patch, which means that there was no associational defence. In contrast, when the branches instead were together in a bundle, within-patch selectivity decreased and between-patch selectivity increased, and the low-tannin branches in the bad patch were less eaten than the low-tannin branches in the good patch, which corresponds to associational defence. We conclude that small inter-plant distances can be crucial for the operation of plant associational defences
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| 5. |
- Cervin, Camilla, et al.
(author)
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Cosegregation of MIDD and MODY in a Pedigree: Functional and Clinical Consequences.
- 2004
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In: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 53:7, s. 1894-1899
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Journal article (peer-reviewed)abstract
- The aim of this study was characterization of a family carrying two mutations known to cause monogenic forms of diabetes, the M626K mutation in the HNF1α gene (MODY3) and the A3243G in mtDNA. β-Cell function and insulin sensitivity were assessed with the Botnia clamp. Heteroplasmy of the A3243G mutation and variants in type 2 diabetes susceptibility genes were determined, and transcriptional activity, DNA binding, and subcellular localization of mutated HNF1α were studied. Thirteen family members carried the mutation in mtDNA; 6 of them also had the M626K mutation, whereas none had only the M626K mutation. The protective Ala12 allele in peroxisome proliferator–activated receptor (PPAR)γ was present in two nondiabetic individuals. Carriers of both mtDNA and HNF1α mutations showed an earlier age at onset of diabetes than carriers of only the mtDNA mutation (median 22 vs. 45 years) but no clear difference in β-cell function or insulin sensitivity. In vitro, the M626K mutation caused a 53% decrease in transcriptional activity in HeLa cells. The mutated protein showed normal nuclear targeting but increased DNA binding. These data demonstrate that several genetic factors might contribute to diabetes risk, even in families with mtDNA and HNF1α mutations.
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| 6. |
- Gaulton, Kyle J, et al.
(author)
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Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.
- 2015
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 47:12, s. 1415-1415
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Journal article (peer-reviewed)abstract
- We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.
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| 7. |
- Heid, Iris M, et al.
(author)
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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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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 949-960
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Journal article (peer-reviewed)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. |
- Mikryukov, Vladimir, et al.
(author)
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Connecting the multiple dimensions of global soil fungal diversity
- 2023
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In: Science advances. - 2375-2548. ; 9:48
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Journal article (peer-reviewed)abstract
- How the multiple facets of soil fungal diversity vary worldwide remains virtually unknown, hindering the management of this essential species-rich group. By sequencing high-resolution DNA markers in over 4000 topsoil samples from natural and human-altered ecosystems across all continents, we illustrate the distributions and drivers of different levels of taxonomic and phylogenetic diversity of fungi and their ecological groups. We show the impact of precipitation and temperature interactions on local fungal species richness (alpha diversity) across different climates. Our findings reveal how temperature drives fungal compositional turnover (beta diversity) and phylogenetic diversity, linking them with regional species richness (gamma diversity). We integrate fungi into the principles of global biodiversity distribution and present detailed maps for biodiversity conservation and modeling of global ecological processes.
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| 9. |
- Mildén, Mikael, 1973-
(author)
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Local and regional dynamics of Succisa pratensis
- 2005
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Doctoral thesis (other academic/artistic)abstract
- Land use change is considered to be one of the biggest threat to global species diversity. In Sweden, abandonment of grazing is one of the most common reasons for decline in species richness in semi-natural grasslands. Today semi-natural grasslands often occur as more or less isolated fragments. The result for species that benefits from grazing is a smaller area of suitable habitat and higher extinction risks and a lowered ability to colonize new areas. Succisa pratensis is a long-lived perennial plant that benefits from grazing and is common in Swedish semi-natural grasslands. I have assessed the performance of Succisa pratensis at various spatial and temporal scales, in a Swedish rural landscape. I performed demographic matrix modelling of populations at grazed and ungrazed sites. A regional level was then added, by incorporating data collected from a large number of populations and habitat types into the matrix models and extinction risks over 50 years were calculated. A dynamic metapopulation model was created and the regional dynamics, in terms of colonisations resulting from long distance dispersal and population extinctions were examined. The effects of management history were incorporated into the model by using historical maps. In addition, I made an analysis of the impact of management history on the distribution and performance of four grassland species, using vegetation maps from 1945 and 2001. Local dynamics of Succisa pratensis was negatively affected by abandonment of grazing. Recorded population sizes were ten times higher in grazed sites than in ungrazed. The turnover rate of the system was estimated to about one extinction or colonisation per year. Both the simulation study and the analyses of vegetation maps suggested a pronounced legacy of management history in Succisa pratensis in the study landscape. Overall, the results of this thesis demonstrate the importance of management history for species in the rural landscape.
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| 10. |
- Nethander, Maria, 1980, et al.
(author)
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An atlas of genetic determinants of forearm fracture.
- 2023
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In: Nature genetics. - : Springer Nature. - 1546-1718 .- 1061-4036. ; 55:11, s. 1820-1830
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Journal article (peer-reviewed)abstract
- Osteoporotic fracture is among the most common and costly of diseases. While reasonably heritable, its genetic determinants have remained elusive. Forearm fractures are the most common clinically recognized osteoporotic fractures with a relatively high heritability. To establish an atlas of the genetic determinants of forearm fractures, we performed genome-wide association analyses including 100,026 forearm fracture cases. We identified 43 loci, including 26 new fracture loci. Although most fracture loci associated with bone mineral density, we also identified loci that primarily regulate bone quality parameters. Functional studies of one such locus, at TAC4, revealed that Tac4-/- mice have reduced mechanical bone strength. The strongest forearm fracture signal, at WNT16, displayed remarkable bone-site-specificity with no association with hip fractures. Tall stature and low body mass index were identified as new causal risk factors for fractures. The insights from this atlas may improve fracture prediction and enable therapeutic development to prevent fractures.
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