| 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. |
- Lindén, Elin, et al.
(författare)
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Circum-Arctic distribution of chemical anti-herbivore compounds suggests biome-wide trade-off in defence strategies in Arctic shrubs
- 2022
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Ingår i: Ecography. - : John Wiley & Sons. - 0906-7590 .- 1600-0587. ; :11
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Tidskriftsartikel (refereegranskat)abstract
- Spatial variation in plant chemical defence towards herbivores can help us understand variation in herbivore top–down control of shrubs in the Arctic and possibly also shrub responses to global warming. Less defended, non-resinous shrubs could be more influenced by herbivores than more defended, resinous shrubs. However, sparse field measurements limit our current understanding of how much of the circum-Arctic variation in defence compounds is explained by taxa or defence functional groups (resinous/non-resinous). We measured circum-Arctic chemical defence and leaf digestibility in resinous (Betula glandulosa, B. nana ssp. exilis) and non-resinous (B. nana ssp. nana, B. pumila) shrub birches to see how they vary among and within taxa and functional groups. Using liquid chromatography–mass spectrometry (LC–MS) metabolomic analyses and in vitro leaf digestibility via incubation in cattle rumen fluid, we analysed defence composition and leaf digestibility in 128 samples from 44 tundra locations.We found biogeographical patterns in anti-herbivore defence where mean leaf triterpene concentrations and twig resin gland density were greater in resinous taxa and mean concentrations of condensing tannins were greater in non-resinous taxa. This indicates a biome-wide trade-off between triterpene- or tannin-dominated defences. However, we also found variations in chemical defence composition and resin gland density both within and among functional groups (resinous/non-resinous) and taxa, suggesting these categorisations only partly predict chemical herbivore defence. Complex tannins were the only defence compounds negatively related to in vitro digestibility, identifying this previously neglected tannin group as having a potential key role in birch anti-herbivore defence.We conclude that circum-Arctic variation in birch anti-herbivore defence can be partly derived from biogeographical distributions of birch taxa, although our detailed mapping of plant defence provides more information on this variation and can be used for better predictions of herbivore effects on Arctic vegetation.
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| 3. |
- 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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| 4. |
- Siefert, Andrew, et al.
(författare)
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A global meta-analysis of the relative extent of intraspecific trait variation in plant communities
- 2015
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Ingår i: Ecology Letters. - : Wiley. - 1461-023X .- 1461-0248. ; 18:12, s. 1406-1419
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Forskningsöversikt (refereegranskat)abstract
- Recent studies have shown that accounting for intraspecific trait variation (ITV) may better address major questions in community ecology. However, a general picture of the relative extent of ITV compared to interspecific trait variation in plant communities is still missing. Here, we conducted a meta-analysis of the relative extent of ITV within and among plant communities worldwide, using a data set encompassing 629 communities (plots) and 36 functional traits. Overall, ITV accounted for 25% of the total trait variation within communities and 32% of the total trait variation among communities on average. The relative extent of ITV tended to be greater for whole-plant (e.g. plant height) vs. organ-level traits and for leaf chemical (e.g. leaf N and P concentration) vs. leaf morphological (e.g. leaf area and thickness) traits. The relative amount of ITV decreased with increasing species richness and spatial extent, but did not vary with plant growth form or climate. These results highlight global patterns in the relative importance of ITV in plant communities, providing practical guidelines for when researchers should include ITV in trait-based community and ecosystem studies.
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| 5. |
- Sundqvist, Emilie
(författare)
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Common viruses and host gene interactions in multiple sclerosis
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Multiple sclerosis (MS) is a neurological disorder, characterised by demyelination and inflammation of the central nervous system, leading to sensory and motor symptoms. MS is thought to be complex disease, with both environmental and genetic risk factors underlying disease susceptibility. Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infections are two environmental risk factors, one with a robust association to MS (EBV) and one where the results have been more inconclusive (CMV). The strongest genetic risk factors lies within the HLA genes, with HLA-DRB1*15 as the strongest susceptibility factor, and HLA-A*02, as the most protective genetic factor. In paper I, the role of EBV infection, and the interaction with HLA-DRB1*15 and HLA-A*02 was studied. Anti-EBNA1 IgG was measured, as was IgG antibodies towards 5 different epitopes of EBNA1. High levels of EBNA1 385-420 IgG antibodies were strongly associated with MS, independent of EBNA1 IgG antibody level. There was interaction on the additive scale between EBNA1 385-420 IgG and HLA-DRB1*15 and absence of HLA-A*02. In paper II, we tried to replicate findings by Simon et al, where they found interaction on the multiplicative scale between EBNA1 IgG levels and smoking (never/ever), but our analysis showed no such interaction. In paper III, the association between CMV and MS was studied, yielding a significant negative association between CMV and MS. To further validate our results, a meta-analysis of published retrospective studies was performed, which provided a similar negative association, supporting our results. In paper IV, the focus shifted from the association of viruses to MS, to dissecting the host genetic influence on anti-JCV seropositivity and anti-JCV antibody levels. JC virus is the virus responsible for Progressive multifocal leukoencephalopathy (PML), a rare but potentially fatal side-effect seen in MS-patients treated with natalizumab. A meta-analysis of three genome wide association studies performed in two sets of MS cases, one Scandinavian and one German, and a set of Swedish controls, strongly indicated that the HLA class II region was involved in regulating anti-JCV antibody response, and anti-JCV antibody levels. Analysis of classically named HLA-alleles supported these findings. The alleles in the DRB1*15-DQB1*06:02-DQA1*01:02-haplotype were all strongly negatively associated with anti-JCV antibody status and low anti-JCV antibody levels. The alleles in the DRB1*13-DQB1*06:02-DQA1*01:03-haplotype were positively associated with anti-JCV antibody status. Several non-HLA loci were suggestively associated with anti-JCV antibody status and anti-JCV antibody levels (p<0.0001). However, these findings will have to be replicated in an independent dataset. This thesis highlights the interactions between environmental and genetic factors in modulating MS risk. It also shows that the HLA genes have a central role in the susceptibility to JCV infection.
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| 6. |
- Sundqvist, Emilie, et al.
(författare)
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Lack of replication of interaction between EBNA1 IgG and smoking in risk for multiple sclerosis
- 2012
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Ingår i: Neurology. - 0028-3878 .- 1526-632X. ; 79:13, s. 1363-1368
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Tidskriftsartikel (refereegranskat)abstract
- Background: Epstein-Barr virus infection, smoking, HLA-A*02, and DRB1*15 have all been proposed as risk factors for multiple sclerosis (MS). In 2010, Simon et al. described an interaction on the multiplicative scale between EBNA1 immunoglobulin G (IgG) and smoking regarding risk of MS, a finding that we attempted to replicate. Methods: This Swedish case-control study consisted of patients with newly diagnosed MS and matched controls. Using logistic regression, we analyzed association to MS risk and interactions between EBNA1 IgG and smoking, HLA-DRB1*15, and A*02, respectively, on the multiplicative scale. In addition, we analyzed interactions on the additive scale using attributable proportion due to interaction (AP). Results: We did not observe any interaction on the multiplicative scale between EBNA1 IgG and any of the 3 risk factors, smoking, DRB1*15, or absence of A*02, although in a conditional analysis the interaction with absence of A*02 becomes significant. However, we observed interactions on the additive scale between EBNA1 IgG and DRB1*15 (AP = 0.34, 95% confidence interval 0.11-0.57, p = 5 x 10(-3)) and between EBNA1 IgG and absence of A*02 (AP = 0.36, 0.13-0.59, p = 2 x 10(-3)) but not between smoking and DRB1*15 and EBNA1 IgG. The interaction between EBNA1 IgG and DRB1*15 was not significant in the conditional analysis. Conclusion: We did not observe any interaction between EBNA1 IgG and smoking, regardless of scale used, and thus did not replicate the observations from Simon et al. Neurology (R) 2012;79:1363-1368
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| 7. |
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