| 1. |
- Takeuchi, Fumihiko, et al.
(författare)
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Interethnic analyses of blood pressure loci in populations of East Asian and European descent
- 2018
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Blood pressure (BP) is a major risk factor for cardiovascular disease and more than 200 genetic loci associated with BP are known. Here, we perform a multi-stage genome-wide association study for BP (max N = 289,038) principally in East Asians and meta-analysis in East Asians and Europeans. We report 19 new genetic loci and ancestry-specific BP variants, conforming to a common ancestry-specific variant association model. At 10 unique loci, distinct non-rare ancestry-specific variants colocalize within the same linkage disequilibrium block despite the significantly discordant effects for the proxy shared variants between the ethnic groups. The genome-wide transethnic correlation of causal-variant effect-sizes is 0.898 and 0.851 for systolic and diastolic BP, respectively. Some of the ancestry-specific association signals are also influenced by a selective sweep. Our results provide new evidence for the role of common ancestry-specific variants and natural selection in ethnic differences in complex traits such as BP.
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| 2. |
- Ishigaki, Kazuyoshi, et al.
(författare)
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Multi-ancestry genome-wide association analyses identify novel genetic mechanisms in rheumatoid arthritis
- 2022
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 54:11, s. 1640-1651
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Tidskriftsartikel (refereegranskat)abstract
- Rheumatoid arthritis (RA) is a highly heritable complex disease with unknown etiology. Multi-ancestry genetic research of RA promises to improve power to detect genetic signals, fine-mapping resolution and performances of polygenic risk scores (PRS). Here, we present a large-scale genome-wide association study (GWAS) of RA, which includes 276,020 samples from five ancestral groups. We conducted a multi-ancestry meta-analysis and identified 124 loci (P < 5 × 10−8), of which 34 are novel. Candidate genes at the novel loci suggest essential roles of the immune system (for example, TNIP2 and TNFRSF11A) and joint tissues (for example, WISP1) in RA etiology. Multi-ancestry fine-mapping identified putatively causal variants with biological insights (for example, LEF1). Moreover, PRS based on multi-ancestry GWAS outperformed PRS based on single-ancestry GWAS and had comparable performance between populations of European and East Asian ancestries. Our study provides several insights into the etiology of RA and improves the genetic predictability of RA.
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| 3. |
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| 4. |
- 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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| 5. |
- Okada, Yukinori, et al.
(författare)
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Genetics of rheumatoid arthritis contributes to biology and drug discovery
- 2014
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Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 506:7488, s. 376-381
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Tidskriftsartikel (refereegranskat)abstract
- A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA)(1). Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating similar to 10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2-4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation(5), cis-acting expression quantitative trait loci(6) and pathway analyses(7-9)-as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes-to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.
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| 6. |
- Takahashi, Daisuke, et al.
(författare)
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Abrupt community transitions and cyclic evolutionary dynamics in complex food webs
- 2013
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Ingår i: Journal of Theoretical Biology. - : Academia Press. - 0022-5193 .- 1095-8541. ; 337, s. 181-189
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Tidskriftsartikel (refereegranskat)abstract
- Understanding the emergence and maintenance of biodiversity ranks among the most fundamental challenges in evolutionary ecology. While processes of community assembly have frequently been analyzed from an ecological perspective, their evolutionary dimensions have so far received less attention. To elucidate the eco-evolutionary processes underlying the long-term build-up and potential collapse of community diversity, here we develop and examine an individual-based model describing coevolutionary dynamics driven by trophic interactions and interference competition, of a pair of quantitative traits determining predator and prey niches. Our results demonstrate the (1) emergence of communities with multiple trophic levels, shown here for the first time for stochastic models with linear functional responses, and (2) intermittent and cyclic evolutionary transitions between two alternative community states. In particular, our results indicate that the interplay of ecological and evolutionary dynamics often results in extinction cascades that remove the entire trophic level of consumers from a community. Finally, we show the (3) robustness of our results under variations of model assumptions, underscoring that processes of consumer collapse and subsequent rebound could be important elements of understanding biodiversity dynamics in natural communities.
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| 7. |
- Takahashi, Daisuke, et al.
(författare)
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Cyclic transitions in simulated food-web evolution
- 2011
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Ingår i: Journal of Plant Interactions. - : Taylor & Francis. - 1742-9145 .- 1742-9153. ; 6:2-3, s. 181-182
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Tidskriftsartikel (refereegranskat)abstract
- Eco-evolutionary food-web models help elucidate the processes responsible for the emergence and maintenance of complex community structures. Using an individual-based model of evolving trophic and competitive interactions, we highlight a pattern of community macroevolution involving two meta-stable states, corresponding to a plant-herbivore community and a plant community, respectively. On the evolutionary timescale, our model exhibits cyclic transitions between these alternative community states. The model also helps understand the eco-evolutionary mechanisms underlying these recurrent rapid transitions, which end intermittent periods of near-stasis or punctuated equilibrium.
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| 8. |
- Yamauchi, Atsushi, et al.
(författare)
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Environmental variation does not always promote plasticity : evolutionarily realized reaction norm for costly plasticity
- 2014
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Ingår i: Evolutionary Ecology Research. - 1522-0613 .- 1937-3791. ; 16:8, s. 631-647
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Tidskriftsartikel (refereegranskat)abstract
- Question: How does environmental variability influence evolutionarily realized phenotypic plasticity? Mathematical method: Optimization in a spatially fluctuating environment. Key assumptions: Either the maintenance cost of plasticity results from the amount of phenotypic response, or it results from the slope of the reaction norm. And there are two alternative types of state-specific benefit functions: either the benefit is maximal at an intermediate phenotype, or it is a monotonically increasing function of phenotype. Conclusion: Organisms may not respond to rare environmental states. In this case, environmental variability suppresses two indices of phenotypic plasticity, i. e. the range of plasticity and the maximum slope of the reaction norm.
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