| 1. |
- Locke, Adam E, et al.
(author)
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Genetic studies of body mass index yield new insights for obesity biology.
- 2015
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 197-401
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Journal article (peer-reviewed)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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| 2. |
- Marouli, Eirini, et al.
(author)
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Rare and low-frequency coding variants alter human adult height
- 2017
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 542:7640, s. 186-190
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Journal article (peer-reviewed)abstract
- Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.
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| 3. |
- Turcot, Valerie, et al.
(author)
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Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity
- 2018
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In: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 50:1, s. 26-41
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Journal article (peer-reviewed)abstract
- Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are similar to 10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed similar to 7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
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| 4. |
- Ebersole, Charles R., et al.
(author)
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Many Labs 5: Testing Pre-Data-Collection Peer Review as an Intervention to Increase Replicability
- 2020
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In: Advances in Methods and Practices in Psychological Science. - : Sage. - 2515-2467 .- 2515-2459. ; 3:3, s. 309-331
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Journal article (peer-reviewed)abstract
- Replication studies in psychological science sometimes fail to reproduce prior findings. If these studies use methods that are unfaithful to the original study or ineffective in eliciting the phenomenon of interest, then a failure to replicate may be a failure of the protocol rather than a challenge to the original finding. Formal pre-data-collection peer review by experts may address shortcomings and increase replicability rates. We selected 10 replication studies from the Reproducibility Project: Psychology (RP:P; Open Science Collaboration, 2015) for which the original authors had expressed concerns about the replication designs before data collection; only one of these studies had yielded a statistically significant effect (p < .05). Commenters suggested that lack of adherence to expert review and low-powered tests were the reasons that most of these RP:P studies failed to replicate the original effects. We revised the replication protocols and received formal peer review prior to conducting new replication studies. We administered the RP:P and revised protocols in multiple laboratories (median number of laboratories per original study = 6.5, range = 3-9; median total sample = 1,279.5, range = 276-3,512) for high-powered tests of each original finding with both protocols. Overall, following the preregistered analysis plan, we found that the revised protocols produced effect sizes similar to those of the RP:P protocols (Delta r = .002 or .014, depending on analytic approach). The median effect size for the revised protocols (r = .05) was similar to that of the RP:P protocols (r = .04) and the original RP:P replications (r = .11), and smaller than that of the original studies (r = .37). Analysis of the cumulative evidence across the original studies and the corresponding three replication attempts provided very precise estimates of the 10 tested effects and indicated that their effect sizes (median r = .07, range = .00-.15) were 78% smaller, on average, than the original effect sizes (median r = .37, range = .19-.50).
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| 5. |
- Ntalla, Ioanna, et al.
(author)
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Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction
- 2020
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Journal article (peer-reviewed)abstract
- The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N=293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease. On the electrocardiogram, the PR interval reflects conduction from the atria to ventricles and also serves as risk indicator of cardiovascular morbidity and mortality. Here, the authors perform genome-wide meta-analyses for PR interval in multiple ancestries and identify 141 previously unreported genetic loci.
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| 6. |
- Eich, Andreas, et al.
(author)
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Positive association between epiphytes and competitiveness of the brown algal genus Lobophora against corals
- 2019
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In: PeerJ. - : PeerJ. - 2167-8359. ; 7
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Journal article (peer-reviewed)abstract
- Observations of coral-algal competition can provide valuable information about the state of coral reef ecosystems. Here, we report contact rates and apparent competition states for six shallow lagoonal reefs in Fiji. A total of 81.4% of examined coral perimeters were found to be in contact with algae, with turf algae (54.7%) and macroalgae of the genus Lobophora (16.8%) representing the most frequently observed contacts. Turf algae competitiveness was low, with 21.8% of coral-turf contacts being won by the algae (i.e. overgrowth or bleaching of coral tissue). In contrast, Lobophora competitiveness against corals was high, with 62.5% of contacts being won by the alga. The presence of epiphytic algae on Lobophora was associated with significantly greater algal competitiveness against corals, with 75.8% and 21.1% of interactions recorded as algal wins in the presence and absence of epiphytes, respectively. Sedimentation rate, herbivorous fish biomass, and coral colony size did not have a significant effect on Lobophora-coral interactions. This research indicates a novel and important role of epiphytes in driving the outcome of coral-algal contacts.
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| 7. |
- Ford, Amanda K., et al.
(author)
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First insights into the impacts of benthic cyanobacterial mats on fish herbivory functions on a nearshore coral reef
- 2021
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1
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Journal article (peer-reviewed)abstract
- Benthic cyanobacterial mats (BCMs) are becoming increasingly common on coral reefs. In Fiji, blooms generally occur in nearshore areas during warm months but some are starting to prevail through cold months. Many fundamental knowledge gaps about BCM proliferation remain, including their composition and how they influence reef processes. This study examined a seasonal BCM bloom occurring in a 17-year-old no-take inshore reef area in Fiji. Surveys quantified the coverage of various BCM-types and estimated the biomass of key herbivorous fish functional groups. Using remote video observations, we compared fish herbivory (bite rates) on substrate covered primarily by BCMs (>50%) to substrate lacking BCMs (<10%) and looked for indications of fish (opportunistically) consuming BCMs. Samples of different BCM-types were analysed by microscopy and next-generation amplicon sequencing (16S rRNA). In total, BCMs covered 514% (mean +/- s.e.m) of the benthos. Herbivorous fish biomass was relatively high (212 +/- 36 kg/ha) with good representation across functional groups. Bite rates were significantly reduced on BCM-dominated substratum, and no fish were unambiguously observed consuming BCMs. Seven different BCM-types were identified, with most containing a complex consortium of cyanobacteria. These results provide insight into BCM composition and impacts on inshore Pacific reefs.
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| 8. |
- Ford, Amanda K., et al.
(author)
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Local Human Impacts Disrupt Relationships Between Benthic Reef Assemblages and Environmental Predictors
- 2020
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In: Frontiers in Marine Science. - : Frontiers Media SA. - 2296-7745. ; 7
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Journal article (peer-reviewed)abstract
- Human activities are changing ecosystems at an unprecedented rate, yet large-scale studies into how local human impacts alter natural systems and interact with other aspects of global change are still lacking. Here we provide empirical evidence that local human impacts fundamentally alter relationships between ecological communities and environmental drivers. Using tropical coral reefs as a study system, we investigated the influence of contrasting levels of local human impact using a spatially extensive dataset spanning 62 outer reefs around inhabited Pacific islands. We tested how local human impacts (low versus high determined using a threshold of 25 people km(-2) reef) affected benthic community (i) structure, and (ii) relationships with environmental predictors using pre-defined models and model selection tools. Data on reef depth, benthic assemblages, and herbivorous fish communities were collected from field surveys. Additional data on thermal stress, storm exposure, and market gravity (a function of human population size and reef accessibility) were extracted from public repositories. Findings revealed that reefs subject to high local human impact were characterised by relatively more turf algae (>10% higher mean absolute coverage) and lower live coral cover (9% less mean absolute coverage) than reefs subject to low local human impact, but had similar macroalgal cover and coral morphological composition. Models based on spatio-physical predictors were significantly more accurate in explaining the variation of benthic assemblages at sites with low (mean adjusted-R-2 = 0.35) rather than high local human impact, where relationships became much weaker (mean adjusted-R-2 = 0.10). Model selection procedures also identified a distinct shift in the relative importance of different herbivorous fish functional groups in explaining benthic communities depending on the local human impact level. These results demonstrate that local human impacts alter natural systems and indicate that projecting climate change impacts may be particularly challenging at reefs close to higher human populations, where dependency and pressure on ecosystem services are highest.
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| 9. |
- Lagou, Vasiliki, et al.
(author)
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Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability
- 2021
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In: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 12:1
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Journal article (peer-reviewed)abstract
- Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
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| 10. |
- McAndrews, Ryan S., et al.
(author)
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Algae sediment dynamics are mediated by herbivorous fishes on a nearshore coral reef
- 2019
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In: Coral reefs (Print). - : Springer Science and Business Media LLC. - 0722-4028 .- 1432-0975. ; 38:3, s. 431-441
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Journal article (peer-reviewed)abstract
- Epilithic algae are a ubiquitous component of coral reefs. Components of the epilithic algal matrix (EAM) can have a significant influence on coral settlement and benthic feeding by fishes. We employed a herbivore exclusion experiment on a fringing reef in Viti Levu, Fiji, to investigate the functional role of herbivorous fishes in affecting the EAM between different habitat types and levels of community-based fishing restriction. We surveyed the herbivorous fish community and deployed experimental tiles on the reef flat and lagoonal slope and inside and outside of an area where fishing is restricted (tabu). Tiles were deployed for 3months, half within cages to exclude herbivorous fishes. We then identified algal type and quantified epilithic algal turf height, sediment dry weight, and detritus within the EAM on each tile. EAM that developed under herbivory was remarkably similar, regardless of the differences in habitat or fishing restriction. In contrast, EAM within cages was characterised by longer turf, heavier sediment load, and high variance in turf length and sediment load. Habitat type played a strong role in determining EAM characteristics where herbivores were excluded. Caged EAM on the reef flat was characterised by algal turf and fleshy macroalgae, whereas EAM in cages on the lagoonal slope was overwhelmingly dominated by filamentous and mat-forming cyanobacteria. The results presented here demonstrate the importance of herbivorous fishes in maintaining a benthic environment favourable to coral settlement and survival. Our results suggest that herbivore biomass per se is not a reliable predictor of foraging activity. Moreover, these results show that the absence of herbivore foraging can have different consequences depending on the habitat type, even within the same reef.
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