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opencc-zeroDec 2019View details →

Sex-specific patterns of senescence in artificial insect populations varying in sex-ratio to manipulate reproductive effort

Background: The disposable soma theory of ageing assumes that organisms optimally trade-off limited resources between reproduction and longevity to maximize fitness. Early reproduction should especially trade-off against late reproduction and longevity because of reduced investment into somatic protection, including immunity. Moreover, as optimal reproductive strategies of males and females differ, sexually dimorphic patterns of senescence may evolve. In particular, as males gain fitness through mating success, sexual competition should be a major factor accelerating male senescence. In a single experiment, we examined these possibilities by establishing artificial populations of the mealworm beetle, Tenebrio molitor, in which we manipulated the sex-ratio to generate variable levels of investment into reproductive effort and sexual competition in males and females. Results: As predicted, variation in sex-ratio affected male and female reproductive efforts, with contrasted sex-specific trade-offs between lifetime reproduction, survival and immunity. High effort of reproduction accelerated mortality in females, without affecting immunity, but high early reproductive success was observed only in balanced sex-ratio condition. Male reproduction was costly on longevity and immunity, mainly because of their investment into copulations rather than in sexual competition. Conclusions: Our results suggest that T. molitor males, like females, maximize fitness through enhanced longevity, partly explaining their comparable longevity.

opencc-zeroOct 2020View details →

Antibiotics can be used to contain drug-resistant bacteria by maintaining sufficiently large sensitive populations

Standard infectious disease practice calls for aggressive drug treatment that rapidly eliminates the pathogen population before resistance can emerge. When resistance is absent, this elimination strategy can lead to complete cure. However, when resistance is already present, removing drug-sensitive cells as quickly as possible removes competitive barriers that may slow the growth of resistant cells. In contrast to the elimination strategy, the containment strategy aims to maintain the maximum tolerable number of pathogens, exploiting competitive suppression to achieve chronic control. Here we combine in vitro experiments in computer-controlled bioreactors with mathematical modeling to investigate whether containment strategies can delay failure of antibiotic treatment regimens. To do so, we measured the "escape time" required for drug-resistant E. coli populations to eclipse a threshold density maintained by adaptive antibiotic dosing. Populations containing only resistant cells rapidly escape the threshold density, but we found that matched resistant populations that also contain the maximum possible number of sensitive cells could be contained for significantly longer. The increase in escape time occurs only when the threshold density--the acceptable bacterial burden--is sufficiently high, an effect that mathematical models attribute to increased competition. The findings provide decisive experimental confirmation that maintaining the maximum number of sensitive cells can be used to contain resistance when the size of the population is sufficiently large.

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Enhanced Zika virus susceptibility of globally invasive Aedes aegypti populations

The worldwide variation of Aedes aegypti susceptibility to ZIKV infection was investigated using a panel of 14 laboratory colonies recently established from field-collected specimens.

opencc-by-4.0Aug 2020View details →

Mixed-stock analysis using Rapture genotyping to evaluate stock-specific exploitation of a walleye population despite weak genetic structure

Mixed-stock analyses using genetic markers have informed fisheries management in cases where strong genetic differentiation occurs among local spawning populations, yet many fisheries are supported by multiple spawning stocks that are weakly differentiated. Freshwater fisheries exemplify this problem, with many harvested populations supported by multiple stocks of young evolutionary age and that are isolated across small spatial scales. As a result, attempts to conduct genetic mixed-stock analyses of inland fisheries have often been unsuccessful. Advances in genomic sequencing now offer the ability to discriminate among populations with weak population structure, by providing the necessary resolution to conduct mixed-stock assignment among previously indistinguishable stocks. We demonstrate the use of genomic data to conduct a mixed-stock analysis of Lake Erie's commercial and recreational walleye (Sander vitreus) fisheries and estimate the relative harvest of weakly differentiated stocks. We used RAD-capture (Rapture) to sequence and genotype individuals at 12,081 loci that had been previously determined to be capable of discriminating between western and eastern basin stocks (mean pairwise FST = 0.001) with 95% reassignment accuracy. An outcome not possible in the past with microsatellite markers. Genetic assignment of 1,075 fish harvested from recreational and commercial fisheries in the eastern basin indicated that western basin stocks supported the majority of the harvest during peak harvest (July – September). Composition of harvest changed seasonally, with eastern basin fish comprising much of the early season harvest (May – June). Clear spatial structure in stock-specific harvest existed; more easterly sites contained more individuals of east basin origin than did westerly sites. Our study provides important stock contribution estimates for Lake Erie fishery management and demonstrates the power of genomic data to facilitate mixed-stock analysis in exploited fish populations with weak population structure or limited existing genetic resources.

Recent extinctions among Little Spotted Kiwi (Apteryx owenii) and the origin of extant populations

Little Spotted Kiwi (LSK; Apteryx owenii) have the lowest genetic diversity of five currently recognised kiwi species apparently due to a bottleneck when at most five individuals were translocated to Kapiti Island in 1912. Ancient DNA analyses show that LSK also had the lowest genetic diversity of kiwi species historically, possibly due to population bottlenecks during Pleistocene glaciation. We compare genetic diversity between LSK from Kapiti Island (extant), D'Urville Island (extinct) and the South Island of mainland New Zealand (extinct) at 495 bp of the mitochondrial control region (mtDNA) and 15 nuclear microsatellite loci (nDNA). Despite higher sample sizes in extant (n = 31 mtDNA, 97 nDNA) than recently extinct (n = 10 mtDNA, 9 nDNA) populations, extant LSK have at least 78% fewer mtDNA haplotypes and 52% fewer microsatellite alleles than recently extinct LSK. Extant LSK were strongly divergent from historical LSK for both mtDNA and nDNA (FST = 0.237 to 0.480), but showed greatest similarity with historical samples from Fiordland near the putative source population of Kapiti founders. Microsatellite data suggest that Kapiti LSK could have arisen from as few as three birds and our mtDNA data show that at least two of the founders were female. Our results indicate that substantial genetic diversity has been lost with the recent extinctions of remnant populations. Locating and protecting any last surviving individuals in presumed extinct populations will require intensive conservation efforts, but could also provide an invaluable source of genetic diversity for the species.

Risk factors for non-communicable diseases in Bangladesh: Findings of the population-based cross-sectional national survey 2018

Objectives: To determine the national prevalence of risk factors of non-communicable diseases (NCD) in the adult population of Bangladesh. Design: The study was a population-based national cross-sectional study. Setting: This study used 496 primary sampling units (PSUs) developed by the Bangladesh Bureau of Statistics. The PSUs were equally allocated to each division and urban and rural stratum within each division. Participants: The participants were adults aged 18-69 years, who were usual residents of the households for at least six months, and stayed the night before the survey. Out of 9900 participants, 8185 (82.7%) completed STEP-1 and STEP-2, and 7208 took part in STEP-3. Primary and secondary outcome: The prevalence of behavioral, physical, and biochemical risk factors of NCD. Data were weighted to generate national estimates. Results: Tobacco use was significantly (p<0.05) higher in the rural (45.2%) than the urban (38.8%) population. Inadequate fruit/vegetable intake was significantly (P<0.05) higher in the urban (92.1%) than in the rural (88.9%) population. The mean salt intake per day was higher in the rural (9.0 gm) than urban (8.9 gm) population. Among all, 3.0% had no, 70.9% had 1-2, and 26.2% had ≥3 NCD risk factors. The urban population was more likely to have insufficient physical activity (AOR: 1.2, 95% CI: 1.2–1.2), obesity (AOR: 1.5, 95% CI: 1.5–1.5), hypertension (AOR: 1.3, 95% CI: 1.3–1.3), diabetes (AOR: 1.6, 95% CI: 1.6–1.6), and hyperglycemia (AOR: 1.1, 95% CI: 1.1–1.1). Conclusions: Considering the high prevalence of the behavioral, physical, and biochemical risk factors, diverse population and high-risk group targeted interventions are essential to combat the rising burden of NCDs.

opencc-zeroDec 2019View details →

Data for: Coevolution fails to maintain genetic variation in a host-parasite model with constant finite population size

Coevolutionary negative frequency-dependent selection has been hypothesized to maintain genetic variation in host and parasites. Despite the extensive literature pertaining to host-parasite coevolution, the dynamics of genetic variation has not been examined in a matching-alleles model (MAM) with a finite population size relative to the expectation under neutral genetic drift alone. The dynamics of the MA coevolution in an infinite population, in fact, suggests that genetic variation in these coevolving populations behaves neutrally. By comparing host heterozygosity to the expectation in a single-species model of neutral genetic drift we find that while this is also largely true in finite populations two additional phenomena arise. First, reciprocal natural selection acting on stochastic perturbations in host and pathogen allele frequencies results in a slight increase or decrease in genetic variation depending on the parameter conditions. Second, following the fixation of an allele in the parasite, selection in the MAM becomes directional, which then rapidly erodes genetic variation in the host. Hence, rather than maintain it, we find that, on average, matching-alleles coevolution depletes genetic variation.

Quantifying thermal exposure for migratory riverine species: phenology of Chinook salmon populations predicts thermal stress

Migratory species are particularly vulnerable to climate change because habitat throughout their entire migration cycle must be suitable for the species to persist. For migratory species in rivers, predicting climate change impacts is especially difficult because there is a lack of spatially-continuous and seasonally-varying stream temperature data, habitat conditions can vary for an individual throughout its life cycle, and vulnerability can vary by life stage and season. To predict thermal impacts on migratory riverine populations, we first expanded a spatial stream network model to predict mean monthly temperature for 465,775 river km in the western U.S., and then applied simple yet plausible future stream-temperature change scenarios. We then joined stream temperature predictions to 44,396 spatial observations and life stage-specific phenology (timing) for 26 ecotypes (i.e. geographically distinct population groups expressing one of four distinct seasonal migration patterns) of Chinook salmon (Oncorhynchus tshawytscha), a phenotypically diverse anadromous salmonid that is ecologically and economically important but declining throughout its range. Thermal stress, assessed for each life stage and ecotype based on federal criteria, was influenced by migration timing rather than latitude, elevation, or migration distance, such that sympatric ecotypes often showed differential thermal exposure. Early-migration phenotypes were especially vulnerable due to prolonged residency in inland streams during the summer. We evaluated the thermal suitability of 31,699 stream km which are currently blocked by dams to explore reintroduction above dams as an option to mitigate the negative effects of our warmer stream temperature scenarios. Our results showed that negative impacts of stream temperature warming can be offset for almost all ecotypes if formerly occupied habitat above dams is made available. Our approach of combining spatial distribution and phenology data with spatially- and temporally-explicit temperature predictions enables researchers to examine thermal exposure of migrating populations that use seasonally-varying habitats.

Does genetic diversity protect host populations from parasites? A meta-analysis across natural and agricultural systems

If parasites transmit more readily between closely related hosts, then parasite burdens should decrease with increased genetic diversity of host populations. This important hypothesis is often accepted at face value - notorious epidemics of crop monocultures testify to the vulnerability of host populations that have been purged of diversity. Yet the relationship between genetic diversity and parasitism likely varies across contexts, differing between crop and non-crop hosts and between experimental and natural host populations. Here, we used a meta-analytic approach to ask if host diversity confers protection against parasites over the range of contexts in which it has been tested. We synthesized the results of 102 studies, comprising 2,004 effect sizes representing a diversity of approaches and host-parasite systems. Our results validate a protective effect of genetic diversity, while revealing significant variation in its strength across biological and empirical contexts. In experimental host populations, genetic diversity reduces parasitism by ~20% for non-crop hosts and by ~50% for crop hosts. In contrast, observational studies of natural host populations show no consistent relationship between genetic diversity and parasitism, with both strong negative and positive correlations reported. This result supports the idea that, if parasites preferentially attack close relatives, the correlation of genetic diversity with parasitism could be positive or negative depending upon the potential for host populations to evolve in response to parasite selection. Taken together, these results reinforce genetic diversity as a priority for both conservation and agriculture and emphasize the challenges inherent to drawing comparisons between controlled experimental populations and dynamic natural populations.

opencc-by-4.0Nov 2020View details →

zenodo36/100

Robust estimates of the true (population) infection rate for COVID-19: a backcasting approach

Differences in COVID-19 testing and tracing across countries, as well as changes in testing within each country over time, make it difficult to estimate the true (population) infection rate based on the confirmed number of cases obtained through RNA viral testing. We applied a backcasting approach to estimate a distribution for the true (population) cumulative number of infections (infected and recovered) for 15 developed countries. Our sample comprised countries with similar levels of medical care and with populations that have similar age distributions. Monte Carlo methods were used to robustly sample parameter uncertainty. We found a strong and statistically significant negative relationship between the proportion of the population who test positive and the implied true detection rate. Despite an overall improvement in detection rates as the pandemic has progressed, our estimates showed that, as at 31 August 2020, the true number of people to have been infected across our sample of 15 countries was 6.2 (95% CI: 4.3–10.9) times greater than the reported number of cases. In individual countries, the true number of cases exceeded the reported figure by factors that range from 2.6 (95% CI: 1.8–4.5) for South Korea to 17.5 (95% CI: 12.2–30.7) for Italy.

Population genetic structure and classification of cultivated and wild pea (Pisum sp.) based on morphological traits and SSR markers

Pea (Pisum sativum L.) is an important legume crop that is widely grown worldwide for human consumption and livestock feed. Despite extensive studies, the population genetic structure and classification of cultivated and wild pea (Pisum sp.) are remaining controversial. To characterize patterns of genetic and morphological variation and investigate the classification of Pisum, we conducted comprehensive population genetic analyses for 323 accessions from cultivated and wild pea representing three species of Pisum utilizing 34 morphological traits and 87 polymorphic SSR markers. First, we identified three distinct genetic groups among all samples. Group I was primarily composed of Pisum fulvum, Pisum abyssinicum and some wild P. sativum accessions, whereas groups II and III consisted of the two genetic groups under P. sativum representing different geographic distributions of cultivated pea. Analyses of morphological variation revealed significant differences among the three species. Second, among pea germplasms representing eight taxa of Pisum, P. fulvum and P. abyssinicum possessed unique genetic backgrounds and morphological characteristics, corroborating their independent species status. The intraspecific subdivisions of P. sativum described by some authors were not supported in this study, with the exception of several genotypes of P. sativum subsp. elatius that were clustered with P. fulvum and P. abyssinicum. Finally, we confirmed that the Chinese pea germplasm was genetically distinct and could be divided into two genetic groups, each of which included both spring-sowing and autumn-sowing ecotypes. These results provide a robust foundation for understanding pea domestication and the utilization of wild genetic resources of pea.

Microsatellite genotypes and associated data for: The contribution of clonality to population genetic structure in the sea anemone Diadumene lineata

Ecological and evolutionary processes differ depending on how genetic diversity is organized in space. For clonal organisms, the organization of both genetic and genotypic diversity can influence the fitness effects of competition, the mating system, and reproductive mode, which are key drivers of life cycle evolution. Understanding how individual reproductive behavior contributes to population genetic structure is essential for disentangling these forces, particularly in species with complex and plastic life cycles. The widespread sea anemone Diadumene lineata exhibits temperature-dependent fission which contributes to predictable variation in clonal rate along the Atlantic coast of the United States, part of its non-native range. Because warmer conditions lead to higher rates of clonality, we expected to find lower genotypic and genetic diversity in lower versus higher latitude populations. We developed primers for 11 microsatellite loci and genotyped 207 anemones collected from 8 sites ranging from Florida to Massachusetts. We found clonal influence at all sites, and as predicted, the largest clones were found at lower latitude sites. We also found genetic signatures of sex in the parts of the range where gametogenesis is most common. Evidence of sex outside the native range is novel for this species and provides insights into the dynamics of this successful invader. Our findings also illustrate challenges that partially clonal taxa pose for eco-evolutionary studies, such as difficulty sampling statistically robust numbers of genets and interpretating common population genetic metrics. For example, we found high among-locus variation in Fis, which makes the meaning of mean multilocus Fis unclear.

opencc-zeroDec 2019View details →

Centaurea population effects on nematode communities

Data set belonging to the study 'Plant population and soil origin effects on nematode community composition in the rhizosphere of a range-expanding plant species and a native congener'. In this study, we experimentally compared the development of nematode communities originating from northern and southern European soils in the rhizospheres of different populations of the range-expanding plant species Centaurea stoebe and the native plant species Centaurea jacea. The experiment was carried out in a greenhouse of the Netherlands Institute of Ecology (NIOO-KNAW; Wageningen, The Netherlands).

Population genomics reveals repeated signals of adaptive divergence in the Atlantic salmon of northeastern Europe

Our ability to examine genetic variation across entire genomes have enabled many studies searching for the genetic basis of local adaptation. These studies have identified numerous loci as candidates for differential local selection, however relatively few have examined the overlap among candidate loci identified from independent studies of the same species in different geographic areas or evolutionary lineages. We used an allelotyping approach with a 220K SNP array to characterize the population genetic structure of Atlantic salmon in northeastern Europe and ask whether the same genomic segments emerged as outliers among populations in different geographic regions. Genome-wide data recapitulated the phylogeographic structure previously inferred from mtDNA and microsatellite markers. Independent analyses of three genetically and geographically distinct groups of populations repeatedly inferred the same 17 haploblocks to contain loci under differential local selection. The most strongly supported of these replicated haploblocks had known strong associations with life history variation or immune response in Atlantic salmon. Our results are consistent with these genomic segments harbouring large-effect loci which have a major role in Atlantic salmon diversification and are ideal targets for validation studies.

opencc-by-4.0Nov 2020View details →

zenodo36/100

Using UCEs to track the influence of sea-level change on leafy seadragon populations

Data and code used in bioinformatic processing, bathymetry calculations, population genetic analyses and their output files. Ultraconserved Elements (UCEs) were sequenced in 68 individuals of leafy seadragons (Phycodurus eques, Syngnathidae) sampled across their range along the southern Australian coast. The repository contains A) Scripts to process the sequence data and the resulting <ul> <li>BAM read mapping files</li> <li>VCF files with SNPs before and after filtering</li> </ul>   B) Scripts, input files, and output files for the analyses to <ul> <li>reconstruct shallow water areas at different sea levels</li> <li>estimate population structure (PCA, DAPC, Structure, SVDquartets), and spatial genetic patterns (IBD plots, EEMS)</li> <li>calculate genetic diversity (individual-level heterozygosity, population-level heterozygosity, Tajima's D)</li> <li>perform phylogeographic modeling (DIYABC).</li> </ul>

Portfolio simplification arising from a century of change in salmon population diversity and artificial production

1. Population and life-history diversity can buffer species from environmental variability and contribute to long-term stability through differing responses to varying conditions akin to the stabilizing effect of asset diversity on financial portfolios. While it is well known that many salmon populations have declined in abundance over the last century, we understand less about how different dimensions of diversity may have shifted. Specifically, how has diminished wild abundance and increased artificial production (i.e., enhancement) changed portfolios of salmon populations, and how might such change influence fisheries and ecosystems? 2. We apply modern genetic tools to century-old sockeye salmon (Oncorhynchus nerka) scales from Canada's Skeena River watershed to (i) reconstruct historical abundance and age-trait data for 1913–1947 to compare with recent information, (ii) quantify changes in population and life-history diversity and the role of enhancement in population dynamics, and (iii) quantify the risk to fisheries and local ecosystems resulting from observed changes in diversity and enhancement. 3. The total number of wild sockeye returning to the Skeena River during the modern era is 69% lower than during the historical era; all wild populations have declined, several by more than 90%. However, enhancement of a single population has offset declines in wild populations such that aggregate abundances now are similar to historical levels. 4. Population diversity has declined by 70%, and life-history diversity has shifted: populations are migrating from freshwater at an earlier age, and spending more time in the ocean. There also has been a contraction in abundance throughout the watershed, which likely has decreased the spatial extent of salmon provisions to Indigenous fisheries and local ecosystems. Despite the erosion of portfolio strength that this salmon complex hosted a century ago, total returns now are no more variable than they were historically perhaps in part due to the stabilizing effect of artificial production. 5. Policy implications. Our study provides a rare example of the extent of erosion of within-species biodiversity over the last century of human influence. Rebuilding a diversity of abundant wild populations – that is, maintaining functioning portfolios - may help ensure that watershed complexes like the Skeena are robust to global change.

Populations of arable weed species show intra-specific variability in germination base temperature but not in early growth rate

Key plant traits affecting growth performance can differ among and within species, influencing competitive plant community dynamics. We determined the intra-specific variability of germination base temperature among 13 arable weed species and the seedlings' early post-emergence relative growth rate among 21 species in climate chamber and green house experiments. Intra-specific variability was quantified with two seed populations (originating from contrasting climate in Germany & France) for the germination base temperature of 6 species and for the early growth rate of 16 species. Inter-specific variability for both traits was always higher than intra-specific variability. Within a given species, we found that germination base temperatures were higher in seeds stemming from colder climate populations. Seedling relative growth rates did not differ between seed populations. Models simulating weed growth should reflect these differences in germination traits among populations, especially when they are used for weed community assembly studies in a local to regional extent.

Migration trajectories of the diamondback moth Plutella xylostella in China inferred from population genomic variation

BACKGROUND: The diamondback moth (DBM), Plutella xylostella (Lepidoptera: Plutellidae), is a notorious pest of cruciferous plants. In temperate areas, annual populations of DBM originate from adult migrants. However, the source populations and migration trajectories of immigrants remain unclear. Here, we investigated migration trajectories of DBM in China with genome-wide single nucleotide polymorphisms (SNPs) genotyped using double-digest RAD (ddRAD) sequencing. We first analyzed patterns of spatial and temporal genetic structure among southern source and northern recipient populations, then inferred migration trajectories into northern regions using discriminant analysis of principal components (DAPC), assignment tests and spatial kinship patterns. RESULTS: Temporal genetic differentiation among populations was low, indicating sources of recipient populations and migration trajectories are stable. Spatial genetic structure indicated three genetic clusters in the southern source populations. Assignment tests linked northern populations to the Sichuan cluster, and central-eastern populations to the South and Yunnan clusters, indicating that Sichuan populations are sources of northern immigrants and South and Yunnan populations are sources of central-eastern populations. First-order (full-sib) and second-order (half-sib) kin pairs were always found within populations, but about 35-40% of third-order (cousin) pairs were found in different populations. Closely related individuals in different populations were in about 35-40% of cases found at distances of 900 to 1500 km, while some were separated by over 2000 km. CONCLUSION: This study unravels seasonal migration patterns in the DBM. We demonstrate how careful sampling and population genomic analyses can be combined to help understand cryptic migration patterns in insects.

Data from: Heterozigosity-fitness correlations in a continental island population of Thorn-tailed Rayadito

Heterozygosity-fitness correlations (HFCs) have been used to monitor the effects of inbreeding in threatened populations. HFCs can also be useful to investigate the potential effects of inbreeding in isolated relict populations of long-term persistence, and to better understand the role of inbreeding and outbreeding as drivers of changes in genetic diversity. We studied a continental island population of thorn-tailed rayadito (Aphrastura spinicauda) inhabiting the relict forest of Fray Jorge National Park, north-central Chile. This population has experienced a long-term, gradual process of isolation since the end of the Tertiary. Using 10 years of field data in combination with molecular techniques, we tested for HFCs to assess the importance of inbreeding depression. If inbreeding depression is important, we predict a positive relationship between individual heterozygosity and fitness-related traits. We genotyped 183 individuals at 12 polymorphic microsatellite loci, and used seven measures of reproductive success and estimates of apparent survival to calculate HFCs. We found weak to moderate statistical support (P-values between 0.05 and 0.01) for a linear effect of female multi-locus heterozygosity (MLH) on clutch size, and non-linear effects on laying date and fledging success. While more heterozygous females laid smaller clutches, non-linear effects indicated that females with intermediate values of MLH started laying earlier and had higher fledging success. We found no evidence for effects of MLH on annual fecundity or on apparent survival. Our results along with the long-term demographic stability of the study population contradict the hypothesis that inbreeding depression occurs in this population.

Data from: Large-scale meta-analysis on rheumatoid arthritis across East Asian and European populations

Objective: Nearly 110 susceptibility loci for rheumatoid arthritis (RA) with modest effect sizes have been identified by population-based genetic association studies, suggesting a large number of undiscovered variants behind a highly polygenic genetic architecture of RA. Here, we performed the largest-ever trans-ancestral meta-analysis with the aim to identify new RA loci and to better understand RA biology underlying genetic associations. Methods: Genome-wide RA association summary statistics in three large case-control collections consisting of 311,292 individuals of Korean, Japanese, and European populations were used in an inverse-variance-weighted fixed-effects meta-analysis. Several computational analyses using public omics resources were conducted to prioritize causal variants and genes, RA variant-implicating features (tissues, pathways, and transcription factors), and potentially repurposable drugs for RA treatment. Results: We identified 11 new RA susceptibility loci that explained 6.9% and 1.8% of the SNP-based heritability in East Asians and Europeans, respectively, and confirmed 71 known non-HLA susceptibility loci, identifying 90 independent association signals. The RA variants were preferentially located in binding sites of various transcription factors and in cell type-specific transcription-activation histone marks that simultaneously highlighted the importance of CD4+ T-cell activation and the potential role of non-immune organs in RA pathogenesis. A total of 615 plausible effector genes, based on gene-based associations, expression-associated variants, and chromatin interaction, included targets of drugs approved for RA treatments and potentially repurposable drugs approved for other indications. Conclusion: Our findings provide useful insights regarding RA genetic etiology and variant-driven RA pathogenesis.