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Purpose: Population-based studies on the associations of plant-based foods, red meat or dairy with gut microbiome are scarce. We examined whether the consumption of plant-based foods (vegetables, potatoes, fruits, cereals), red and processed meat (RPM) or dairy (fermented milk, cheese, other dairy products) are related to gut microbiome in Finnish adults. Methods: We utilized data from the National FINRISK/FINDIET 2002 Study (n = 1273, aged 25–64 years, 55% women). Diet was assessed with 48-hour dietary recalls. Gut microbiome was analyzed using shallow shotgun sequencing. We applied multivariate analyses with linear models and permutational ANOVAs adjusted for relevant confounders. Results: Fruit consumption was positively (beta = 0.03, SE = 0.01, P = 0.04), while a dairy subgroup including milk, cream and ice-creams was inversely associated (beta=-0.03, SE 0.01, P = 0.02) with intra-individual gut microbiome diversity (alpha-diversity). Plant-based foods (R2 = 0.001, P = 0.03) and dairy (R2 = 0.002, P = 0.01) but not RPM (R2 = 0.001, P = 0.38) contributed to the compositional differences in gut microbiome (beta-diversity). Plant-based foods were associated with several butyrate producers/cellulolytic species including Roseburia hominis. RPM associations included an inverse association with R. hominis. Dairy was positively associated with several lactic producing/probiotic species including Lactobacillus delbrueckii and potentially opportunistic pathogens including Citrobacter freundii. Dairy, fermented milk, vegetables, and cereals were associated with specific microbial functions. Conclusion: Our results suggest a potential association between plant-based foods and dairy or their subgroups with microbial diversity measures. Furthermore, our findings indicated that all the food groups were associated with distinct overall microbial community compositions. Plant-based food consumption particularly was associated with a larger number of putative beneficial species. [ABSTRACT FROM AUTHOR]

Studies using 16S rRNA and shotgun metagenomics typically yield different results, usually attributed to PCR amplification biases. We introduce Greengenes2, a reference tree that unifies genomic and 16S rRNA databases in a consistent, integrated resource. By inserting sequences into a whole-genome phylogeny, we show that 16S rRNA and shotgun metagenomic data generated from the same samples agree in principal coordinates space, taxonomy and phenotype effect size when analyzed with the same tree. A comprehensive microbial resource reconciles genomic and 16S rRNA data in a single tree. [ABSTRACT FROM AUTHOR]

The chromium (Cr) limit values are currently tightened to 25 μg L−1 (EU), 5 μg L−1 (Germany), and possibly 10 μg L−1 Cr(VI) (California). The combined process of chemical reduction, coagulation, and biotic filtration (RCbF) efficiently removes Cr(VI) in drinking water. In this study, redox-active substances (O2, NO3−, Fe2+, MnO2) were investigated concerning their effect on the RCbF process. The experiments were performed at two-stage pilot waterworks for biological iron and manganese removal. O2 or NO3− as oxidants affected the RCbF process, neither by consumption of the reductant Fe(II) nor by re-oxidation of already formed Cr(III) in the supernatant of the filter bed. However, the oxidation of Cr(III) by O2 to Cr(VI) with MnO2 as a mediator was identified as potential risk for Cr breakthrough. Up to one third of the initial Cr(III) concentration was oxidized to Cr(VI) in the second filter bed within a contact time of only 5 min. The kinetically relevant mechanism seemed to be the formation of Cr(III)Fe(III)-hydroxides and not the reduction of Cr(VI) by Fe(II). Further, the mixing of Cr(VI) containing raw water with Fe(II) containing groundwater was determined as a chemical-free alternative for the RCbF process, depending on the resulting Fe(II) concentration after mixing. [ABSTRACT FROM AUTHOR]

Selenium (Se) is essential to human health, yet harmful in high doses. Of the water-soluble Se redox species, Se(IV) readily adsorbs onto iron and aluminium oxides. Se(VI), the dominant form in oxygenated waters, is more mobile and less readily adsorbed. In this study, the removal of Se(VI) by reduction with Fe(II) to Se(IV) and subsequent adsorption onto iron hydroxides is investigated in a pilot plant for biological iron and manganese removal from groundwater to investigate an economical approach for Se removal during drinking water production. While Se(IV) is removed by up to 90%, Se(VI) shows no removal over 48 h. In batch-shaking tests, the adsorption of Se(IV) and Se(VI) onto iron hydroxides with and without addition of Fe(II) or dithionite as reducing agents was studied. Se(IV) was removed to a greater extent by adsorption than Se(VI) (7% and 2.6%, respectively, at a starting concentration of 0.1 mg/L) and the addition of reducing agents resulted in no significantly higher removal of Se(VI). Reducing Se(VI) with Fe(II) or dithionite and consequent adsorption onto iron hydroxides can therefore be excluded as viable removal mechanism for Se(VI). [ABSTRACT FROM AUTHOR]

Data resource basics Nationwide health-related registry data provide comprehensive insights into population health and, combined with other data such as demographics, familial relations and socioeconomic data, enable the exploration of various dimensions of human behaviour and health. Data resource access Access to FinRegistry data can be obtained by submitting a data permit application for individual-level data to the Finnish Social and Health Data Permit Authority Findata [https://asiointi.findata.fi]. Data resource use FinRegistry is a curated, nationwide, register-based data resource for developing statistical and machine learning models, performing high-throughput epidemiological analyses and deriving outcome-specific prediction models. Key Features FinRegistry is a curated, nationwide, register-based data resource for developing statistical and machine learning models, performing high-throughput epidemiological analyses and deriving outcome-specific prediction models. [Extracted from the article]

Aims: Atrial fibrillation (AF) is becoming increasingly common. Traditional cardiovascular risk factors (CVRF) do not explain all AF cases. Blood‐based biomarkers reflecting cardiac injury such as high‐sensitivity troponin I (hsTnI) may help close this gap. Methods: We investigated the predictive ability of hsTnI for incident AF in 45,298 participants (median age 51.4 years, 45.0% men) across European community cohorts in comparison to CVRF and established biomarkers (C‐reactive protein, N‐terminal pro B‐type natriuretic peptide). Results: During a median follow‐up of 7.7 years, 1734 (3.8%) participants developed AF. Those in the highest hsTnI quarter (≥4.2 ng/L) had a 3.91‐fold (95% confidence interval (CI) 3.30, 4.63; p <.01) risk for developing AF compared to the lowest quarter (<1.4 ng/L). In multivariable‐adjusted Cox proportional hazards models a statistically significant association was seen between hsTnI and AF (hazard ratio (HR) per 1 standard deviation (SD) increase in log10(hsTnI) 1.08; 95% CI 1.01, 1.16; p =.03). Inclusion of hsTnI did improve model discrimination (C‐index CVRF 0.811 vs. C‐index CVRF and hsTnI 0.813; p <.01). Higher hsTnI concentrations were associated with heart failure (HR per SD 1.37; 95% CI 1.12, 1.68; p <.01) and overall mortality (HR per SD 1.24; 95% CI 1.09, 1.41; p <.01). Conclusion: hsTnI as a biomarker of myocardial injury does not improve prediction of AF incidence beyond classical CVRF and NT‐proBNP. However, it is associated with the AF‐related disease heart failure and mortality likely reflecting underlying subclinical cardiovascular impairment. [ABSTRACT FROM AUTHOR]

Inflammatory and infectious upper respiratory diseases (ICD-10: J30-J39), such as diseases of the sinonasal tract, pharynx and larynx, are growing health problems yet their genomic similarity is not known. We analyze genome-wide association to eight upper respiratory diseases (61,195 cases) among 260,405 FinnGen participants, meta-analyzing diseases in four groups based on an underlying genetic correlation structure. Aiming to understand which genetic loci contribute to susceptibility to upper respiratory diseases in general and its subtypes, we detect 41 independent genome-wide significant loci, distinguishing impact on sinonasal or pharyngeal diseases, or both. Fine-mapping implicated non-synonymous variants in nine genes, including three linked to immune-related diseases. Phenome-wide analysis implicated asthma and atopic dermatitis at sinonasal disease loci, and inflammatory bowel diseases and other immune-mediated disorders at pharyngeal disease loci. Upper respiratory diseases also genetically correlated with autoimmune diseases such as rheumatoid arthritis, autoimmune hypothyroidism, and psoriasis. Finally, we associated separate gene pathways in sinonasal and pharyngeal diseases that both contribute to type 2 immunological reaction. We show shared heritability among upper respiratory diseases that extends to several immune-mediated diseases with diverse mechanisms, such as type 2 high inflammation.The shared genetics between upper respiratory diseases have not been well studied. Here, the authors find shared and distinct genetic loci for pharyngeal and sinonasal inflammatory conditions, which show shared heritability with autoimmune conditions and immune deficiency, highlighting the TNFR2 pathway. [ABSTRACT FROM AUTHOR]

Otosclerosis is one of the most common causes of conductive hearing loss, affecting 0.3% of the population. It typically presents in adulthood and half of the patients have a positive family history. The pathophysiology of otosclerosis is poorly understood. A previous genome-wide association study (GWAS) identified a single association locus in an intronic region of RELN. Here, we report a meta-analysis of GWAS studies of otosclerosis in three population-based biobanks comprising 3504 cases and 861,198 controls. We identify 23 novel risk loci (p < 5 × 10−8) and report an association in RELN and three previously reported candidate gene or linkage regions (TGFB1, MEPE, and OTSC7). We demonstrate developmental stage-dependent immunostaining patterns of MEPE and RUNX2 in mouse otic capsules. In most association loci, the nearest protein-coding genes are implicated in bone remodelling, mineralization or severe skeletal disorders. We highlight multiple genes involved in transforming growth factor beta signalling for follow-up studies.Otosclerosis is a common form of hearing loss, with an unclear genetic etiology. Here, the authors perform a genome-wide association study meta-analysis of otosclerosis identifying 27 genetic loci, pointing to genes involved in bone remodeling, skeletal disorders and transforming growth factor β signaling. [ABSTRACT FROM AUTHOR]

Pharmaceuticals such as antidepressants are designed to be bioactive at low concentrations. According to their mode of action, they can also influence non-target organisms due to the phylogenetic conservation of molecular targets. In addition to the pollution by environmental chemicals, the topic of microplastics (MP) in the aquatic environment came into the focus of scientific and public interest. The aim of the present study was to investigate the influence of the antidepressant amitriptyline in the presence and absence of irregularly shaped polystyrene MP as well as the effects of MP alone on juvenile brown trout (Salmo trutta f. fario). Fish were exposed to different concentrations of amitriptyline (nominal concentrations between 1 and 1000 µg/L) and two concentrations of MP (104 and 105 particles/L; <50 µm) for three weeks. Tissue cortisol concentration, oxidative stress, and the activity of two carboxylesterases and of acetylcholinesterase were assessed. Furthermore, the swimming behavior was analyzed in situations with different stress levels. Exposure to amitriptyline altered the behavior and increased the activity of acetylcholinesterase. Moreover, nominal amitriptyline concentrations above 300 µg/L caused severe acute adverse effects in fish. MP alone did not affect any of the investigated endpoints. Co-exposure caused largely similar effects such as the exposure to solely amitriptyline. However, the effect of amitriptyline on the swimming behavior during the experiment was alleviated by the higher MP concentration. [ABSTRACT FROM AUTHOR]

Purpose: To investigate whether exposure to systemic antibiotics influences the risk of developing type 2 diabetes and overweight/obesity. Methods: The study sample comprised 2209 (110 with incident diabetes) participants from the population-based Cardiovascular Risk in Young Finns Study (YFS) aged 24–39 years in 2001. The exposure was national linked register data on purchased antibiotic courses between 1993 and 2001. Clinical examinations including BMI were conducted in 2001, 2007 and 2011. Participants with prevalent diabetes in 2001 were excluded. Data on type 2 diabetes was also obtained from two national registers until 2017. Data from four population-based National FINRISK studies were used for replication (N = 24,674, 1866 with incident diabetes). Results: Prior antibiotic exposure (> 5 versus 0–1 antibiotic courses) was associated with subsequent type 2 diabetes in both YFS (OR 2.29; 95%CI 1.33–3.96) and FINRISK (HR 1.73; 95%CI 1.51–1.99). An increased risk for type 2 diabetes was observed in YFS (OR 1.043; 95%CI 1.013–1.074) and FINRISK (HR 1.022; 95%CI 1.016–1.029) per course. Exposure to antibiotics increased the risk of overweight/obesity (BMI > 25 kg/m2) after a 10-year follow-up in YFS (OR 1.043; 95%CI 1.019–1.068) and in FINRISK (OR 1.023; 95%CI 1.018–1.029) at baseline per antibiotic course. Adjustments for confounders from early life in YFS and at baseline in FINRISK, including BMI, socioeconomic status, smoking, insulin, blood pressure, and physical activity, did not appreciably alter the findings. Conclusion: Our results show that exposure to antibiotics was associated with increased risk for future type 2 diabetes and overweight/obesity and support judicious antibiotic prescribing. [ABSTRACT FROM AUTHOR]

As there is still little knowledge of interactions between microplastics (MP) and hydrophilic compounds, we propose ways the toxicity of hydrophilic pesticides can be modulated by MP, when sorption can be excluded. Larvae of Chironomus riparius were exposed to thiacloprid (TH, 1 µg/L) and polystyrene microplastic particles (PS; <50 µm; 150,000 and 1,000,000 particles/L) for 96 h, solely or in co-exposure. Burrowing behavior and mortality were observed. Larvae in treatments containing PS established themselves quicker in the sediment and kept the ability to rebury for a longer time compared to control and TH, respectively. While TH elevated the mortality, exposure to PS alone did not affect the survival of the larvae. In co-exposure of TH and PS, a concentration of 150,000 particles/L significantly reduced the toxicity of 1 µg/L TH after 96 h, an effect that was not observed at 1,000,000 particles/L. Therefore, we hypothesize that this modulation of the toxicity of TH eventually may have resulted from a combination of a 'protective MP layer' in the gut and a higher retention time of particles in larvae exposed to 150,000 particles/L than in those exposed to 1,000,000 particles/L due to the lower number of ingestible particles in the former. [ABSTRACT FROM AUTHOR]

Objective: To examine the previously unknown long-term association between gut microbiome composition and incident type 2 diabetes in a representative population cohort.Research Design and Methods: We collected fecal samples from 5,572 Finns (mean age 48.7 years; 54.1% women) in 2002 who were followed up for incident type 2 diabetes until 31 December 2017. The samples were sequenced using shotgun metagenomics. We examined associations between gut microbiome composition and incident diabetes using multivariable-adjusted Cox regression models. We first used the eastern Finland subpopulation to obtain initial findings and validated these in the western Finland subpopulation.Results: Altogether, 432 cases of incident diabetes occurred over the median follow-up of 15.8 years. We detected four species and two clusters consistently associated with incident diabetes in the validation models. These four species were Clostridium citroniae (hazard ratio [HR] 1.21; 95% CI 1.04-1.42), C. bolteae (HR 1.20; 95% CI 1.04-1.39), Tyzzerella nexilis (HR 1.17; 95% CI 1.01-1.36), and Ruminococcus gnavus (HR 1.17; 95% CI 1.01-1.36). The positively associated clusters, cluster 1 (HR 1.18; 95% CI 1.02-1.38) and cluster 5 (HR 1.18; 95% CI 1.02-1.36), mostly consisted of these same species.Conclusions: We observed robust species-level taxonomic features predictive of incident type 2 diabetes over long-term follow-up. These findings build on and extend previous mainly cross-sectional evidence and further support links between dietary habits, metabolic diseases, and type 2 diabetes that are modulated by the gut microbiome. The gut microbiome can potentially be used to improve disease prediction and uncover novel therapeutic targets for diabetes. [ABSTRACT FROM AUTHOR]

To evaluate risk factors for major adverse cardiac event (MACE) after the first acute coronary syndrome (ACS) and to examine the prevalence of risk factors in post-ACS patients. We used Finnish population-based myocardial infarction register, FINAMI, data from years 1993–2011 to identify survivors of first ACS (n = 12686), who were then followed up for recurrent events and all-cause mortality for three years. Finnish FINRISK risk factor surveys were used to determine the prevalence of risk factors (smoking, hyperlipidaemia, diabetes and blood pressure) in post-ACS patients (n = 199). Of the first ACS survivors, 48.4% had MACE within three years of their primary event, 17.0% were fatal. Diabetes (p = 4.4 × 10−7), heart failure (HF) during the first ACS attack hospitalization (p = 6.8 × 10−15), higher Charlson index (p = 1.56 × 10−19) and older age (p =.026) were associated with elevated risk for MACE in the three-year follow-up, and revascularization (p =.0036) was associated with reduced risk. Risk factor analyses showed that 23% of ACS survivors continued smoking and cholesterol levels were still high (>5mmol/l) in 24% although 86% of the patients were taking lipid lowering medication. Diabetes, higher Charlson index and HF are the most important risk factors of MACE after the first ACS. Cardiovascular risk factor levels were still high among survivors of first ACS. [ABSTRACT FROM AUTHOR]

Background Diet has a major influence on the human gut microbiota, which has been linked to health and disease. However, epidemiological studies on associations of a healthy diet with the microbiota utilizing a whole-diet approach are still scant. Objectives To assess associations between healthy food choices and human gut microbiota composition, and to determine the strength of association with functional potential. Methods This population-based study sample consisted of 4930 participants (ages 25–74; 53% women) in the FINRISK 2002 study. Intakes of recommended foods were assessed using a food propensity questionnaire, and responses were transformed into healthy food choices (HFC) scores. Microbial diversity (alpha diversity) and compositional differences (beta diversity) and their associations with the HFC score and its components were assessed using linear regression. Multiple permutational multivariate ANOVAs were run from whole-metagenome shallow shotgun–sequenced samples. Associations between specific taxa and HFC were analyzed using linear regression. Functional associations were derived from Kyoto Encyclopedia of Genes and Genomes orthologies with linear regression models. Results Both microbial alpha diversity (β/SD, 0.044; SE, 6.18 × 10−5; P  = 2.21 × 10−3) and beta diversity (R 2, 0.12; P  ≤ 1.00 × 10−3) were associated with the HFC score. For alpha diversity, the strongest associations were observed for fiber-rich breads, poultry, fruits, and low-fat cheeses (all positive). For beta diversity, the most prominent associations were observed for vegetables, followed by berries and fruits. Genera with fiber-degrading and SCFA-producing capacities were positively associated with the HFC score. The HFC score was associated positively with functions such as SCFA metabolism and synthesis, and inversely with functions such as fatty acid biosynthesis and the sulfur relay system. Conclusions Our results from a large, population-based survey confirm and extend findings of other, smaller-scale studies that plant- and fiber-rich dietary choices are associated with a more diverse and compositionally distinct microbiota, and with a greater potential to produce SCFAs. [ABSTRACT FROM AUTHOR]

Introduction: Depression in Alzheimer's disease (AD) differs from major depression in terms of clinical features and treatment. Antidepressants do not provide the expected benefits in depressive symptoms accompanying cognitive decline in AD, suggesting distinct mechanisms. Emerging research suggest that compromised mitophagy, the selective removal of damaged mitochondria, may contribute to the pathogenesis of AD. However boosting nicotinamide adenine dinucleotide (NAD+) to induce mitophagy reduces amyloid β (Aβ) aggregation and enhances cognitive function in AD models (Kerr et al.,Trends Neurosci 2017;40:151-66). Nevertheless, data on NAD's impact on depression in AD remains limited. Objectives: This study aimed to examine the impact of the NAD+ precursor nicotinamide riboside (NR) on cognitive and neuropsychiatric symptoms in a AD rat model. Methods: To induce the AD, a single dose of 5 μl Aβ1-42 was injected into each lateral ventricle of rats (day 0), while the control group received an intracerebroventricular (icv) saline (0.9%NaCl).Four experimental groups were designed: control (icv saline+po saline), NR (icv saline+po NR), Aβ (icv Aβ+po saline), and Aβ+NR (icv Aβ+po NR).After the injection, to reduce Aβ clearance (Kang et al. Science. 2009;32 1005-7.) rats were subjected to 96 hours of sleep deprivation.Starting from day 6, rats were given either 700 mg/kg oral NR or saline, and handling test scores were recorded daily.The procedures were repeated daily until the rats were sacrificed on day 28.Behavioral experiments were randomly conducted at the end, and statistical analysis was performed using repeated measures ANOVA, followed by the Tukey post hoc test. Results: Passive avoidance test results showed that the Aβ group had the shortest latency to enter the dark area. However, the Aβ+NR group exhibited a prolonged latency compared to the Aβ group (F(3,2)=5.5;p<0.05). Aβ injection induced depressive-like behavior in rats, as indicated by the forced swim test (FST) for behavioral despair and the sucrose preference test (SPT) for anhedonia. In AD rats treated with NR (Aβ+NR), Aβ-induced depressive-like behavior was reduced, with lower FST immobility scores (F(3,2)=6.2;p<0.05) and increased sucrose preference in the SPT (F(3,2)=7.5;p<0.05). There were no significant differences in anxiety-like behaviors among the groups, assessed by the time spent in the open arm in the elevated plus maze test (F(3,2)=1.9;p>0.05). During the 28-day monitoring period, the Aβ+NR group of rats exhibited a more rapid decrease in aggression levels compared to the other groups in the handling test. This decrease was significant between days 7 and 10 compared to the Aβ group (F(48,5)=1.5;p<0.05). Conclusions: NR improved memory, reduced depressive behavior, and lowered aggression in AD rats. This suggests that NAD+ precursor NR effectively treats cognitive decline and neuropsychiatric symptoms in an AD model. Disclosure of Interest: None Declared [ABSTRACT FROM AUTHOR]

The collection of fecal material and developments in sequencing technologies have enabled standardised and non-invasive gut microbiome profiling. Microbiome composition from several large cohorts have been cross-sectionally linked to various lifestyle factors and diseases. In spite of these advances, prospective associations between microbiome composition and health have remained uncharacterised due to the lack of sufficiently large and representative population cohorts with comprehensive follow-up data. Here, we analyse the long-term association between gut microbiome variation and mortality in a well-phenotyped and representative population cohort from Finland (n = 7211). We report robust taxonomic and functional microbiome signatures related to the Enterobacteriaceae family that are associated with mortality risk during a 15-year follow-up. Our results extend previous cross-sectional studies, and help to establish the basis for examining long-term associations between human gut microbiome composition, incident outcomes, and general health status. Gut microbiome composition has a role in health and disease. Here the authors show that microbiome signatures related to the Enterobacteriaceae family are associated with cause-specific mortality risk in a well phenotyped Finish population over a 15-year follow-up. [ABSTRACT FROM AUTHOR]

Aims: Classical cardiovascular risk factors (CVRFs), biomarkers, and common genetic variation have been suggested for risk assessment of atrial fibrillation (AF). To evaluate their clinical potential, we analysed their individual and combined ability of AF prediction.Methods and Results: In N = 6945 individuals of the FINRISK 1997 cohort, we assessed the predictive value of CVRF, N-terminal pro B-type natriuretic peptide (NT-proBNP), and 145 recently identified single-nucleotide polymorphisms (SNPs) combined in a developed polygenic risk score (PRS) for incident AF. Over a median follow-up of 17.8 years, n = 551 participants (7.9%) developed AF. In multivariable-adjusted Cox proportional hazard models, NT-proBNP [hazard ratio (HR) of log transformed values 4.77; 95% confidence interval (CI) 3.66-6.22; P < 0.001] and the PRS (HR 2.18; 95% CI 1.88-2.53; P < 0.001) were significantly related to incident AF. The discriminatory ability improved asymptotically with increasing numbers of SNPs. Compared with a clinical model, AF risk prediction was significantly improved by addition of NT-proBNP and the PRS. The C-statistic for the combination of CVRF, NT-proBNP, and the PRS reached 0.83 compared with 0.79 for CVRF only (P < 0.001). A replication in the Dutch Prevention of REnal and Vascular ENd-stage Disease (PREVEND) cohort revealed similar results. Comparing the highest vs. lowest quartile, NT-proBNP and the PRS both showed a more than three-fold increased AF risk. Age remained the strongest risk factor with a 16.7-fold increased risk of AF in the highest quartile.Conclusion: The PRS and the established biomarker NT-proBNP showed comparable predictive ability. Both provided incremental predictive value over standard clinical variables. Further improvements for the PRS are likely with the discovery of additional SNPs. [ABSTRACT FROM AUTHOR]

Summary: Microbial communities exhibit spatial structure at different scales, due to constant interactions with their environment and dispersal limitation. While this spatial structure is often considered in studies focusing on free‐living environmental communities, it has received less attention in the context of host‐associated microbial communities or microbiota. The wider adoption of methods accounting for spatial variation in these communities will help to address open questions in basic microbial ecology as well as realize the full potential of microbiome‐aided medicine. Here, we first overview known factors affecting the composition of microbiota across diverse host types and at different scales, with a focus on the human gut as one of the most actively studied microbiota. We outline a number of topical open questions in the field related to spatial variation and patterns. We then review the existing methodology for the spatial modelling of microbiota. We suggest that methodology from related fields, such as systems biology and macro‐organismal ecology, could be adapted to obtain more accurate models of spatial structure. We further posit that methodological developments in the spatial modelling and analysis of microbiota could in turn broadly benefit theoretical and applied ecology and contribute to the development of novel industrial and clinical applications. [ABSTRACT FROM AUTHOR]

Protein-truncating variants (PTVs) affecting dyslipidemia risk may point to therapeutic targets for cardiometabolic disease. Our objective was to identify PTVs that were associated with both lipid levels and the risk of coronary artery disease (CAD) or type 2 diabetes (T2D) and assess their possible associations with risks of other diseases. To achieve this aim, we leveraged the enrichment of PTVs in the Finnish population and tested the association of low-frequency PTVs in 1,209 genes with serum lipid levels in the Finrisk Study (n = 23,435). We then tested which of the lipid-associated PTVs were also associated with the risks of T2D or CAD, as well as 2,683 disease endpoints curated in the FinnGen Study (n = 218,792). Two PTVs were associated with both lipid levels and the risk of CAD or T2D: triglyceride-lowering variants in ANGPTL8 (-24.0[-30.4 to -16.9] mg/dL per rs760351239-T allele, P = 3.4 × 10−9) and ANGPTL4 (-14.4[-18.6 to -9.8] mg/dL per rs746226153-G allele, P = 4.3 × 10−9). The risk of T2D was lower in carriers of the ANGPTL4 PTV (OR = 0.70[0.60–0.81], P = 2.2 × 10−6) than noncarriers. The odds of CAD were 47% lower in carriers of a PTV in ANGPTL8 (OR = 0.53[0.37–0.76], P = 4.5 × 10−4) than noncarriers. Finally, the phenome-wide scan of the ANGPTL8 PTV showed that the ANGPTL8 PTV carriers were less likely to use statin therapy (68,782 cases, OR = 0.52[0.40–0.68], P = 1.7 × 10−6) compared to noncarriers. Our findings provide genetic evidence of potential long-term efficacy and safety of therapeutic targeting of dyslipidemias. Author summary: Studying the health impacts of protein-truncating variants (PTVs) enables detecting the health impact of drugs that inhibit these same genes. Our study aimed to expand our knowledge of genes associated with cardiometabolic disease, along with the side effects of these genes. To detect PTVs associated with cardiometabolic disease, we first performed a genome-wide scan of PTVs associated with serum lipid levels in Finns. We found PTVs in two genes highly enriched in Finns, which were associated with both serum lipid levels and a lower risk of type 2 diabetes or coronary artery disease: ANGPTL4 and ANGPTL8. To evaluate the other health effects of these PTVs, we performed an association scan between the PTVs and 2,683 disease endpoints curated in the FinnGen Study (n = 218,792). We demonstrate that using human populations with PTV-enrichment, such as Finns, offers considerable boosts in statistical power to detect potential long-term efficacy and safety of pharmacologically targeting genes. [ABSTRACT FROM AUTHOR]

Information about individual-level genetic ancestry is central to population genetics, forensics and genomic medicine. So far, studies have typically considered genetic ancestry on a broad continental level, and there is much less understanding of how more detailed genetic ancestry profiles can be generated and how accurate and reliable they are. Here, we assess these questions by developing a framework for individual-level ancestry estimation within a single European country, Finland, and we apply the framework to track changes in the fine-scale genetic structure throughout the 20th century. We estimate the genetic ancestry for 18,463 individuals from the National FINRISK Study with respect to up to 10 genetically and geographically motivated Finnish reference groups and illustrate the annual changes in the fine-scale genetic structure over the decades from 1920s to 1980s for 12 geographic regions of Finland. We detected major changes after a sudden, internal migration related to World War II from the region of ceded Karelia to the other parts of the country as well as the effect of urbanization starting from the 1950s. We also show that while the level of genetic heterogeneity in general increases towards the present day, its rate of change has considerable differences between the regions. To our knowledge, this is the first study that estimates annual changes in the fine-scale ancestry profiles within a relatively homogeneous European country and demonstrates how such information captures a detailed spatial and temporal history of a population. We provide an interactive website for the general public to examine our results. Author summary: We have inherited our genomes from our parents, who, in turn, inherited their genomes from their parents, etc. Hence, a comparison between genomes of present day individuals reveals genetic population structure due to the varying levels of genetic relatedness among the individuals. We have utilized over 18,000 Finnish samples to characterize the fine-scale genetic population structure in Finland starting from a binary East-West division and ending up with 10 Finnish source populations. Furthermore, we have applied the resulting ancestry information to generate records of how the population structure has evolved each year between 1923 and 1987 in 12 geographical regions of Finland. For example, the war-related evacuation of Karelians from Southeast Finland to other parts of the country show up as a clear, sudden increase in the Evacuated ancestry elsewhere in Finland between 1939 and 1945. Additionally, different regions of Finland show very different levels of genetic mixing in 1900s, from little mixed regions like Ostrobothnia to highly mixed regions like Southwestern Finland. To distribute the results among general public, we provide an interactive website for browsing the municipality and region-level genetic ancestry profiles at https://geneviz.aalto.fi/genetic_ancestry_finland/ [ABSTRACT FROM AUTHOR]

Objective: This study aimed to investigate the role of cytokines as intermediates in the pathway from increased adiposity to disease.Methods: BMI and circulating levels of up to 41 cytokines were measured in individuals from three Finnish cohort studies (n = 8,293). Mendelian randomization (MR) was used to assess the impact of BMI on circulating cytokines and the impact of BMI-driven cytokines on risk of obesity-related diseases.Results: Observationally, BMI was associated with 19 cytokines. For every SD increase in BMI, causal effect estimates were strongest for hepatocyte growth factor, monocyte chemotactic protein-1 (MCP-1), and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and were as ratios of geometric means 1.13 (95% CI: 1.08-1.19), 1.08 (95% CI: 1.04-1.14), and 1.13 (95% CI: 1.04-1.21), respectively. TRAIL was associated with a small increase in the odds of coronary artery disease (odds ratio: 1.03; 95% CI: 1.00-1.06). There was inconsistent evidence for a protective role of MCP-1 against inflammatory bowel diseases.Conclusions: Observational and MR estimates of the effect of BMI on cytokine levels were generally concordant. There was little evidence for an effect of raised levels of BMI-driven cytokines on disease. These findings illustrate the challenges of MR when applied in the context of molecular mediation. [ABSTRACT FROM AUTHOR]

To evaluate risk factors for major adverse cardiac event (MACE) after the first acute coronary syndrome (ACS) and to examine the prevalence of risk factors in post-ACS patients. We used Finnish population-based myocardial infarction register, FINAMI, data from years 1993–2011 to identify survivors of first ACS (n = 12686), who were then followed up for recurrent events and all-cause mortality for three years. Finnish FINRISK risk factor surveys were used to determine the prevalence of risk factors (smoking, hyperlipidaemia, diabetes and blood pressure) in post-ACS patients (n = 199). Of the first ACS survivors, 48.4% had MACE within three years of their primary event, 17.0% were fatal. Diabetes (p = 4.4 × 10−7), heart failure (HF) during the first ACS attack hospitalization (p = 6.8 × 10−15), higher Charlson index (p = 1.56 × 10−19) and older age (p =.026) were associated with elevated risk for MACE in the three-year follow-up, and revascularization (p =.0036) was associated with reduced risk. Risk factor analyses showed that 23% of ACS survivors continued smoking and cholesterol levels were still high (>5mmol/l) in 24% although 86% of the patients were taking lipid lowering medication. Diabetes, higher Charlson index and HF are the most important risk factors of MACE after the first ACS. Cardiovascular risk factor levels were still high among survivors of first ACS. [ABSTRACT FROM AUTHOR]

Myeloproliferative neoplasms (MPNs) are blood cancers that are characterized by the excessive production of mature myeloid cells and arise from the acquisition of somatic driver mutations in haematopoietic stem cells (HSCs). Epidemiological studies indicate a substantial heritable component of MPNs that is among the highest known for cancers1. However, only a limited number of genetic risk loci have been identified, and the underlying biological mechanisms that lead to the acquisition of MPNs remain unclear. Here, by conducting a large-scale genome-wide association study (3,797 cases and 1,152,977 controls), we identify 17 MPN risk loci (P < 5.0 × 10−8), 7 of which have not been previously reported. We find that there is a shared genetic architecture between MPN risk and several haematopoietic traits from distinct lineages; that there is an enrichment for MPN risk variants within accessible chromatin of HSCs; and that increased MPN risk is associated with longer telomere length in leukocytes and other clonal haematopoietic states—collectively suggesting that MPN risk is associated with the function and self-renewal of HSCs. We use gene mapping to identify modulators of HSC biology linked to MPN risk, and show through targeted variant-to-function assays that CHEK2 and GFI1B have roles in altering the function of HSCs to confer disease risk. Overall, our results reveal a previously unappreciated mechanism for inherited MPN risk through the modulation of HSC function. A genome-wide association study identifies 17 genetic loci that are associated with the risk of myeloproliferative neoplasms (MPNs), and shows that the modulation of haematopoietic stem cell function drives MPN risk. [ABSTRACT FROM AUTHOR]

Aims: Natriuretic peptides are extensively studied biomarkers for atrial fibrillation (AF) and heart failure (HF). Their role in the pathogenesis of both diseases is not entirely understood and previous studies several single-nucleotide polymorphisms (SNPs) at the NPPA-NPPB locus associated with natriuretic peptides have been identified. We investigated the causal relationship between natriuretic peptides and AF as well as HF using a Mendelian randomization approach.Methods and Results: N-terminal pro B-type natriuretic peptide (NT-proBNP) (N = 6669), B-type natriuretic peptide (BNP) (N = 6674), and mid-regional pro atrial natriuretic peptide (MR-proANP) (N = 6813) were measured in the FINRISK 1997 cohort. N = 30 common SNPs related to NT-proBNP, BNP, and MR-proANP were selected from studies. We performed six Mendelian randomizations for all three natriuretic peptide biomarkers and for both outcomes, AF and HF, separately. Polygenic risk scores (PRSs) based on multiple SNPs were used as genetic instrumental variable in Mendelian randomizations. Polygenic risk scores were significantly associated with the three natriuretic peptides. Polygenic risk scores were not significantly associated with incident AF nor HF. Most cardiovascular risk factors showed significant confounding percentages, but no association with PRS. A causal relation except for small causal betas is unlikely.Conclusion: In our Mendelian randomization approach, we confirmed an association between common genetic variation at the NPPA-NPPB locus and natriuretic peptides. A strong causal relationship between natriuretic peptides and incidence of AF as well as HF at the community-level was ruled out. Therapeutic approaches targeting natriuretic peptides will therefore very likely work through indirect mechanisms. [ABSTRACT FROM AUTHOR]

Individuals with a later chronotype (evening types) tend to have unhealthier behaviors and increased morbidity and mortality as compared with those with an earlier chronotype (morning types). However, the role of genetics in explaining evening types' adverse health and health behavior is unclear. Our aim was to study genetic associations of chronotype among 8433 Finns from the cross-sectional National FINRISK 2007 and 2012 studies. First, we studied associations between chronotype and 20 key clock genes with a candidate-gene approach and then performed a full genome-wide association study (GWAS) of chronotype. We also developed a genetic risk score (GRS) for chronotype based on 313 single nucleotide polymorphisms (SNPs) that have previously been associated with chronotype. Chronotype was assessed with a shortened version of Horne and Östberg's Morningness-Eveningness Questionnaire (sMEQ), and for comparison, we also used the single self-evaluation question on chronotype from the questionnaire. Linear and logistic regression was used for statistical analysis assuming additive effects. The clock gene analysis revealed 1 independent association signal within NR1D2 (lead SNP rs4131403) that was associated with chronotype (p < 0.05; as based on both chronotype assessment methods). The GWAS analysis did not yield any genome-wide significant associations (p > 5 × 10−8). However, higher GRS was associated with evening chronotype (p < 0.001; as based on both chronotype assessment methods). In conclusion, our findings indicated novel genetic associations between chronotype and the NR1D2 clock gene, which has previously been associated with carbohydrate and lipid metabolism. Furthermore, the GRS was able to capture the genetic aspect of chronotype in our study population. These findings expand our knowledge of the genetic basis of chronotype. [ABSTRACT FROM AUTHOR]

Background: Chronic obstructive pulmonary disease (COPD) is a common lung disorder characterized by persistent and progressive airflow limitation as well as systemic changes. Metabolic changes in blood may help detect COPD in an earlier stage and predict prognosis.Methods: We conducted a comprehensive study of circulating metabolites, measured by proton Nuclear Magnetic Resonance Spectroscopy, in relation with COPD and lung function. The discovery sample consisted of 5557 individuals from two large population-based studies in the Netherlands, the Rotterdam Study and the Erasmus Rucphen Family study. Significant findings were replicated in 12,205 individuals from the Lifelines-DEEP study, FINRISK and the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) studies. For replicated metabolites further investigation of causality was performed, utilizing genetics in the Mendelian randomization approach.Results: There were 602 cases of COPD and 4955 controls used in the discovery meta-analysis. Our logistic regression results showed that higher levels of plasma Glycoprotein acetyls (GlycA) are significantly associated with COPD (OR = 1.16, P = 5.6 × 10- 4 in the discovery and OR = 1.30, P = 1.8 × 10- 6 in the replication sample). A bi-directional two-sample Mendelian randomization analysis suggested that circulating blood GlycA is not causally related to COPD, but that COPD causally increases GlycA levels. Using the prospective data of the same sample of Rotterdam Study in Cox-regression, we show that the circulating GlycA level is a predictive biomarker of COPD incidence (HR = 1.99, 95%CI 1.52-2.60, comparing those in the highest and lowest quartile of GlycA) but is not significantly associated with mortality in COPD patients (HR = 1.07, 95%CI 0.94-1.20).Conclusions: Our study shows that circulating blood GlycA is a biomarker of early COPD pathology. [ABSTRACT FROM AUTHOR]

Protein-altering variants that are protective against human disease provide in vivo validation of therapeutic targets. Here we use genotyping data from UK Biobank (n = 337,151 unrelated White British individuals) and FinnGen (n = 176,899) to conduct a search for protein-altering variants conferring lower intraocular pressure (IOP) and protection against glaucoma. Through rare protein-altering variant association analysis, we find a missense variant in ANGPTL7 in UK Biobank (rs28991009, p.Gln175His, MAF = 0.8%, genotyped in 82,253 individuals with measured IOP and an independent set of 4,238 glaucoma patients and 250,660 controls) that significantly lowers IOP (β = -0.53 and -0.67 mmHg for heterozygotes, -3.40 and -2.37 mmHg for homozygotes, P = 5.96 x 10−9 and 1.07 x 10−13 for corneal compensated and Goldman-correlated IOP, respectively) and is associated with 34% reduced risk of glaucoma (P = 0.0062). In FinnGen, we identify an ANGPTL7 missense variant at a greater than 50-fold increased frequency in Finland compared with other populations (rs147660927, p.Arg220Cys, MAF Finland = 4.3%), which was genotyped in 6,537 glaucoma patients and 170,362 controls and is associated with a 29% lower glaucoma risk (P = 1.9 x 10−12 for all glaucoma types and also protection against its subtypes including exfoliation, primary open-angle, and primary angle-closure). We further find three rarer variants in UK Biobank, including a protein-truncating variant, which confer a strong composite lowering of IOP (P = 0.0012 and 0.24 for Goldman-correlated and corneal compensated IOP, respectively), suggesting the protective mechanism likely resides in the loss of interaction or function. Our results support inhibition or down-regulation of ANGPTL7 as a therapeutic strategy for glaucoma. Author summary: Glaucoma is a common eye disease that damages the optic nerve. Using intraocular pressure, which is a known modifiable risk factor and predictive measure for glaucoma, genome-wide association studies have identified dozens of genetic variants likely affecting disease risk. However, the identification of potential therapeutic targets from those discoveries has been challenging because the functional consequences and the causal variants of the suggested common variant associations are typically unclear. Here, we present a strategy to scan for rare protein-altering variants, which provides direct insights into the functional consequence and the therapeutic effects, using more than 514,000 individuals with European ancestries in two population cohorts in the UK and Finland. We discover an allelic series of multiple rare ANGPTL7 missense and nonsense variants in UK Biobank that lower intraocular pressure and reduces the risk of glaucoma. We further identify an ANGPTL7 missense variant in FinnGen cohort with more than 50-fold enrichment in the Finnish population that provides protection against glaucoma and its subtypes. Our results highlight the benefits of multi-cohort analysis for the discovery of rare protein-altering variants in common diseases and indicate ANGPTL7 as a therapeutic target for glaucoma. [ABSTRACT FROM AUTHOR]

Objectives. To examine the validity of ST-elevation myocardial infarction (STEMI) and non-ST-elevation myocardial infarction (NSTEMI) diagnoses in Finnish nation-wide hospital discharge register (HDR). Design. In the first stage of the study, we sampled 180 patients treated in 1996-2012 for MI in three different hospitals, Oulu university hospital, Turku university hospital and North Karelia Central hospital, 60 patients in each hospital. A cardiology resident classified the patients on the basis of ECG finding into following categories: NSTEMI, STEMI or not classifiable myocardial infarction (NCMI). In the second stage of the study, we sampled altogether 270 additional patients i.e. 90 patients per hospital. Patients were treated between 2012-2014 for STEMI (n = 3 × 30), NSTEMI (n = 3 × 30), and NCMI (n = 3 × 30). The ECGs of these patients were independently evaluated by the cardiology resident and a senior cardiologist and compared with the HDR diagnosis. Results. In the first stage of the study, the agreement between the ECG coding of the cardiology resident and the HDR diagnoses was poor (Cohen's kappa coefficient 0.38 (95% CI 0.10-0.32). In the second stage, the agreement remained at the same poor level (Cohen's kappa = 0.22 (95% CI 0.11-0.03)). The agreement between the cardiology resident and the senior cardiologist was, however, good (Cohen's kappa = 0.75 (95% CI 0.65-0.85)). Conclusions. Our results show that the division of MI diagnoses to STEMI and NSTEMI is not reliable in the Finnish HDR. These diagnoses should not be used as outcomes in scientific research without additional verification from the original ECGs. [ABSTRACT FROM AUTHOR]

Background: There has been a rising interest within the scientific community and the public about the environmental risk related to the abundance of microplastics in aquatic environments. Up to now, however, scientific knowledge in this context has been scarce and insufficient for a reliable risk assessment. To remedy this scarcity of data, we investigated possible adverse effects of polystyrene particles (104 particles/L) and the pesticide methiocarb (1 mg/L) in juvenile brown trout (Salmo trutta f. fario) both by themselves as well as in combination after a 96 h laboratory exposure. PS beads (density 1.05 g/mL) were cryogenically milled and fractionated resulting in irregular-shaped particles (< 50 µm). Besides body weight of the animals, biomarkers for proteotoxicity (stress protein family Hsp70), oxidative stress (superoxide dismutase, lipid peroxidation), and neurotoxicity (acetylcholinesterase, carboxylesterases) were analyzed. As an indicator of overall health, histopathological effects were studied in liver and gills of exposed fish. Results: Polystyrene particles by themselves did not influence any of the investigated biomarkers. In contrast, the exposure to methiocarb led to a significant reduction of the activity of acetylcholinesterase and the two carboxylesterases. Moreover, the tissue integrity of liver and gills was impaired by the pesticide. Body weight, the oxidative stress and the stress protein levels were not influenced by methiocarb. Effects caused by co-exposure of polystyrene microplastics and methiocarb were the same as those caused by methiocarb alone. Conclusions: Overall, methiocarb led to negative effects in juvenile brown trout. In contrast, polystyrene microplastics in the tested concentration did not affect the health of juvenile brown trout and did not modulate the toxicity of methiocarb in this fish species. [ABSTRACT FROM AUTHOR]