Population isolates such as those in Finland benefit genetic research because deleterious alleles are often concentrated on a small number of low-frequency variants (0.1% ≤ minor allele frequency < 5%). These variants survived the founding bottleneck rather than being distributed over a large number of ultrarare variants. Although this effect is well established in Mendelian genetics, its value in common disease genetics is less explored1,2. FinnGen aims to study the genome and national health register data of 500,000 Finnish individuals. Given the relatively high median age of participants (63 years) and the substantial fraction of hospital-based recruitment, FinnGen is enriched for disease end points. Here we analyse data from 224,737 participants from FinnGen and study 15 diseases that have previously been investigated in large genome-wide association studies (GWASs). We also include meta-analyses of biobank data from Estonia and the United Kingdom. We identified 30 new associations, primarily low-frequency variants, enriched in the Finnish population. A GWAS of 1,932 diseases also identified 2,733 genome-wide significant associations (893 phenome-wide significant (PWS), P < 2.6 × 10–11) at 2,496 (771 PWS) independent loci with 807 (247 PWS) end points. Among these, fine-mapping implicated 148 (73 PWS) coding variants associated with 83 (42 PWS) end points. Moreover, 91 (47 PWS) had an allele frequency of <5% in non-Finnish European individuals, of which 62 (32 PWS) were enriched by more than twofold in Finland. These findings demonstrate the power of bottlenecked populations to find entry points into the biology of common diseases through low-frequency, high impact variants.

Population isolates such as Finland provide benefits in genetic studies because the allelic spectrum of damaging alleles in any gene is often concentrated on a small number of low-frequency variants (0.1% ≤ minor allele frequency < 5%), which survived the founding bottleneck, as opposed to being distributed over a much larger number of ultra--rare variants. While this advantage is well-- established in Mendelian genetics, its value in common disease genetics has been less explored. FinnGen aims to study the genome and national health register data of 500,000 Finns, already reaching 224,737 genotyped and phenotyped participants. Given the relatively high median age of participants (63 years) and dominance of hospital-based recruitment, FinnGen is enriched for many disease endpoints often underrepresented in population-based studies (e.g., rarer immune-mediated diseases and late onset degenerative and ophthalmologic endpoints). We report here a genome-wide association study (GWAS) of 1,932 clinical endpoints defined from nationwide health registries. We identify genome--wide significant associations at 2,491 independent loci. Among these, finemapping implicates 148 putatively causal coding variants associated with 202 endpoints, 104 with low allele frequency (AF<10%) of which 62 were over two-fold enriched in Finland.We studied a benchmark set of 15 diseases that had previously been investigated in large genome-wide association studies. FinnGen discovery analyses were meta-analysed in Estonian and UK biobanks. We identify 30 novel associations, primarily low-frequency variants strongly enriched, in or specific to, the Finnish population and Uralic language family neighbors in Estonia and Russia.These findings demonstrate the power of bottlenecked populations to find unique entry points into the biology of common diseases through low-frequency, high impact variants. Such high impact variants have a potential to contribute to medical translation including drug discovery.

BackgroundDiarrhea is the most frequent health problem among children in developing countries. This study investigated the bacterial and viral etiology and related clinical and epidemiological factors in children with acute diarrhea in Ouagadougou, Burkina Faso.MethodsStool specimens were collected from 283 children under 5 years of age visiting hospital due to acute diarrhea and from 60 healthy controls of similar age. Pathogens were investigated by using conventional culture techniques, PCR and immunochromatographic testing. Salmonella and Shigella strains were serotyped and their susceptibility to 23 antimicrobial agents was determined by the agar dilution method.ResultsAt least one pathogen was detected in 64% of the 283 patients and in 8% of the 60 controls (p < 0.001). Rotavirus was found in 30% of the patients, followed by diarrheagenic Escherichia coli (24%), Salmonella enterica ssp. enterica (9%), Shigella spp. (6%), adenovirus (5%) and Campylobacter spp. (2%). Multiple pathogens were found in 11% of the patients and in 2% of the controls (p = 0.028). Viruses were found mainly in children of ≤ 2 years of age, whereas bacteria were equally prevalent among all the age groups. Viral infections occurred mostly during the cool dry season and the bacterial infections during the rainy season. Fever (64%) and vomiting (61%) were the most common symptoms associated with diarrhea. Only one Salmonella strain was resistant to nalidixic acid and ciprofloxacin. Of the Shigella strains, one was resistant to nalidixic acid but 81% to trimethoprim- sulfamethoxazole, 63% to streptomycin and 50% to ampicillin. Most of all the other Salmonella and Shigella strains were sensitive to all antimicrobials tested.ConclusionRotaviruses and diarrheal E. coli were the most predominant pathogens associated with acute diarrhea in Burkinabe children. Constant antimicrobial surveillance is warranted to observe for the emergence of enteric bacteria resistant to antimicrobials that are important in treatment also of severe infections.

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Enterobacteria in fecal flora are often reported to be highly resistant. Escherichia coli is the main species; resistance data on other species are rare. To assess the effect of the host's environment, antimicrobial resistance was determined in fecal species of the family Enterobacteriaceae from three populations: healthy people (HP)(n ‫؍‬ 125) with no exposure to antimicrobials for 3 months preceding sampling, university hospital patients (UP) (n ‫؍‬ 159) from wards where the antibiotic use was 112 defined daily doses (DDD)/bed/month, and geriatric long-term patients (LTP) (n ‫؍‬ 74) who used 1.8 DDD/bed/month. The mean length of hospital stay was 5 days for the UP and 22 months for the LTP. The isolates were identified to at least genus level, and MICs of 16 antimicrobials were determined. From the university hospital, resistance data on clinical Enterobacteriaceae isolates were also collected. Resistance data for on average two different isolates per sample (range, 1 to 5) were analyzed: 471 E. coli isolates and 261 other Enterobacteriaceae spp. Resistance was mainly found among E. coli; even in HP, 18% of E. coli isolates were resistant to two or more antimicrobial groups, with MIC patterns indicative of transferable resistance. Other fecal enterobacteria were generally susceptible, with little typically transferable multiresistance. Clinical Klebsiella and Enterobacter isolates were significantly more resistant than fecal isolates. The resistance patterns at both hospitals mirrored the patterns of antibiotic use, but LTP E. coli isolates were significantly more resistant than those from UP. Conditions permitting an efficient spread may have been more important in sustaining high resistance levels in the LTP. E. coli was the main carrier of antimicrobial resistance in fecal flora; resistance in other species was rare in the absence of antimicrobial selection.

The Carba NP test was evaluated against a panel of 61 carbapenemase-producing bacterial species (15 producing class A carbapenemases, 15 producing class D carbapenemases, and 31 producing metallo-␤-lactamases) and against 111 isolates with nonwild-type carbapenem susceptibility but not producing carbapenemase. Carbapenemase production was verified by PCR and UV-spectrophotometric measurement of imipenem hydrolysis. No false positives were seen, but there were consistent problems with the detection of OXA-48-like enzymes and also some rarer class A enzymes.

ObjectivesThe common cold is the main cause of medical time loss in elite sport. Rapid diagnosis has been a challenge that may be amenable to molecular point-of-care testing (POCT).MethodsWe performed a prospective observational study of the common cold in Team Finland during the 2018 Winter Olympic Games. There were 44 elite athletes and 68 staff members. The chief physician recorded the symptoms of the common cold daily on a standardised form. Two nasal swabs were taken at the onset of symptoms. One swab was analysed within 45 min using a molecular POCT for respiratory syncytial virus and influenza A and B viruses. After the Games, the other swab was tested for 16 possible causative respiratory viruses using PCR in laboratory-based testing.Results20 out of 44 (45%) athletes and 22 out of 68 (32%) staff members experienced symptoms of the common cold during a median stay of 21 days. Eleven (26%) samples tested virus-positive using POCT. All subjects with influenza (n=6) and 32 close contacts were treated with oseltamivir. The aetiology of the common cold was finally detected in 75% of the athletes and 68 % of the staff members. Seven virus clusters were identified. They were caused by coronaviruses 229E, NL63 and OC43, influenza B virus, respiratory syncytial virus A, rhinovirus and human metapneumovirus. The virus infections spread readily within the team, most commonly within the same sport discipline.ConclusionsThe cold was indeed a common illness in Team Finland during the Winter Olympic Games. POCT proved to be clinically valuable, especially for influenza. The aetiology of the common cold was identified in most cases.

Macrolides still appear to be the first-choice alternative for suspected C. jejuni enteritis, if antimicrobial treatment is needed. The in vitro susceptibilities suggest that clinical trials to treat enteritis caused by multidrug-resistant C. jejuni with co-amoxiclav, and life-threatening infections with a carbapenem, may be valuable.