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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 and treatment options are limited. 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 2,413 cases and 762,382 controls. We identify 15 novel risk loci (p < 5*10−8) and replicate the regions of RELN and two previously reported candidate genes (TGFB1 and MEPE). Implicated genes in many loci are essential for bone remodelling or mineralization. Otosclerosis is genetically correlated with height and fracture risk, and the association loci overlap with severe skeletal disorders. Our results highlight TGFβ1 signalling for follow-up mechanistic studies.

With decades of electronic health records linked to genetic data, large biobanks provide unprecedented opportunities for systematically understanding the genetics of the natural history of complex diseases. Genome-wide survival association analysis can identify genetic variants associated with ages of onset, disease progression and lifespan. We developed an efficient and accurate frailty (random effects) model approach for genome-wide survival association analysis of censored time-to-event (TTE) phenotypes in large biobanks by accounting for both population structure and relatedness. Our method utilizes state-of-the-art optimization strategies to reduce the computational cost. The saddlepoint approximation is used to allow for analysis of heavily censored phenotypes (>90%) and low frequency variants (down to minor allele count 20). We demonstrated the performance of our method through extensive simulation studies and analysis of five TTE phenotypes, including lifespan, with heavy censoring rates (90.9% to 99.8%) on ~400,000 UK Biobank participants with white British ancestry and ~180,000 samples in FinnGen, respectively. We further performed genome-wide association analysis for 871 TTE phenotypes in UK Biobank and presented the genome-wide scale phenome-wide association (PheWAS) results with the PheWeb browser.

In Finland, laboratory diagnostics of infectious diseases is done in clinical microbiology laboratories that are approved by the Regional State Administrative Agencies (RSAAs). The Finnish National Institute for Health and Welfare (THL) has given elaborated instructions for laboratories seeking approval. The main purpose of this licensure procedure is to ensure the reliability of diagnostics for infectious diseases regardless of the laboratory performing these investigations. The two main requirements for the approval are a sufficient number of skilled personnel and mandatory participation in external quality assessment (EQA) schemes for each test type that a laboratory offers. The licensure process for clinical microbiology laboratory is mandatory and independent of voluntary accreditation processes. This thesis focuses on three common clinical microbiological investigations: quantitative urine culture, faecal bacterial culture, and point-of care (POC) testing for infectious mononucleosis (IM) caused by the Epstein-Barr virus (EBV IM POC). External quality control (EQC) results were obtained from corresponding EQA schemes. The results of laboratory investigations will have a direct impact on patient care and in the case of infectious diseases also have epidemiological and public health implications, including a role in recognising disease outbreaks and assessing of epidemiological prevention and control measures effectiveness. For this reason, the high quality of these results is important. According to the Finnish Communicable Diseases Act laboratories have to give information on EQA schemes to THL by request. However the results from the EQC results sent to EQA provider are confidential. In this study Finnish laboratories were asked for permission to study their EQC results directly from the database provided a Finnish company specialised in producing a wide range of EQA services, Labquality Lt. Altogether 26,398 EQC results over a nine-year period (2009–2017) from 413 laboratories were collected and evaluated. Of the 413 laboratories, 335 took part in quantitative urine culture rounds, 17 in faecal bacterial pathogens rounds and 273 in EBV IM POC rounds. This study showed that the commitment to EQA was good in Finnish clinical microbiology laboratories. The laboratories typically attended all four rounds per year. The rate by which the laboratories replied to the EQA by submitting their results for the EQC samples varied from 95% to 99.5% according to the investigation studied in this thesis. This is referred as the response rate. The success rate for quantitative urine culture testing was 83%. The most common reasons for the 17% false results were due to interpreting the growth of expected pathogens as non-significant, or due to mixed growth, or no growth at all. There were differences in detecting and quantifying of the growth of Gram-negative and Gram-positive bacteria. In those EQC samples where Gram-negative rods were present, the quantitative result was correct in 91% of the results. The most common bacterial pathogen causing urinary tract infections (UTI), Escherichia coli was correctly reported in 93% of the EQC results. In those EQC samples where Gram-positive bacteria were present; the quantitative result was correct in 68% of the results. The most common Gram-positive bacterial pathogens found in urine culture samples, Enterococcus sp. and Staphylococcus saprophyticus were correctly reported in 85% of the EQC results. More untypical findings, Streptococcus agalactiae and Aerococcus urinae were reported correctly only in 23% and 31% of the EQC results, respectively. If the same sample contains several isolates, it is considered contaminated. In this study, two EQC samples containing mixed growth were correctly reported only in 66% of the results. The success rate for faecal bacterial culture testing was 92%. The common reasons for false results were improper identification of Shigella sp. and according to the collected data, the success rate was 89% for Shigella flexneri and 71% for Shigella sonnei. The success rate for the detection of Salmonella sp. was 95%. All false results with Salmonella were caused by two samples, one with low number of Salmonella Typhimurium cells, and other with Salmonella Infantis strain. The success in finding Yersinia sp. was 96% and for Campylobacter jejuni it was 98%. The overall success in the EBV IM POC rounds was 99.3%. The success varied between 94.3% for the immunofiltration method to 99.4% for the immunochromatographic method and 99.6% for latex agglutination method. The most significant factor regarding the results’ correctness was the clinical classification of the sample. The samples that represented old EBV immunity were the most difficult to interpreted with a 98.9% success rate. In order to evaluate the effect of the laboratory size on the EQC results, laboratories conducting quantitative urine culture and EBV IM POC investigations were divided according to the size, categorised by the number of named investigations they conducted per year. The laboratory type or size did not influence the success of the EQC results in this setting where all participants were licenced clinical microbiology laboratories. Suomessa tartuntatautien laboratoriodiagnostiikkaa tehdään aluehallintovirastojen hyväksymissä kliinisen mikrobiologian laboratorioissa. Terveyden ja hyvinvoinnin laitos (THL) on ohjeistanut hyväksyntää hakevia laboratorioita toimintaedellytyksien täyttämisessä. Toimilupamenettelyn päätavoite on taata diagnostiikan luotettavuus riippumatta siitä missä laboratoriossa tutkimukset suoritetaan. Toimintaedellytyksistä kaksi tärkeintä ovat riittävä ja ammattitaitoinen henkilöstö, sekä jokaisen tutkimusnimikkeen kohdalla osallistuminen ulkoisen laadunarvioinnin (EQA) kierroksille, jos niitä on saatavilla. Kliinisen mikrobiologian laboratorioiden toimilupamenettely on pakollinen ja akkreditoinnista riippumaton prosessi. Tässä tutkimuksessa käsiteltiin kolmea yleistä mikrobiologista tutkimusta, kvantitatiivista virtsaviljelyä, ulosteen bakteeriviljelyä, sekä mononukleoosipikatestiä (EBV IM POC) näiden ulkoisen laadunarvioinnin tulosten pohjalta. Laboratoriotulokset vaikuttavat suoraan potilaan hoitoon liittyviin päätöksiin ja infektiotautien ollessa kyseessä niillä on myös rooli taudinpurkausten tunnistamisessa sekä epidemiologisten torjuntatoimien vaikuttavuuden arvioinnissa. Tästä syystä näiden tutkimusten korkea laatu on tärkeä. Tartuntatautilain mukaan laboratorioiden on pyynnöstä toimitettava EQA kierrosten tulokset THL:lle. Koska EQA palvelun tuottajalle toimitetut tulokset ovat luottamuksellisia, Suomalaisilta kliinisen mikrobiologian laboratorioilta pyydettiin lupaa saada ulkoisen laaduntarkkailun (EQC) tulokset suoraan Labquality Oy:n tietokannasta. Koko yhdeksän vuoden (2009 — 2017) tutkimusjakson aikana kerättiin ja analysoitiin yhteensä 26 398 EQC tulosta 413 laboratoriosta. Näistä laboratorioista 335 osallistui kvantitatiivisiin virtsan viljelykierroksiin, 17 ulosteen bakteeriviljelykierroksiin ja 273 EBV IM POC -kierroksiin. Tämän tutkimuksen pohjalta voidaan todeta että sitoutuminen ulkoiseen laaduntarkkailuun oli hyvä suomalaisissa kliinisen mikrobiologian laboratorioissa. Laboratoriot osallistuivat tyypillisesti kaikkiin neljään kierrokseen vuodessa. Laboratoriot palauttivat kierroksen järjestäjälle vastauksen 95% — 99,5% tutkittavaksi lähetetyistä näytteistä. Tähän viitataan vastausprosenttina. Laboratorioiden menestys kvantitatiivisen virtsaviljelyn kierroksilla oli 83%. Virheellisistä vastauksista 17% johtui löydöksen tulkitsemisesta merkityksettömäksi, sekakasvuksi tai täysin negatiiviseksi. Grampositiivisten ja gramnegatiivisten bakteerien tunnistamisessa ja kasvun runsauden arvioinnissa oli eroja. Niissä EQC näytteissä joissa löydöksenä oli gramnegatiivinen bakteeri, oikea kvantitatiivinen tulos raportoitiin 91% vastauksista. Kaikkein yleisin virtsatiepatogeeni Escherichia coli oli raportoitu oikein 93% EQC vastauksissa. Niissä EQC näytteissä joissa löydöksenä oli grampositiivinen bakteeri, oikea kvantitatiivinen tulos raportoitiin 68% vastauksissa. Kaikkein yleisimmät grampositiiviset virtsatiepatogeenit, Enterococcus sp. ja Staphylococcus saprophyticus oli raportoitu oikein 85% EQC vastauksissa. Harvinaisempien löydösten, Streptococcus agalactiae ja Aerococcus urinae tulokset olivat oikein 23% ja 31% analysoiduissa kierrosvastauksissa. Virtsanäytteiden, joissa kasvaa kaksi tai useampia bakteereita katsotaan olevan kontaminoituneita. Tämän tutkimuksen aineistossa tällaisia laaduntarkkailunäytteitä oli kaksi. Näiden näytteiden osalta osallistuneiden laboratorioiden tulkinta oli oikein vain 66% palautetuista vastauksista. Ulosteen bakteeriviljelykierroksilla onnistumisprosentti oli 92%. Tässä tutkimuksessa analysoitujen EQC vastausten perusteella vaikeimpia näytteitä olivat ne, joissa odotettuna löydöksenä oli Shigella sp., Shigella flexneri oli oikein 89% vastauksista ja Shigella sonnei. 71% vastauksista. Näytteissä joissa löydöksenä oli Salmonella sp. onnistumisprosentti oli 95%. Kaikki väärät vastaukset salmonellaa sisältävien näytteiden kohdalla johtuivat kahdesta EQC näytteestä, joista toisessa oli vain vähän Salmonella Typhimurium soluja, ja toisessa rikkivetynegatiivinen Salmonella Infantis kanta. Analysoitujen EQC vastausten perusteella Yersinia sp. oli oikein 96% vastauksista. Aiemmista tutkimuksista poiketen Campylobacter jejuni oli tässä tutkimuksessa raportoitu oikein 98% EQC vastauksessa ja ainoa väärä vastaus johtui mahdollisesta näytesekaannuksesta. Tässä tutkimuksessa analysoitujen EQC tulosten pohjalta onnistumisprosentti EBV IM POC kierroksilla oli 99,3%. Onnistumisprosentti vaihteli menetelmien välillä ollen 94,3% immunofiltraatiomenetelmillä, 99,4% immunokromatograafisilla menetelmillä ja 99,6% latex-agglutinaation menetelmillä. Tämän tutkimuksen perusteella kaikkein suurin vaikutus tulosten oikeellisuudelle oli analysoidun EQC näytteen edustama kliininen tulkinta. Vanhaa EBV- immuniteettia edustavien negatiivisten näytteiden tulkinta oli näiden EQC raporttien perusteella kaikkein vaikeinta ja niiden kohdalla onnistumisprosentti oli 98,9%. Vastoin ennakko-odotuksia, laboratorion tyypillä tai koolla ei näyttänyt olevan vaikutusta menestykseen EQA kierroksilla tutkimusasetelmassa jossa kaikki osallistujat olivat toimiluvallisia kliinisen mikrobiologian laboratorioita.

ObjectiveTo investigate if obstructive sleep apnoea (OSA) is an independent risk factor for severe COVID-19. To examine whether the risk for contracting COVID-19 is elevated among OSA patients.Design and settingRegistry based retrospective case-control study using Finnish nationwide health registries and the FinnGen Study cohort.ParticipantsInformation regarding OSA diagnosis and COVID-19 infection was extracted from the FinnGen study (N=260,405) with a total of 305 patients who had a recorded PCR-validated COVID-19 infection including 26 (8.5%) individuals who were also OSA patients. Severe COVID-19 (N=83; 27.2%) was defined as an infection requiring hospitalization. Among the hospitalized individuals there were 16 (19.3%) with OSA diagnosis. In addition, we also included in our analysis previously reported risk factors for both severe COVID-19 or risk factors and comorbidities for OSA from FinnGen.Main outcome measuresOSA diagnosis, information concerning COVID-19 infection such as hospitalization, were derived from Finnish National Hospital Discharge Registry, Causes of Death Registry and the National Infectious Diseases Registry.ResultsWe show that OSA is a risk factor for COVID-19 hospitalization independent from age, sex, body mass index (BMI), hypertension, diabetes, coronary heart disease (CHD), asthma and chronic obstructive pulmonary disease (COPD), (p-unadjusted=1.04×10−4, OR-adjusted=5.24 [95%CI 1.33 to 23.43], p-adjusted=0.022). OSA was not associated with the risk of contracting COVID-19 (p=0.49).ConclusionWhile an OSA patient’s risk of contracting COVID-19 is the same as non-OSA individuals, the OSA patients have a five-fold risk to be hospitalized when affected by COVID-19 than non-OSA individuals. Our findings suggest that, in assessment of patients with suspected or confirmed COVID-19 infection, OSA needs to be recognized as one of the comorbidity risk factors for developing a severe form of the disease.

AimsEarly prediction of acute coronary syndrome (ACS) is a major goal for prevention of coronary heart disease (CHD). Genetic information has been proposed to improve prediction beyond well-established clinical risk factors. While polygenic scores (PS) can capture an individual’s genetic risk for ACS, its prediction performance may vary in the context of diverse correlated clinical conditions. Here, we aimed to test whether clinical conditions impact the association between PS and ACS.Methods and ResultsWe explored the association between 405 clinical conditions diagnosed before baseline and 9,080 incident cases of ACS in 387,832 individuals from the UK Biobank. We identified 80 conventional (e.g., stable angina pectoris (SAP), type 2 diabetes mellitus) and unconventional (e.g., diaphragmatic hernia, inguinal hernia) associations with ACS. Results were replicated in 6,430 incident cases of ACS in 177,876 individuals from FinnGen. The association between PS and ACS was consistent in individuals with and without most clinical conditions. However, a diagnosis of SAP yielded a differential association between PS and ACS. PS was associated with a significantly reduced (interaction p-value=2.87×10−8) risk for ACS in individuals with SAP (HR=1.163 [95% CI: 1.082–1.251]) compared to individuals without SAP (HR=1.531 [95% CI: 1.497–1.565]). These findings were replicated in FinnGen (interaction p-value=1.38×10−6).ConclusionIn summary, while most clinical conditions did not impact utility of PS for prediction of ACS, we found that PS was substantially less predictive of ACS in individuals with prevalent stable CHD. PS for ACS may be more appropriate for asymptomatic individuals than symptomatic individuals with clinical suspicion for CHD.

There is currently limited understanding of the genetic aetiology of obstructive sleep apnoea (OSA). We aimed to identify genetic loci associated with OSA risk, and to test if OSA and its comorbidities share a common genetic background.We conducted the first large-scale genome-wide association study of OSA using the FinnGen study (217 955 individuals) with 16 761 OSA patients identified using nationwide health registries.We estimated 0.08 (95% CI 0.06–0.11) heritability and identified five loci associated with OSA (p−8): rs4837016 nearGAPVD1(GTPase activating protein and VPS9 domains 1), rs10928560 nearCXCR4(C-X-C motif chemokine receptor type 4), rs185932673 nearCAMK1D(calcium/calmodulin-dependent protein kinase ID) and rs9937053 nearFTO(fat mass and obesity-associated protein; a variant previously associated with body mass index (BMI)). In a BMI-adjusted analysis, an association was observed for rs10507084 nearRMST/NEDD1(rhabdomyosarcoma 2 associated transcript/NEDD1 γ-tubulin ring complex targeting factor). We found high genetic correlations between OSA and BMI (rg=0.72 (95% CI 0.62–0.83)), and with comorbidities including hypertension, type 2 diabetes, coronary heart disease, stroke, depression, hypothyroidism, asthma and inflammatory rheumatic disease (rg>0.30). The polygenic risk score for BMI showed 1.98-fold increased OSA risk between the highest and the lowest quintile, and Mendelian randomisation supported a causal relationship between BMI and OSA.Our findings support the causal link between obesity and OSA, and the joint genetic basis between OSA and comorbidities.

There is currently only limited understanding of the genetic aetiology of obstructive sleep apnoea (OSA). The aim of our study is to identify genetic loci associated with OSA risk and to test if OSA and its comorbidities share a common genetic background.We conducted the first large-scale genome-wide association study of OSA using FinnGen Study (217,955 individuals) with 16,761 OSA patients identified using nationwide health registries.We estimated 8.3% [0.06-0.11] heritability and identified five loci associated with OSA (P < 5.0 × 10−8): rs4837016 near GTPase activating protein and VPS9 domains 1 (GAPVD1), rs10928560 near C-X-C motif chemokine receptor 4 (CXCR4), rs185932673 near Calcium/calmodulin-dependent protein kinase ID (CAMK1D) and rs9937053 near Fat mass and obesity-associated protein (FTO) - a variant previously associated with body mass index (BMI). In a BMI-adjusted analysis, an association was observed for rs10507084 near Rhabdomyosarcoma 2 associated transcript (RMST)/NEDD1 gamma-tubulin ring complex targeting factor (NEDD1).We found genetic correlations between OSA and BMI (rg=0.72 [0.62-0.83]) and with comorbidities including hypertension, type 2 diabetes (T2D), coronary heart disease (CHD), stroke, depression, hypothyroidism, asthma and inflammatory rheumatic diseases (IRD) (rg > 0.30). Polygenic risk score (PRS) for BMI showed 1.98-fold increased OSA risk between the highest and the lowest quintile and Mendelian randomization supported a causal relationship between BMI and OSA.Our findings support the causal link between obesity and OSA and joint genetic basis between OSA and comorbidities.

Clinical laboratory tests are a critical component of the continuum of care. We evaluate the genetic basis of 35 blood and urine laboratory measurements in the UK Biobank (n = 363,228 individuals). We identify 1,857 loci associated with at least one trait, containing 3,374 fine-mapped associations and additional sets of large-effect (>0.1 s.d.) protein-altering, human leukocyte antigen (HLA) and copy number variant (CNV) associations. Through Mendelian randomization (MR) analysis, we discover 51 causal relationships, including previously known agonistic effects of urate on gout and cystatin C on stroke. Finally, we develop polygenic risk scores (PRSs) for each biomarker and build 'multi-PRS' models for diseases using 35 PRSs simultaneously, which improved chronic kidney disease, type 2 diabetes, gout and alcoholic cirrhosis genetic risk stratification in an independent dataset (FinnGen; n = 135,500) relative to single-disease PRSs. Together, our results delineate the genetic basis of biomarkers and their causal influences on diseases and improve genetic risk stratification for common diseases.

Protein-truncating variants (PTVs) affecting dyslipidemia risk may point to therapeutic targets for cardiometabolic disease. Our objective was to identify PTVs that associated with both lipid levels and cardiometabolic disease risk 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 also associated with risks of cardiometabolic diseases or 2,264 disease endpoints curated in the FinnGen Study (n = 176,899). Three PTVs were associated with both lipid levels and the risk of cardiometabolic disease: 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) and the HDL cholesterol-elevating variant in LIPG (10.2[7.5 to 13.0] mg/dL per rs200435657-A allele, P = 5.0 × 10−13). The risk of type 2 diabetes was lower in carriers of ANGPTL8 (odds ratio [OR] = 0.67[0.47-0.92], P = 0.01), ANGPTL4 (OR = 0.70[0.60-0.82], P = 1.4× 10−5) and LIPG (OR = 0.67[0.48-0.91], P = 0.01) PTVs than in noncarriers. Moreover, the odds of coronary artery disease were 44% lower in carriers of a PTV in ANGPTL8 (OR = 0.56[0.38-0.83], P = 0.004). Finally, the phenome-wide scan of the ANGPTL8 PTV showed a markedly higher associated risk of esophagitis (585 cases, OR = 174.3[17.7-1715.1], P = 9.7 × 10−6) and sensorineural hearing loss (12,250 cases, OR = 2.45[1.63-3.68], P = 1.8 × 10−5). The ANGPTL8 PTV carriers were less likely to use statin therapy (53,518 cases, OR = 0.53[0.41-0.71], P = 1.2 × 10−5). Our findings provide genetic evidence of potential long-term efficacy and safety of therapeutic targeting of dyslipidemias.

Drainage of high-consistency fiber-laden foams

Supplemental Digital Content is available in the text., Background: Hyperlipidemia is a highly heritable risk factor for coronary artery disease (CAD). While monogenic familial hypercholesterolemia associates with severely increased CAD risk, it remains less clear to what extent a high polygenic load of a large number of LDL (low-density lipoprotein) cholesterol (LDL-C) or triglyceride (TG)-increasing variants associates with increased CAD risk. Methods: We derived polygenic risk scores (PRSs) with ≈6M variants separately for LDL-C and TG with weights from a UK Biobank–based genome-wide association study with ≈324K samples. We evaluated the impact of polygenic hypercholesterolemia and hypertriglyceridemia to lipid levels in 27 039 individuals from the National FINRISK Study (FINRISK) cohort and to CAD risk in 135 638 individuals (13 753 CAD cases) from the FinnGen project (FinnGen). Results: In FINRISK, median LDL-C was 3.39 (95% CI, 3.38–3.40) mmol/L, and it ranged from 2.87 (95% CI, 2.82–2.94) to 3.78 (95% CI, 3.71–3.83) mmol/L between the lowest and highest 5% of the LDL-C PRS distribution. Median TG was 1.19 (95% CI, 1.18–1.20) mmol/L, ranging from 0.97 (95% CI, 0.94–1.00) to 1.55 (95% CI, 1.48–1.61) mmol/L with the TG PRS. In FinnGen, comparing the highest 5% of the PRS to the lowest 95%, CAD odds ratio was 1.36 (95% CI, 1.24–1.49) for the LDL-C PRS and 1.31 (95% CI, 1.19–1.43) for the TG PRS. These estimates were only slightly attenuated when adjusting for a CAD PRS (odds ratio, 1.26 [95% CI, 1.16–1.38] for LDL-C and 1.24 [95% CI, 1.13–1.36] for TG PRS). Conclusions: The CAD risk associated with a high polygenic load for lipid-increasing variants was proportional to their impact on lipid levels and partially overlapping with a CAD PRS. In contrast with a PRS for CAD, the lipid PRSs point to known and directly modifiable risk factors providing additional guidance for clinical translation.

SummaryBackground Hip fractures are a major health concern among older persons with Alzheimer's disease, who usually use many concomitant drugs for several diseases. Evidence of the association between proton pump inhibitor use and risk of hip fracture is contradictory. Aim To investigate whether the long-term use of proton pump inhibitor is associated with risk of hip fractures among community-dwelling persons with Alzheimer's disease. Methods In this nested case-control study, the nationwide MEDALZ data were utilised. Community-dwelling persons with Alzheimer's disease who encountered incident hip fracture (N = 4818; mean age 84.1) were included as cases. Four controls were matched for each case at the date of hip fracture (N = 19 235; mean age 84.0). The association between hip fracture and duration of current PPI use (ongoing use during 0-30 days before the index date), and cumulative duration of use during 10 years before was investigated with conditional logistic regression. Results Long-term or cumulative proton pump inhibitor use was not associated with an increased risk of hip fracture. Current proton pump inhibitor use was associated with an increased risk of hip fracture (adjusted OR 1.12, 95% CI 1.03-1.22). The risk was increased in short-term current use (

While polygenic risk scores (PRS) have been shown to predict many diseases and risk factors, the potential of genomic prediction in harm caused by alcohol use has not yet been extensively studied. Here, we built a novel polygenic risk score of 1.1 million variants for alcohol consumption and studied its predictive capacity in 96,499 participants from the FinnGen study and 39,695 participants from prospective cohorts with detailed baseline data and up to 25 years of follow-up time. A 1 SD increase in the PRS was associated with 11.2 g (=0.93 drinks) higher weekly alcohol consumption (CI = 9.85–12.58 g, p = 2.3 × 10–58). The PRS was associated with alcohol-related morbidity (4785 incident events) and the risk estimate between the highest and lowest quintiles of the PRS was 1.83 (95% CI = 1.66–2.01, p = 1.6 × 10–36). When adjusted for self-reported alcohol consumption, education, marital status, and gamma-glutamyl transferase blood levels in 28,639 participants with comprehensive baseline data from prospective cohorts, the risk estimate between the highest and lowest quintiles of the PRS was 1.58 (CI = 1.26–1.99, p = 8.2 × 10–5). The PRS was also associated with all-cause mortality with a risk estimate of 1.33 between the highest and lowest quintiles (CI = 1.20–1.47, p = 4.5 × 10–8) in the adjusted model. In conclusion, the PRS for alcohol consumption independently associates for both alcohol-related morbidity and all-cause mortality. Together, these findings underline the importance of heritable factors in alcohol-related health burden while highlighting how measured genetic risk for an important behavioral risk factor can be used to predict related health outcomes.

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.

This recommendation is created in a working group within the Finnish Open Science and Research Coordination (openscience.fi). It is aimed at research organisations and institutions and may be used as a supporting document, when creating a PID policy. The focus is on static dataset publications and research data repositories. The poster was presented at the CODATA seminar in Helsinki on 21st and 22nd of October 2019.

Poster presented at the CODATA 2019 workshop in Helsinki, Finland, 20 to 21 October 2019. The poster discusses the various challenges in research data management practices by small institutions.

Myeloproliferative neoplasms (MPNs) are blood cancers characterized by excessive production of mature myeloid cells that result from the acquisition of somatic driver mutations in hematopoietic stem cells (HSCs)1. While substantial progress has been made to define the causal somatic mutation profile for MPNs2, epidemiologic studies indicate a significant heritable component for the disease that is among the highest known for all cancers3. However, only a limited set of genetic risk loci have been identified, and the underlying biological mechanisms leading to MPN acquisition remain unexplained. Here, to define the inherited risk profile, we conducted the largest genome-wide association study of MPNs to date (978,913 individuals with 3,224 cases) and identified 14 genome-wide significant loci, as well as a polygenic signature that increases the odds for disease acquisition by nearly 3-fold between the top and median deciles. Interestingly, we find a shared genetic architecture between MPN risk and several hematopoietic traits spanning distinct lineages, as well as an association between increased MPN risk and longer leukocyte telomere length, collectively implicating HSC function and self-renewal. Strikingly, we find a significant enrichment for risk variants mapping to accessible chromatin in HSCs compared with other hematopoietic populations. Finally, gene mapping identifies modulators of HSC biology and targeted variant-to-function analyses suggest likely roles for CHEK2 and GFI1B in altering HSC function to confer disease risk. Overall, we demonstrate the power of human genetic studies to illuminate a previously unappreciated mechanism for MPN risk through modulation of HSC function.

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

BackgroundHyperlipidemia is a highly heritable risk factor for coronary artery disease (CAD). Monogenic familial hypercholesterolemia associates with higher increase in CAD risk than expected from a single LDL-C measurement, likely due to lifelong cumulative exposure to high LDL-C. It remains unclear to what extent a high polygenic load of LDL-C or TG-increasing variants associates with increased CAD risk.Methods and ResultsWe derived polygenic risk scores (PRS) with ∼6M variants for LDL-C and TG with weights from a UK biobank-based genome-wide association study with ∼500K samples. We evaluated the impact of polygenic hypercholesterolemia and hypertriglyceridemia to lipid levels in 27 039 individuals from the FINRISK cohort, and to CAD risk in 135 300 individuals (13 695 CAD cases) from the FinnGen project.In FINRISK, LDL-C ranged from 2.83 (95% CI 2.79-2.89) to 3.80 (3.72-3.88) and TG from 0.99 (0.95-1.01) to 1.52 (1.48-1.58) mmol/l between the lowest and highest 5% of the respective PRS distributions. The corresponding CAD prevalences ranged from 8.2% to 12.7% for the LDL-C PRS and from 8.2% to 12.1% for the TG PRS in FinnGen. Furthermore, CAD risk was 1.36-fold higher (OR, 95% CI 1.24-1.49) for the LDL-C PRS and 1.31-fold higher (1.20-1.44) for the TG PRS for those with the PRS >95thpercentile vs those without. These estimates were only slightly attenuated when adjusting for a CAD PRS (OR 1.26 [95% CI 1.15-1.39] for LDL-C and 1.21 [1.10-1.32] for TG PRS).ConclusionsThe CAD risk associated with a high polygenic load for lipid-increasing variants was proportional to their impact on lipid levels and mostly independent of a CAD PRS. In contrast with a PRS for CAD, the lipid PRSs point to known and directly modifiable risk factors providing more direct guidance for clinical translation.