Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals

Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10−8), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets. © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc. There are 286 authors of this articles not all are listed in this record

PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study

BACKGROUND: Statin treatment and variants in the gene encoding HMG-CoA reductase are associated with reductions in both the concentration of LDL cholesterol and the risk of coronary heart disease, but also with modest hyperglycaemia, increased bodyweight, and modestly increased risk of type 2 diabetes, which in no way offsets their substantial benefits. We sought to investigate the associations of LDL cholesterol-lowering PCSK9 variants with type 2 diabetes and related biomarkers to gauge the likely effects of PCSK9 inhibitors on diabetes risk. METHODS: In this mendelian randomisation study, we used data from cohort studies, randomised controlled trials, case control studies, and genetic consortia to estimate associations of PCSK9 genetic variants with LDL cholesterol, fasting blood glucose, HbA1c, fasting insulin, bodyweight, waist-to-hip ratio, BMI, and risk of type 2 diabetes, using a standardised analysis plan, meta-analyses, and weighted gene-centric scores. FINDINGS: Data were available for more than 550 000 individuals and 51 623 cases of type 2 diabetes. Combined analyses of four independent PCSK9 variants (rs11583680, rs11591147, rs2479409, and rs11206510) scaled to 1 mmol/L lower LDL cholesterol showed associations with increased fasting glucose (0·09 mmol/L, 95% CI 0·02 to 0·15), bodyweight (1·03 kg, 0·24 to 1·82), waist-to-hip ratio (0·006, 0·003 to 0·010), and an odds ratio for type diabetes of 1·29 (1·11 to 1·50). Based on the collected data, we did not identify associations with HbA1c (0·03%, -0·01 to 0·08), fasting insulin (0·00%, -0·06 to 0·07), and BMI (0·11 kg/m(2), -0·09 to 0·30). INTERPRETATION: PCSK9 variants associated with lower LDL cholesterol were also associated with circulating higher fasting glucose concentration, bodyweight, and waist-to-hip ratio, and an increased risk of type 2 diabetes. In trials of PCSK9 inhibitor drugs, investigators should carefully assess these safety outcomes and quantify the risks and benefits of PCSK9 inhibitor treatment, as was previously done for statins. FUNDING: British Heart Foundation, and University College London Hospitals NHS Foundation Trust (UCLH) National Institute for Health Research (NIHR) Biomedical Research Centre.This work was supported by a British Heart Foundation Programme Grant (RG/10/12/28456). AFS is funded by University College London Hospitals NHS Foundation Trust (UCLH) National Institute for Health Research (NIHR) Biomedical Research Centre (BRC10200) and by a UCL springboard population science fellowship. FWA is supported by a Dekker scholarship-Junior Staff Member 2014T001–Netherlands Heart Foundation and UCL Hospitals NIHR Biomedical Research Centre. ADH is an NIHR Senior Investigator. Funding information and acknowledgments for studies contributing data are reported in the appendix

A saturated map of common genetic variants associated with human height

Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40–50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes1. Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel2) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10–20% (14–24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.publishedVersionPeer reviewe

A saturated map of common genetic variants associated with human height.

Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes1. Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel2) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries

Publisher Correction : Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals (Nature Genetics, (2020), 52, 12, (1314-1332), 10.1038/s41588-020-00713-x)

Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.In the version of this article originally published, the e-mail address of corresponding author Patricia B. Munroe was incorrect. The error has been corrected in the HTML and PDF versions of the article

Air pollution exposure is associated with restrictive ventilatory patterns

Exposure to ambient air pollution is associated with a substantial burden of morbidity and mortality worldwide [1]. In a recent paper, Adam et al. [2] showed significantly impaired levels of forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) associated with exposure to the ambient air pollutants nitrogen dioxide (NO2) and particles with a 50% cut-off aerodynamic diameter of 10 μm (PM10) in 7613 adults included in the European Study of Cohorts for Air Pollution Effects (ESCAPE). Effect estimates for FVC were of similar magnitude (for NO2) or larger (for PM10) than those for FEV1. In line with these findings, Forbes et al. [3] showed negative associations of PM10 and NO2 with the level of FEV1 in 40 329 adults included in the Health Survey for England between 1995 and 2001, whereas no significant associations with FEV1/FVC were observed. In 1997, the Swiss Study on Air Pollution and Lung Disease in Adults (SAPALDIA), including 9651 adults, showed negative associations of ambient air pollutants NO2 and PM10 with both FEV1 and FVC [4]. The effect estimates for FVC were stronger than for FEV1 for various pollutants, and this was consistently the case in most subgroups (according to smoking status and respiratory symptoms). Reduced FVC, with FEV1 being normal or reduced to a lesser degree than FVC, suggests restrictive rather than obstructive lung disease (in which FEV1 specifically is reduced, resulting in a low FEV1/FVC ratio). Thus, findings from several European studies suggest that restrictive rather than obstructive ventilatory patterns associate with long-term low levels of exposure to ambient air pollution. A study with slightly different findings is the German Study on the influence of Air Pollution on Lung Function, Inflammation and Ageing (SALIA), including 2593 women. This study also found negative associations of NO2 and PM10 exposure with both FEV1 and FVC, yet the effects estimates for FEV1 were stronger than for FVC, and consequently there were small significant negative associations with the FEV1/FVC ratio [5]. A review article concluded that despite biological plausible mechanisms, there is suggestive, but not conclusive evidence that chronic exposure to air pollution is associated with the prevalence and incidence of chronic obstructive pulmonary disease (COPD), a disease characterised by airway obstruction [6]. Thus far, no studies have focused explicitly on whether air pollution exposure is associated with obstructive or restrictive ventilatory patterns

Wnt Signaling and Dupuytren's Disease

BACKGROUND Dupuytren's disease is a benign fibromatosis of the hands and fingers that leads to flexion contractures. We hypothesized that multiple genetic and environmental factors influence susceptibility to this disease and sought to identify susceptibility genes to better understand its pathogenesis. METHODS We conducted a genomewide association study of 960 Dutch persons with Dupuytren's disease and 3117 controls (the discovery set) to test for association between the disease and genetic markers. We tested the 35 single-nucleotide polymorphisms (SNPs) most strongly associated with Dupuytren's disease (P< 1x10-4) in the discovery set in three additional, independent case series comprising a total of 1365 affected persons and 8445 controls from Germany, the United Kingdom, and the Netherlands. RESULTS Initially, we observed a significant genomewide association between Dupuytren's disease and 8 SNPs at three loci. Tests of replication and joint analysis of all data from 2325 patients with Dupuytren's disease and 11,562 controls yielded an association with 11 SNPs from nine different loci (P< 5.0x10(-8)). Six of these loci contain genes known to be involved in the Wnt-signaling pathway: WNT4 (rs7524102) (P = 2.8x10(-9); odds ratio, 1.28), SFRP4 (rs16879765) (P = 5.6x10-39; odds ratio, 1.98), WNT2 (rs4730775) (P = 3.0x10(-8); odds ratio, 0.83), RSPO2 (rs611744) (P = 7.9x10(-15); odds ratio, 0.75), SULF1 (rs2912522) (P = 2.0x10(-13); odds ratio, 0.72), and WNT7B (rs6519955) (P = 3.2x10(-33); odds ratio, 1.54). CONCLUSIONS This study implicates nine different loci involved in genetic susceptibility to Dupuytren's disease. The fact that six of these nine loci harbor genes encoding proteins in the Wnt-signaling pathway suggests that aberrations in this pathway are key to the process of fibromatosis in Dupuytren's disease

A saturated map of common genetic variants associated with human height

Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40–50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes1. Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel2) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10–20% (14–24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries. © 2022, The Author(s)

PCSK9 genetic variants and risk of type 2 diabetes : a mendelian randomisation study

BACKGROUND: Statin treatment and variants in the gene encoding HMG-CoA reductase are associated with reductions in both the concentration of LDL cholesterol and the risk of coronary heart disease, but also with modest hyperglycaemia, increased bodyweight, and modestly increased risk of type 2 diabetes, which in no way offsets their substantial benefits. We sought to investigate the associations of LDL cholesterol-lowering PCSK9 variants with type 2 diabetes and related biomarkers to gauge the likely effects of PCSK9 inhibitors on diabetes risk. METHODS: In this mendelian randomisation study, we used data from cohort studies, randomised controlled trials, case control studies, and genetic consortia to estimate associations of PCSK9 genetic variants with LDL cholesterol, fasting blood glucose, HbA1c, fasting insulin, bodyweight, waist-to-hip ratio, BMI, and risk of type 2 diabetes, using a standardised analysis plan, meta-analyses, and weighted gene-centric scores. FINDINGS: Data were available for more than 550 000 individuals and 51 623 cases of type 2 diabetes. Combined analyses of four independent PCSK9 variants (rs11583680, rs11591147, rs2479409, and rs11206510) scaled to 1 mmol/L lower LDL cholesterol showed associations with increased fasting glucose (0·09 mmol/L, 95% CI 0·02 to 0·15), bodyweight (1·03 kg, 0·24 to 1·82), waist-to-hip ratio (0·006, 0·003 to 0·010), and an odds ratio for type diabetes of 1·29 (1·11 to 1·50). Based on the collected data, we did not identify associations with HbA1c(0·03%, -0·01 to 0·08), fasting insulin (0·00%, -0·06 to 0·07), and BMI (0·11 kg/m2, -0·09 to 0·30). INTERPRETATION: PCSK9 variants associated with lower LDL cholesterol were also associated with circulating higher fasting glucose concentration, bodyweight, and waist-to-hip ratio, and an increased risk of type 2 diabetes. In trials of PCSK9 inhibitor drugs, investigators should carefully assess these safety outcomes and quantify the risks and benefits of PCSK9 inhibitor treatment, as was previously done for statins. FUNDING: British Heart Foundation, and University College London Hospitals NHS Foundation Trust (UCLH) National Institute for Health Research (NIHR) Biomedical Research Centre

Selvitys toiminnanohjausjärjestelmistä ja niiden käyttöönotosta U-landshjälp från Folk till Folk i Finland rf:lle

Tämän opinnäytetyön aiheena oli selvittää, mitä on otettava huomioon toiminnanohjausjärjestelmää hankkiessa ja millainen olisi sopivin. Työn tilaaja oli Nurmijärvellä Klaukkalassa toimiva U-landshjälp från Folk till Folk i Finland rf, kansankielellä UFF. Yhdistys kerää lahjoitusvaatteita ympäri Suomea kehitysapukohteidensa avustamiseksi. Tavoitteena opinnäytetyössä oli luoda kattava ohje tukemaan päätöstä toiminnanohjausjärjestelmän hankkimiseksi. Opinnäytetyö rajattiin käsittelemään toiminnanohjausjärjestelmän hankinnan kannalta tärkeisiin teorioihin ja käyttöönottoon sekä vertailevaan analyysiin muutamasta markkinoilla olevista järjestelmästä. Opinnäytetyö aloitettiin perehtymällä toiminnanohjausjärjestelmien teoriaan ja käyttöönot-toon sekä UFF:n toimintaan kattavasti. Tietolähteinä käytettiin haastatteluja, alan kirjallisuutta sekä ohjelmistotalojen esitelmiä. Opinnäytetyön alussa käsitellään toiminnanohjausjärjestelmien toiminta ja teoria monipuolisesti ja perusteellisesti. Tämän jälkeen käydään kattavasti UFF:n historia, luvut ja toiminta vaihe vaiheelta. Seuraavassa osiossa pohditaan, miten toiminnanohjausjärjestelmän käyttöönotto vaikuttaisi UFF:n keräystoimintaan. Lopussa esitellään valitut vaihtoehdot toiminnanohjausjärjestelmäksi UFF:lle ja vertaillaan näitä pistetaulukon avulla. Lopputuloksen jälkeen pohditaan vielä, mitkä voisivat olla UFF:n seuraavat loogiset kehityskohteet tämän toiminnan parantamiseksi tulevaisuudessa. Toiminnanohjausjärjestelmän löytäminen UFF:n kaltaiselle yhdistykselle loi monia kriteerejä ja vaatimuksia verrattuna tavallisiin kuljetusyrityksiin. Toiminta oli kuitenkin helposti verrattavissa jätealan kuljetustoimintaan, jota käytetiin vertailuja tehdessä referenssinä. Tämä opinnäytetyö antaa kattavan tietopaketin toiminnanohjausjärjestelmän valintaan ja sen hankintaan. Työn tilaajaa ja toiminnanohjausjärjestelmän valintaa koskeva osuus on luovutettu vain työn tilaajan käyttöön.The objective of this Bachelors’ thesis was to determine what needs to be taken into ac-count when acquiring and implementing an ERP in a company and finding the most suitable system. This thesis was commissioned by U-landshjälp från Folk till Folk i Finland rf, commonly known as UFF. The organization collects donated clothes all around Finland to aid their development cooperation. The goal for this thesis was to create a comprehensive guide to support the decision to procure and ERP. The thesis covers the vital theories regarding the ERP and its implementation and a comparative analysis of a few software systems on the market. The study was started by familiarizing with the theories and implementation of an ERP and taking a close look on how UFF operates. The data was gathered by interviews, literature and presentations from software companies. Firstly, the principles and theories of ERP were covered diversely and thoroughly. Secondly, the history, key figures and the operation of UFF were detailed step by step. In the next section, it was examined how the implementation of an ERP would affect the collection of donations in UFF. After this, a few potential software companies and their software systems were showcased and compared to find the most suitable ERP for UFF using a score chart. Finally, it was discussed on what could be the next step to improve the operations of UFF in the future. Finding an ERP for UFF created certain criteria and demands compared to the more traditional transport companies. Operations are correlative with garbage transportations and this was used as a basis when making references. This thesis contains a comprehensive amount of information when choosing, procuring and implementing an ERP and suggests a few alternative solutions. The sections concerning the organization and the ERP selection have been made available only for the client