Analysis of protein-coding genetic variation in 60,706 humans

Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. Here we describe the aggregation and analysis of high-quality exome (protein-coding region) DNA sequence data for 60,706 individuals of diverse ancestries generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We have used this catalogue to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; identifying 3,230 genes with near-complete depletion of predicted protein-truncating variants, with 72% of these genes having no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human 'knockout' variants in protein-coding genes

New Blood Pressure-Associated Loci Identified in Meta-Analyses of 475,000 Individuals

Background - Genome-wide association studies have recently identified >400 loci that harbor DNA sequence variants that influence blood pressure (BP). Our earlier studies identified and validated 56 single nucleotide variants (SNVs) associated with BP from meta-analyses of exome chip genotype data. An additional 100 variants yielded suggestive evidence of association. Methods and Results - Here, we augment the sample with 140 886 European individuals from the UK Biobank, in whom 77 of the 100 suggestive SNVs were available for association analysis with systolic BP or diastolic BP or pulse pressure. We performed 2 meta-analyses, one in individuals of European, South Asian, African, and Hispanic descent (pan-ancestry, ≈475 000), and the other in the subset of individuals of European descent (≈423 000). Twenty-one SNVs were genome-wide significant (P<5×10-8) for BP, of which 4 are new BP loci: rs9678851 (missense, SLC4A1AP), rs7437940 (AFAP1), rs13303 (missense, STAB1), and rs1055144 (7p15.2). In addition, we identified a potentially independent novel BP-associated SNV, rs3416322 (missense, SYNPO2L) at a known locus, uncorrelated with the previously reported SNVs. Two SNVs are associated with expression levels of nearby genes, and SNVs at 3 loci are associated with other traits. One SNV with a minor allele frequency <0.01, (rs3025380 at DBH) was genome-wide significant. Conclusions - We report 4 novel loci associated with BP regulation, and 1 independent variant at an established BP locus. This analysis highlights several candidate genes with variation that alter protein function or gene expression for potential follow-up

New blood pressure-associated loci identified in meta-analyses of 475 000 individuals

Genome-wide association studies have recently identified >400 loci that harbor DNA sequence variants that influence blood pressure (BP). Our earlier studies identified and validated 56 single nucleotide variants (SNVs) associated with BP from meta-analyses of exome chip genotype data. An additional 100 variants yielded suggestive evidence of association.Here, we augment the sample with 140 886 European individuals from the UK Biobank, in whom 77 of the 100 suggestive SNVs were available for association analysis with systolic BP or diastolic BP or pulse pressure. We performed 2 meta-analyses, one in individuals of European, South Asian, African, and Hispanic descent (pan-ancestry, ≈475 000), and the other in the subset of individuals of European descent (≈423 000). Twenty-one SNVs were genome-wide significant (P<5×10-8) for BP, of which 4 are new BP loci: rs9678851 (missense, SLC4A1AP), rs7437940 (AFAP1), rs13303 (missense, STAB1), and rs1055144 (7p15.2). In addition, we identified a potentially independent novel BP-associated SNV, rs3416322 (missense, SYNPO2L) at a known locus, uncorrelated with the previously reported SNVs. Two SNVs are associated with expression levels of nearby genes, and SNVs at 3 loci are associated with other traits. One SNV with a minor allele frequency <0.01, (rs3025380 at DBH) was genome-wide significant.We report 4 novel loci associated with BP regulation, and 1 independent variant at an established BP locus. This analysis highlights several candidate genes with variation that alter protein function or gene expression for potential follow-up

Analysis of protein-coding genetic variation in 60,706 humans

Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. Here we describe the aggregation and analysis of high-quality exome (protein-coding region) DNA sequence data for 60,706 individuals of diverse ancestries generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We have used this catalogue to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; identifying 3,230 genes with near-complete depletion of predicted protein-truncating variants, with 72% of these genes having no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human 'knockout' variants in protein-coding genes

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

New Blood Pressure-Associated Loci Identified in Meta-Analyses of 475 000 Individuals.

Genome-wide association studies have recently identified >400 loci that harbor DNA sequence variants that influence blood pressure (BP). Our earlier studies identified and validated 56 single nucleotide variants (SNVs) associated with BP from meta-analyses of exome chip genotype data. An additional 100 variants yielded suggestive evidence of association.Here, we augment the sample with 140 886 European individuals from the UK Biobank, in whom 77 of the 100 suggestive SNVs were available for association analysis with systolic BP or diastolic BP or pulse pressure. We performed 2 meta-analyses, one in individuals of European, South Asian, African, and Hispanic descent (pan-ancestry, ≈475 000), and the other in the subset of individuals of European descent (≈423 000). Twenty-one SNVs were genome-wide significant (P<5×10-8) for BP, of which 4 are new BP loci: rs9678851 (missense, SLC4A1AP), rs7437940 (AFAP1), rs13303 (missense, STAB1), and rs1055144 (7p15.2). In addition, we identified a potentially independent novel BP-associated SNV, rs3416322 (missense, SYNPO2L) at a known locus, uncorrelated with the previously reported SNVs. Two SNVs are associated with expression levels of nearby genes, and SNVs at 3 loci are associated with other traits. One SNV with a minor allele frequency <0.01, (rs3025380 at DBH) was genome-wide significant.We report 4 novel loci associated with BP regulation, and 1 independent variant at an established BP locus. This analysis highlights several candidate genes with variation that alter protein function or gene expression for potential follow-up

Analysis of protein-coding genetic variation in 60,706 humans

Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. Here we describe the aggregation and analysis of high-quality exome (protein-coding region) DNA sequence data for 60,706 individuals of diverse ancestries generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We have used this catalogue to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; identifying 3,230 genes with near-complete depletion of predicted protein-truncating variants, with 72% of these genes having no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human 'knockout' variants in protein-coding genes