Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes.

We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10-7); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent 'false leads' with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition

Publisher Correction: Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity (Nature Genetics, (2018), 50, 1, (26-41), 10.1038/s41588-017-0011-x)

An amendment to this paper has been published and can be accessed via a link at the top of the paper.</p

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

Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution.

Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants

Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes.

We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P &lt; 2.2 × 10-7); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent 'false leads' with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition

Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.

Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity

Rare and low-frequency coding variants alter human adult heigh

Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways