Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

Pleiotropy among common genetic loci identified for cardiometabolic disorders and C-reactive protein.

Pleiotropic genetic variants have independent effects on different phenotypes. C-reactive protein (CRP) is associated with several cardiometabolic phenotypes. Shared genetic backgrounds may partially underlie these associations. We conducted a genome-wide analysis to identify the shared genetic background of inflammation and cardiometabolic phenotypes using published genome-wide association studies (GWAS). We also evaluated whether the pleiotropic effects of such loci were biological or mediated in nature. First, we examined whether 283 common variants identified for 10 cardiometabolic phenotypes in GWAS are associated with CRP level. Second, we tested whether 18 variants identified for serum CRP are associated with 10 cardiometabolic phenotypes. We used a Bonferroni corrected p-value of 1.1×10-04 (0.05/463) as a threshold of significance. We evaluated the independent pleiotropic effect on both phenotypes using individual level data from the Women Genome Health Study. Evaluating the genetic overlap between inflammation and cardiometabolic phenotypes, we found 13 pleiotropic regions. Additional analyses showed that 6 regions (APOC1, HNF1A, IL6R, PPP1R3B, HNF4A and IL1F10) appeared to have a pleiotropic effect on CRP independent of the effects on the cardiometabolic phenotypes. These included loci where individuals carrying the risk allele for CRP encounter higher lipid levels and risk of type 2 diabetes. In addition, 5 regions (GCKR, PABPC4, BCL7B, FTO and TMEM18) had an effect on CRP largely mediated through the cardiometabolic phenotypes. In conclusion, our results show genetic pleiotropy among inflammation and cardiometabolic phenotypes. In addition to reverse causation, our data suggests that pleiotropic genetic variants partially underlie the association between CRP and cardiometabolic phenotypes

New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk

To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P <5 x 10(-8)), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk.Peer reviewe

Talouden raportointiohjelmistojen vertailu : Case PRT-Forest Oy

Talousraportointi on aina ollut oleellinen osa liiketoimintaa. Jo lainsäädäntö määrittelee joukon raportointivelvoitteita, mutta raportoinnille on paljon muitakin tarpeita. Luotettava raportointi toimii vahvasti yrityksen päätöksenteon tukena. Opinnäytetyöni toimeksiantaja on PRT-Forest Oy. PRT-Forest on perheomisteinen, vuonna 1968 toimintansa aloittanut konserni. Konsernin päätoimialoja ovat puu- ja valmistaloteollisuus sekä mekaaninen puu- ja rakennustarviketeollisuus. Opinnäytetyöni kehittämistehtävän tarkoituksena oli löytää tulevaisuuden tarpeisiin vastaava talouden raportointiohjelmisto toimeksiantajalle. Opinnäytetyöni tietoperusta rakentuu johdon laskentatoimen, maksuvalmiuden seuraamisen, budjetoinnin, talouden ennustamisen ja tiedolla johtamisen käsitteiden ympärille. Raportointi on oleellinen osa johdon laskentatoimea. Jotta tietoa voidaan hyödyntää päätöksenteossa, tulee sen olla luotettavaa ja ajantasaista sekä helposti saatavilla. Kehittämistehtävä toteutettiin pyytämällä ohjelmistotarjoajia pitämään esittely tarjoamistaan ratkaisuista yritykseen ja aineisto vertailuun kerättiin näistä esittelyistä ja esittelyn aikana syntyneestä keskusteluista. Vertailun helpottamiseksi laadittiin luettelo tarvittavista ominaisuuksista. Nämä ominaisuudet pisteytettiin vertailun helpottamiseksi. Ominaisuuksia ja käytettävyyttä vertailemalla selvitettiin parhaiten raportoinnin tarpeisiin vastaava ratkaisu.Economic financial reporting has always been an integral part of business. Already the legislation defines a number of reporting obligations, but there are many other needs for reporting. Reliable reporting supports significantly the company's decision making. My thesis was commissioned PRT-Forest Oy. PRT-Forest is a family-owned group that started its operations in 1968. The group's main activities are wooden single-house and prefabricated house industry, mechanical wood and construction equipment industry. The purpose of the development task in this thesis was to find the financial reporting software for future needs for the company. The theoretical framework for my thesis is structured around management accounting, liquidity monitoring, budgeting, economic forecasting and information management concepts. Reporting is an integral part of management accounting. In order to make use of the information in decision-making, it must be reliable, timely and accessible. The development task was carried out by requesting software providers to hold a demonstration of the solutions they offered to the company. The material for comparison was collected from these presentations and the discussions that emerged during the demonstration. To facilitate comparison, a list of the necessary characteristics was established. These features were scored to facilitate the comparison. By comparing the features and usability, the best suited solution to reporting needs was identified

Riksväg 4 Vehniä-Äänekoski : Miljökonsekvensbeskrivning

Valtatien 4 suunnittelu Keski-Suomessa Laukaan Vehniän ja Äänekosken Huutomäen välillä on käynnistynyt vuonna 2013 ja vaikutusten arvioinnin YVA-lain mukainen ensimmäinen vaihe, YVA-ohjelma valmistui keväällä 2014. Suunnitelma käsittää noin 16 kilometrin pituisen osuuden, jolla on kolme erillistä toteutusvaihtoehtoa. Nämä eroavat toisistaan siten, että vaihtoehto N mukailee nykyistä maastokäytävää ja vaihtoehdot B ja C1 sijoittuvat Iso-Hirvasen järven itäpuolelle. Ympäristövaikutusten arviointiselostuksessa kuvataan arvioitavat vaihtoehdot, niiden vaikutusalueiden nykytila ja vaikutukset vaihtoehdoittain. Ympäristövaikutusten arviointi on tehty YVA-lain ja asetuksen edellyttämällä tavalla ja tarkkuudella. Toteutusvaihtoehdot N, B ja C1 ovat liikenne- maankäyttö- ja melu- ja muiden ihmisvaikutustensa osalta myönteisempiä kuin hankkeen toteuttamatta jättäminen (0-vaihtoehto). Vaihtoehto N on liito-oravavaikutusten osalta kielteisin, vaikkakin muiden luonnonolojen osalta myönteisempi. Maankäytön osalta vaihtoehto N on myönteisin. Alueen asukkailla ja muilla intressiryhmillä on ollut mahdollisuus osallistua suunnitteluun ja antaa mielipiteensä hankkeesta ja sen vaikutusten arvioinnista YVA-menettelyn ajan. Näkemyksiä hankkeesta on voinut antaa useiden kanavien kautta hankkeesta vastaavalle ja muille tahoille. Näkemyksiä on voinut esittää myös järjestetyissä yleisötilaisuuksissa