Blood pressure loci identified with a gene-centric array.

Raised blood pressure (BP) is a major risk factor for cardiovascular disease. Previous studies have identified 47 distinct genetic variants robustly associated with BP, but collectively these explain only a few percent of the heritability for BP phenotypes. To find additional BP loci, we used a bespoke gene-centric array to genotype an independent discovery sample of 25,118 individuals that combined hypertensive case-control and general population samples. We followed up four SNPs associated with BP at our p < 8.56 × 10(-7) study-specific significance threshold and six suggestively associated SNPs in a further 59,349 individuals. We identified and replicated a SNP at LSP1/TNNT3, a SNP at MTHFR-NPPB independent (r(2) = 0.33) of previous reports, and replicated SNPs at AGT and ATP2B1 reported previously. An analysis of combined discovery and follow-up data identified SNPs significantly associated with BP at p < 8.56 × 10(-7) at four further loci (NPR3, HFE, NOS3, and SOX6). The high number of discoveries made with modest genotyping effort can be attributed to using a large-scale yet targeted genotyping array and to the development of a weighting scheme that maximized power when meta-analyzing results from samples ascertained with extreme phenotypes, in combination with results from nonascertained or population samples. Chromatin immunoprecipitation and transcript expression data highlight potential gene regulatory mechanisms at the MTHFR and NOS3 loci. These results provide candidates for further study to help dissect mechanisms affecting BP and highlight the utility of studying SNPs and samples that are independent of those studied previously even when the sample size is smaller than that in previous studies.

New gene functions in megakaryopoiesis and platelet formation.

Platelets are the second most abundant cell type in blood and are essential for maintaining haemostasis. Their count and volume are tightly controlled within narrow physiological ranges, but there is only limited understanding of the molecular processes controlling both traits. Here we carried out a high-powered meta-analysis of genome-wide association studies (GWAS) in up to 66,867 individuals of European ancestry, followed by extensive biological and functional assessment. We identified 68 genomic loci reliably associated with platelet count and volume mapping to established and putative novel regulators of megakaryopoiesis and platelet formation. These genes show megakaryocyte-specific gene expression patterns and extensive network connectivity. Using gene silencing in Danio rerio and Drosophila melanogaster, we identified 11 of the genes as novel regulators of blood cell formation. Taken together, our findings advance understanding of novel gene functions controlling fate-determining events during megakaryopoiesis and platelet formation, providing a new example of successful translation of GWAS to function.

Kuljetus- ja maarakennusyrityksen ympäristöohjelma

Ympäristöohjelma on osa ympäristöjärjestelmää. Ympäristöohjelma sisältää käytännön toimenpiteet, joilla varmistetaan ympäristötavoitteiden saavuttaminen. Tavoitteiden saavuttamiseksi ympäristöohjelmaan määritetään myös tarvittavat vastuuhenkilöt, keinot, aikataulut, resurssit ja mittarit, joilla tavoitteita mitataan. Insinöörityön tarkoituksena oli laatia Esko Gustafsson Oy:lle ympäristöohjelma vuosille 2007 - 2009. Tavoitteena oli myös laatia käytännön ohjeistukset merkittävien ympäristönäkökohtien hallintaan. Työ aloitettiin tunnistamalla yrityksen toiminnat ja määrittelemällä toimintojen ympäristönäkökohdat. Tämän jälkeen arvioitiin yrityksen merkittävät ympäristönäkökohdat, joiden pohjalta ympäristöohjelma laadittiin. Työn tuloksena saatiin laadittua tehokas ympäristöohjelma. Ympäristöohjelma pystytään viemään läpi erittäin pienillä resursseilla. Jos ympäristöohjelman tavoitteet saadaan täytettyä, säästetään merkittävästi kustannuksissa.

Lämpökuvaus laadunvarmistustyökaluna talonrakentamisessa

Tutkimuksen tavoitteena oli luoda NCC Rakennus Oy:lle uusi lämpökuvaus-toimintamalli, joka mahdollistaa rakentamisen ja rakennusten työvaiheiden laadunvarmistamisen entistä tehokkaammin. Tutkimuksessa käsiteltiin lämpökuvauksen perusteita, lämpökuvaustoiminnan roolia yrityksen laatujärjestelmässä ja erityispiirteitä eri työlajien laadunvarmistuksessa. Tutkimuksessa keskityttiin uudishankkeisiin toimitilarakentamisessa, asunto-, takuu- ja korjauspuolen aiheita käsiteltiin yleisesti. Insinöörityön lähdemateriaalina käytettiin lämpökuvaus- ja rakennuskirjallisuutta, yleisiä rakennusmääräyksiä ja -ohjeita, haastatteluja ja lämpökuvausraportteja. Teoriaosuuden jälkeen selvitettiin NCC:n kokemuksia lämpökuvauksesta ja kohteissa havaituista lämpöteknisistä ongelmakohdista. Kokeellisia lämpökuvauksia suoritettiin lämpökuvausolosuhteiden salliessa yhteensä seitsemässä toimitilakohteessa, yhdessä rivitalokohteessa, julkisivusaneerauskohteen 14:sta kerrostaloasunnossa ja yhdessä yksityisessä paritaloasunnossa. Toimintamalli osoittautui erittäin tarpeelliseksi ja tehokkaaksi rakennusten lämpöteknisen tiiveyden ja talotekniikan lämmitysjärjestelmien toiminnan varmistamisessa. Toistuvien lämpökuvausten aikana selvisi mittauslaitteiston ominaisuuksien merkitys, aputyökalujen ja tutkimusajan tarve sekä työnaikaisen lämpökuvausraportin rakenne. Insinöörityön tuloksena syntyi lämpökuvauksen avuksi toimintamalli, josta selviää rakennusvaiheittain lämpökuvauksen vaikutustapa, paikka, tiedonkulku, lämpökuvauksessa toistuvat vaiheet, osapuolet, tehtävät ja työkalut. Lämpökuvauksen avuksi luotiin aputyökaluja, jotka ovat avaintyölajien lämpökuvausohjekortit sekä suunnittelussa ja kuvaustilanteessa käytettävä apumateriaali kuten lämpökuvauksen tilauspohja, käyttäjätiedote, mittauspöytäkirja- pohja ja valmiit lämpötilaindeksien mukaiset pintalämpötilojen ohjearvotaulukot.

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.

A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance.

Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and β-cell dysfunction but have contributed little to the understanding of the genetic basis of insulin resistance. We hypothesized that genes implicated in insulin resistance pathways might be uncovered by accounting for differences in body mass index (BMI) and potential interactions between BMI and genetic variants. We applied a joint meta-analysis approach to test associations with fasting insulin and glucose on a genome-wide scale. We present six previously unknown loci associated with fasting insulin at P < 5 × 10(-8) in combined discovery and follow-up analyses of 52 studies comprising up to 96,496 non-diabetic individuals. Risk variants were associated with higher triglyceride and lower high-density lipoprotein (HDL) cholesterol levels, suggesting a role for these loci in insulin resistance pathways. The discovery of these loci will aid further characterization of the role of insulin resistance in T2D pathophysiology.

Genome-wide association analyses identify 18 new loci associated with serum urate concentrations.

Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.

A new highly penetrant form of obesity due to deletions on chromosome 16p11.2.

Obesity has become a major worldwide challenge to public health, owing to an interaction between the Western 'obesogenic' environment and a strong genetic contribution. Recent extensive genome-wide association studies (GWASs) have identified numerous single nucleotide polymorphisms associated with obesity, but these loci together account for only a small fraction of the known heritable component. Thus, the 'common disease, common variant' hypothesis is increasingly coming under challenge. Here we report a highly penetrant form of obesity, initially observed in 31 subjects who were heterozygous for deletions of at least 593 kilobases at 16p11.2 and whose ascertainment included cognitive deficits. Nineteen similar deletions were identified from GWAS data in 16,053 individuals from eight European cohorts. These deletions were absent from healthy non-obese controls and accounted for 0.7% of our morbid obesity cases (body mass index (BMI) >or= 40 kg m(-2) or BMI standard deviation score >or= 4; P = 6.4 x 10(-8), odds ratio 43.0), demonstrating the potential importance in common disease of rare variants with strong effects. This highlights a promising strategy for identifying missing heritability in obesity and other complex traits: cohorts with extreme phenotypes are likely to be enriched for rare variants, thereby improving power for their discovery. Subsequent analysis of the loci so identified may well reveal additional rare variants that further contribute to the missing heritability, as recently reported for SIM1 (ref. 3). The most productive approach may therefore be to combine the 'power of the extreme' in small, well-phenotyped cohorts, with targeted follow-up in case-control and population cohorts.

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.

Jean Sibeliuksen kootut teokset

Esko Häkli

Kansallisbibliografian pitkä taival

Esko Häkli

Painovoimaa

Esko Rahikainen

Sodan ja rauhan perusteet : Ruotsin suurvaltakauden sotapolitiikka pappissäädyn ja suomalaisen papiston arvioimana 1630-1678

Esko M. Laine