A genome-wide association study of anorexia nervosa.

Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome-wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2907 cases with AN from 14 countries (15 sites) and 14 860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery data sets. Seventy-six (72 independent) single nucleotide polymorphisms were taken forward for in silico (two data sets) or de novo (13 data sets) replication genotyping in 2677 independent AN cases and 8629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication data sets comprised 5551 AN cases and 21 080 controls. AN subtype analyses (1606 AN restricting; 1445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01 × 10(-7)) in SOX2OT and rs17030795 (P=5.84 × 10(-6)) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76 × 10(-)(6)) between CUL3 and FAM124B and rs1886797 (P=8.05 × 10(-)(6)) near SPATA13. Comparing discovery with replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P=4 × 10(-6)), strongly suggesting that true findings exist but our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field.

Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index.

Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ∼ 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10⁻⁸), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.

Pitkittäisaineistojen analyysista latenttien muuttujien malleilla

Summary: Analyzing longitudinal data using latent-variable models

Suomi-promootiota yhteistyössä : Kansalliskirjasto ja UM

kysymykset Esko Rahikainen

Genetic studies of body mass index yield new insights for obesity biology

Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways.

To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 × 10(-8)). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-κB signaling and mitochondrial dysfunction as biological processes related to timing of menopause.

Osaaminen tietämyksen tukena kehitettäessä aikuisopiston työprosesseja

Osaaminen voi muodostua ongelmaksi yritysten kilpailukyvylle, jos siihen ei kiinnitetä huomiota jo strategiasuunnittelusta lähtien. Vaikka asiakkaiden muuttuneet odotukset kyettäisiinkin kohdentamaan ennen kilpailijoita, saattaa olla, että siihen ei pystytä vastaamaan, jos ei ehditä oppimaan uutta tai uudella tavalla. Diplomityön tavoitteena on laatia Etelä-Karjalan aikuisopistollehenkilöstön osaamisen kehittämiskuvaus siitä, kuinka strategian määrittämisestälähtien voidaan henkilöstön osaamista parantaa ja pyrkiä luomaan kilpailuetua markkinoilla. Henkilöstön osaamisen kehittäminen tulee olla suunnitelmallista, tarvittaessa yksilön, ryhmän ja organisaation edut huomioivaa, riittävän yksinkertaista ja konkreettista, jotta suunnitelma voidaan toteuttaa, seurata ja edelleenkehittää. Työn teoriaosassa on kuvattu vision ja strategian merkitystä osaamisen kehittämiseen. Lisäksi on tarkasteltu yksilön oppimista, oppimisen prosessia ja sen kehittymistä organisaation kyvykkyydeksi. Osaamisen infrastruktuuria on lähestytty organisaatiokulttuurin, sitouttamisen ja kehittämisjärjestelmän näkökulmasta. Empiirisessä osuudessa on tuotu esiin aikuisopiston henkilöstön osaamisen kehittämisen tavoitteet, nykyiset käytännöt, kehittämisen vaihtoehdot sekä jatkotoimenpiteet. Osaaminen on aikuisopiston henkilöstön ammattitaidon perusta. Osaamistarpeen määrittämisen tulee keskittyä aikuisopiston ydinosaamisen kehittämiseen. Henkilöstö tulisi nähdä motivoinnin ja sitouttamisen kautta inhimillistä tietopääomaa kasvattavana tekijänä, johon voidaan sujuvasti liittää aineeton pääoma (data, informaatio jne.) sekä strateginen reservi, kuten kilpailuetua tuottava innovointitoiminta.

Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture.

Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.

Sähkölaitekaapelipäätteiden kokoonpanotuotannon siirtäminen alihankkijalle

Työn tavoitteena oli selvittää kustannussäästöjä sähkölaitekomponentin kokoonpano- tuotannossa. Työssä vertaillaan oman ja alihankintatuotannon välisiä kustannuksia sekä tarkastellaan toiminnan joustavuutta, kun kokoonpano muodostuu kokonaisuudessaan ostettavista osista ja kuljetusmatka osien tuottajilta sekä myyjiltä on lyhyempi alihankkijalle, kuin omalle tehtaalle. Työssä järjestellään tuotteen kokoonpanolle edellytykset siirtymiseen alihankkijan hoidetta-vaksi niin, ettei siitä aiheudu ongelmia osavalmistuksen ja hankinnan, sekä valmiiden tuotteiden hallinnassa. Työssä selvitellään tuotteenmerkitystä ja sen kehittämistä sähkölaiteteollisuudelle. Tuotteen ja tuotannon kehittämisestä oli kohdeyrityksessä perustettu erityinen projekti, johon kuului myös muita sähkökaapeliliitäntään kuuluvia osia. Tuoteryhmä,jota tämä tutkimus käsittelee, siirrettiin alihankkijan kokoonpanotuotantoon vuonna 2000. Kaapelipäätteet kuuluvat yhtenä vaihtoehtoisena osana sähkölaitteiden voimakaape- loinnin läpivientiin ja suojaukseen. Projektissa kehitettiin 3 erilaista kaapelipäättä, joiden tehtävänä oli korvata 20 aikaisempaa mallia. Tällä tavoin kyseisen tuotteen ja sen komponenttien valmistussarjakokoja voitiin nostaa ja silti tuotannonkiertoa nopeuttaa, koska puskurivarastossa olevien variaatioiden määrä väheni 20:sta 3:een. Myös osa kokoonpanossa käytettävistä komponenteista voitiin käyttää kaikkien kaapelipäätemallien kokoonpanossa. Työssä vertaillaan kuljetuskustannusten eroa osahankinnassa oman ja alihankinta- tuotannon välillä, sekä vertaillaan varaston ja tuotannon tilankäyttöä ja tuotantokapasiteettia. Työn tarkoituksena on perustella ajatusta, että kuljetusmatkoja lyhentämällä voitaisiin saada kustannussäästöjä. Oman ja alihankintatyön kustannuksia vertaillaan ja huomattava säästö kokoonpanotyössä on tässä tapauksessa se, että alihankkijan laskutushinta työlle on alhaisempi, kuin mitä työn osuudelle on määritelty omassa tuotannossa. Varastotilan osalta vertailuatehtiin ainoastaan tilan käytön suhteen.

A mathematical study of fuzzy logic; an algebraic approach

Fuzzy set theory and Fuzzy logic is studied from a mathematical point of view. The main goal is to investigatecommon mathematical structures in various fuzzy logical inference systems and to establish a general mathematical basis for fuzzy logic when considered as multi-valued logic. The study is composed of six distinct publications. The first paper deals with Mattila'sLPC+Ch Calculus. THis fuzzy inference system is an attempt to introduce linguistic objects to mathematical logic without defining these objects mathematically.LPC+Ch Calculus is analyzed from algebraic point of view and it is demonstratedthat suitable factorization of the set of well formed formulae (in fact, Lindenbaum algebra) leads to a structure called ET-algebra and introduced in the beginning of the paper. On its basis, all the theorems presented by Mattila and many others can be proved in a simple way which is demonstrated in the Lemmas 1 and 2and Propositions 1-3. The conclusion critically discusses some other issues of LPC+Ch Calculus, specially that no formal semantics for it is given.In the second paper the characterization of solvability of the relational equation RoX=T, where R, X, T are fuzzy relations, X the unknown one, and o the minimum-induced composition by Sanchez, is extended to compositions induced by more general products in the general value lattice. Moreover, the procedure also applies to systemsof equations. In the third publication common features in various fuzzy logicalsystems are investigated. It turns out that adjoint couples and residuated lattices are very often present, though not always explicitly expressed. Some minor new results are also proved.The fourth study concerns Novak's paper, in which Novak introduced first-order fuzzy logic and proved, among other things, the semantico-syntactical completeness of this logic. He also demonstrated that the algebra of his logic is a generalized residuated lattice. In proving that the examination of Novak's logic can be reduced to the examination of locally finite MV-algebras.In the fifth paper a multi-valued sentential logic with values of truth in an injective MV-algebra is introduced and the axiomatizability of this logic is proved. The paper developes some ideas of Goguen and generalizes the results of Pavelka on the unit interval. Our proof for the completeness is purely algebraic. A corollary of the Completeness Theorem is that fuzzy logic on the unit interval is semantically complete if, and only if the algebra of the valuesof truth is a complete MV-algebra. The Compactness Theorem holds in our well-defined fuzzy sentential logic, while the Deduction Theorem and the Finiteness Theorem do not. Because of its generality and good-behaviour, MV-valued logic can be regarded as a mathematical basis of fuzzy reasoning. The last paper is a continuation of the fifth study. The semantics and syntax of fuzzy predicate logic with values of truth in ana injective MV-algerba are introduced, and a list of universally valid sentences is established. The system is proved to be semanticallycomplete. This proof is based on an idea utilizing some elementary properties of injective MV-algebras and MV-homomorphisms, and is purely algebraic.

Modulation of genetic associations with serum urate levels by body-mass-index in humans.

We tested for interactions between body mass index (BMI) and common genetic variants affecting serum urate levels, genome-wide, in up to 42569 participants. Both stratified genome-wide association (GWAS) analyses, in lean, overweight and obese individuals, and regression-type analyses in a non BMI-stratified overall sample were performed. The former did not uncover any novel locus with a major main effect, but supported modulation of effects for some known and potentially new urate loci. The latter highlighted a SNP at RBFOX3 reaching genome-wide significant level (effect size 0.014, 95% CI 0.008-0.02, Pinter= 2.6 x 10-8). Two top loci in interaction term analyses, RBFOX3 and ERO1LB-EDARADD, also displayed suggestive differences in main effect size between the lean and obese strata. All top ranking loci for urate effect differences between BMI categories were novel and most had small magnitude but opposite direction effects between strata. They include the locus RBMS1-TANK (men, Pdifflean-overweight= 4.7 x 10-8), a region that has been associated with several obesity related traits, and TSPYL5 (men, Pdifflean-overweight= 9.1 x 10-8), regulating adipocytes-produced estradiol. The top-ranking known urate loci was ABCG2, the strongest known gout risk locus, with an effect halved in obese compared to lean men (Pdifflean-obese= 2 x 10-4). Finally, pathway analysis suggested a role for N-glycan biosynthesis as a prominent urate-associated pathway in the lean stratum. These results illustrate a potentially powerful way to monitor changes occurring in obesogenic environment.