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.

Identifying the index lesion with template prostate mapping biopsies.

PURPOSE: The natural history of prostate cancer might be driven by the index lesion. We determined the percent of men in whom the index lesion could be defined using transperineal template prostate mapping biopsies. MATERIALS AND METHODS: Included in study were consecutive men undergoing transperineal template prostate mapping biopsies with biopsies grouped into 20 zones. Men with clinically significant disease in only 1 prostate area were considered to have an identifiable index lesion. We evaluated the impact of using 2 definitions of clinically significant disease (Gleason grade pattern 4 and/or lesion volume 0.5 cc or greater) and 2 clustering rules (stringent and tolerant) to define the index lesion. RESULTS: Included in study were 391 men with a median age of 62 years (IQR 58-67) and a median prostate specific antigen of 6.9 ng/ml (IQR 4.8-10.0). Of the men 269 (69%) were previously diagnosed with prostate cancer. By deploying a median of 1.2 cores per ml (IQR 0.9-1.7) cancer was diagnosed in 82.9% of the men (324 of 391) with a median of 6 positive cores (IQR 2-9), a median maximum cancer core length of 5 mm (IQR 3-8) and a total cancer core length per zone of 7 mm (IQR 3-13). Insignificant disease was found in 26.3% to 42.9% of cases. When a stringent spatial relationship was used to define individual lesions, 44.4% to 54.6% of patients had 1 index lesion and 12.7% to 19.1% had more than 1 area with clinically significant disease. These proportions changed to 46.6% to 59.2% and 10.5% to 14.5%, respectively, when less stringent spatial clustering was applied. CONCLUSIONS: Transperineal template prostate mapping biopsies enable the index lesion to be localized in most men with clinically significant disease. This information may be important to select appropriate candidates for targeted therapy and to plan a tailored treatment strategy in men undergoing radical therapy.

Directional dominance on stature and cognition in diverse human populations.

Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.

Tunnusluku- ja tuottohistoria-pohjaisten sijoitusstrategioiden toimivuus ja sykliriippuvuus suomalaisilla osakemarkkinoilla

Tutkielman tavoitteena oli analysoida tunnuslukuihin ja tuottohistoriaan perustuvien sijoitusstrategioiden toimivuutta ja sykliriippuvuutta HEX:iin listatuista yrityksistä koostuvalla aineistolla. Tutkitut sijoitusstrategiat perustuivat arvostuskertoimien, betan ja menneiden tuottojen käyttöön analysointivälineinä käytettyjen kvintiiliportfolioiden muodostamiskriteereinä. Kontribuutiota tutkimukseen pyrittiin luomaan tarkastelemalla ensimmäistä kertaa suhdannesyklin vaikutuksia edellä mainittujen sijoitusstrategioiden toimivuuteen tutkimusaineistolla, joka kattoi useita suhdannesyklejä (pisimmillään vuodet 1991 - 2002). Suhdannesyklien käänteiden määrittämiseen käytettiin ostopäälliköiden indeksiä (PMI-indeksi), jonka on todettu toimivan hyvin esimerkiksi pörssikurssien kehitystä ennakoivana indikaattorina. Tulokset osoittivat P/E-, P/B-, EV/EBIT-, EV/EBITDA-, beta- ja momentumanomalioiden esiintyneen myös suomalaisilla osakemarkkinoilla vuosina 1991 – 2002. Tutkimuksessa saatiin näyttöä myös tuottohistoriaan pohjautuvien momentum-strategian ja winner-loser –strategian toimivuudesta. Näistä etenkin jälkimmäinen oli voimakkaasti sykliriippuvaista. Näiden tulosten mukaan suomalaiset osakemarkkinat eivät olisi käytetyillä tarkasteluperiodilla olleet edes heikosti tehokkaat, ts. osakemarkkinoiden keskimääräinen tuottotaso olisi ollut mahdollista ylittää pelkkään kurssihistoriaan perustuvien sijoitusstrategioiden avulla.

The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study.

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR<5%) age-specific effects, of which 11 had larger effects in younger (<50y) than in older adults (≥50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may provide further insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.

Caloric restriction induces energy-sparing alterations in skeletal muscle contraction, fiber composition and local thyroid hormone metabolism that persist during catch-up fat upon refeeding.

Weight regain after caloric restriction results in accelerated fat storage in adipose tissue. This catch-up fat phenomenon is postulated to result partly from suppressed skeletal muscle thermogenesis, but the underlying mechanisms are elusive. We investigated whether the reduced rate of skeletal muscle contraction-relaxation cycle that occurs after caloric restriction persists during weight recovery and could contribute to catch-up fat. Using a rat model of semistarvation-refeeding, in which fat recovery is driven by suppressed thermogenesis, we show that contraction and relaxation of leg muscles are slower after both semistarvation and refeeding. These effects are associated with (i) higher expression of muscle deiodinase type 3 (DIO3), which inactivates tri-iodothyronine (T3), and lower expression of T3-activating enzyme, deiodinase type 2 (DIO2), (ii) slower net formation of T3 from its T4 precursor in muscles, and (iii) accumulation of slow fibers at the expense of fast fibers. These semistarvation-induced changes persisted during recovery and correlated with impaired expression of transcription factors involved in slow-twitch muscle development. We conclude that diminished muscle thermogenesis following caloric restriction results from reduced muscle T3 levels, alteration in muscle-specific transcription factors, and fast-to-slow fiber shift causing slower contractility. These energy-sparing effects persist during weight recovery and contribute to catch-up fat.

No association between ApoE polymorphism and febrile seizures.

Seizures associated with fever are a common pediatric problem, affecting about 2-7 % of children between 3 months and 5 years of age. Differentiation of febrile seizures from acute symptomatic seizures secondary to central nervous system infections or seizures associated with fever in children with epilepsy is essential to provide appropriate treatment and follow-up care. Here, we tested the hypothesis that children who exhibit simple febrile seizures during early childhood, but do not develop epileptic seizures later in life, might preferentially carry the ApoE2 allele of the gene coding for the apolipoprotein E. We did not find any differences in the distribution of ApoE alleles or genotypes between individuals who exhibited simple febrile seizures (n = 93) and age-matched, typically developing subjects (n = 80). We found that the observed allele and genotype frequencies did not deviate from Hardy-Weinberg equilibrium, which suggests that the frequencies of ApoE alleles and genotypes are stable in the Swiss population from which our samples were derived. Across both groups of subjects (n = 173), we found an ApoE2 allele frequency of 0.064, an ApoE3 frequency of 0.829 and an ApoE4 frequency of 0.107. Our findings are consistent with previous reports of the distribution of ApoE polymorphism for European subjects free of any neurological disorders, and show that the different alleles of the gene coding for the apolipoprotein E are not associated with the occurrence of simple febrile seizures.

Immune correlates of vaccine protection against HIV-1 acquisition.

The partial efficacy reported in the RV144 HIV vaccine trial in 2009 has driven the HIV vaccine field to define correlates of risk associated with HIV-1 acquisition and connect these functionally to preventing HIV infection. Immunological correlates, mainly including CD4(+) T cell responses to the HIV envelope and Fc-mediated antibody effector function, have been connected to reduced acquisition. These immunological correlates place immunological and genetic pressure on the virus. Indeed, antibodies directed at conserved regions of the V1V2 loop and antibodies that mediate antibody-dependent cellular cytotoxicity to HIV envelope in the absence of inhibiting serum immunoglobulin A antibodies correlated with decreased HIV risk. More recently, researchers have expanded their search with nonhuman primate studies using vaccine regimens that differ from that used in RV144; these studies indicate that non-neutralizing antibodies are associated with protection from experimental lentivirus challenge as well. These immunological correlates have provided the basis for the design of a next generation of vaccine regimens to improve upon the qualitative and quantitative degree of magnitude of these immune responses on HIV acquisition.

Safety and Immunogenicity of a Recombinant Adenovirus Serotype 35-Vectored HIV-1 Vaccine in Adenovirus Serotype 5 Seronegative and Seropositive Individuals.

BACKGROUND: Recombinant adenovirus serotype 5 (rAd5)-vectored HIV-1 vaccines have not prevented HIV-1 infection or disease and pre-existing Ad5 neutralizing antibodies may limit the clinical utility of Ad5 vectors globally. Using a rare Ad serotype vector, such as Ad35, may circumvent these issues, but there are few data on the safety and immunogenicity of rAd35 directly compared to rAd5 following human vaccination. METHODS: HVTN 077 randomized 192 healthy, HIV-uninfected participants into one of four HIV-1 vaccine/placebo groups: rAd35/rAd5, DNA/rAd5, and DNA/rAd35 in Ad5-seronegative persons; and DNA/rAd35 in Ad5-seropositive persons. All vaccines encoded the HIV-1 EnvA antigen. Antibody and T-cell responses were measured 4 weeks post boost immunization. RESULTS: All vaccines were generally well tolerated and similarly immunogenic. As compared to rAd5, rAd35 was equally potent in boosting HIV-1-specific humoral and cellular immunity and responses were not significantly attenuated in those with baseline Ad5 seropositivity. Like DNA, rAd35 efficiently primed rAd5 boosting. All vaccine regimens tested elicited cross-clade antibody responses, including Env V1/V2-specific IgG responses. CONCLUSIONS: Vaccine antigen delivery by rAd35 is well-tolerated and immunogenic as a prime to rAd5 immunization and as a boost to prior DNA immunization with the homologous insert. Further development of rAd35-vectored prime-boost vaccine regimens is warranted.

Impact of a cis-associated gene expression SNP on chromosome 20q11.22 on bipolar disorder susceptibility, hippocampal structure and cognitive performance.

BackgroundBipolar disorder is a highly heritable polygenic disorder. Recent enrichment analyses suggest that there may be true risk variants for bipolar disorder in the expression quantitative trait loci (eQTL) in the brain.AimsWe sought to assess the impact of eQTL variants on bipolar disorder risk by combining data from both bipolar disorder genome-wide association studies (GWAS) and brain eQTL.MethodTo detect single nucleotide polymorphisms (SNPs) that influence expression levels of genes associated with bipolar disorder, we jointly analysed data from a bipolar disorder GWAS (7481 cases and 9250 controls) and a genome-wide brain (cortical) eQTL (193 healthy controls) using a Bayesian statistical method, with independent follow-up replications. The identified risk SNP was then further tested for association with hippocampal volume (n = 5775) and cognitive performance (n = 342) among healthy individuals.ResultsIntegrative analysis revealed a significant association between a brain eQTL rs6088662 on chromosome 20q11.22 and bipolar disorder (log Bayes factor = 5.48; bipolar disorder P = 5.85×10(-5)). Follow-up studies across multiple independent samples confirmed the association of the risk SNP (rs6088662) with gene expression and bipolar disorder susceptibility (P = 3.54×10(-8)). Further exploratory analysis revealed that rs6088662 is also associated with hippocampal volume and cognitive performance in healthy individuals.ConclusionsOur findings suggest that 20q11.22 is likely a risk region for bipolar disorder; they also highlight the informative value of integrating functional annotation of genetic variants for gene expression in advancing our understanding of the biological basis underlying complex disorders, such as bipolar disorder.

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.

Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels.

Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.

Arvostrategioiden menestys Suomen osakemarkkinoilla

Tämän tutkimuksen tavoitteena on selvittää saavutetaanko passiivisilla arvostrategioilla riskikorjattuna ylisuuria tuottoja Suomen osakemarkkinoilla. Tuottaako matalien tunnuslukujen perusteella valittujen osakkeiden portfolio enemmän kuin korkeiden tunnuslukujen portfolio? Ovatko alfat tilastollisesti merkitseviä? Tutkimuksen tavoitteena on myös selvittää, ovatko korkeimman ja matalimman arvostustason portfolioiden menestyserot tilastollisesti merkitseviä. Tunnuslukuina on tarkasteltu P/E-, EV/EBIT- ja EV/EBITDA-tunnuslukuja sekä P/B- ja P/S–lukuja. Lisäksi on tutkittu yhdistelmätunnuslukuina P/E- ja P/B–lukujen tulon muodostamaa tunnuslukua, sekä suhteellisiin EV/EBITDA-, P/B- ja P/S-lukuihin perustuvaa arvostusmittaria. Tutkimusaineisto koostuu Suomen osakemarkkinoilla julkisesti noteeratuista yrityksistä toukokuusta 1991 toukokuuhun 2006. Osakkeet järjestettiin tunnuslukujen arvostustason perusteella kvintiiliportfolioihin. Myöhemmin portfoliot muodostettiin uudelleen kolmen ja viiden vuoden välein. Lopuksi tarkasteltiin kvintiiliportfolioiden kuukausittaisia tuottoja tunnuslukukohtaisesti koko tutkimusjakson ajalta. Tulosten perusteella on selkeästi havaittavissa, että matalan tunnusluvun kvintiiliportfoliot menestyivät paremmin kuin korkean tunnusluvun kvintiiliportfoliot. Kolmen vuoden jaksoissa P/E-, EV/EBITDA-, P/B-, P/S- ja kolmen tunnusluvun yhdistelmällä muodostetuilla kvintiiliportfolioilla arvopreemio oli selkeästi havaittavissa. Viiden vuoden jaksoissa vastaava ilmiö toistui EV/EBITDA-tunnusluvulla muodostetuilla kvintiiliportfolioilla. Eniten tuotti absoluuttisesti sekä riskikorjattuna tutkimuksessa esiteltävä kolmen vuoden jaksoissa kolmen tunnusluvun yhdistelmällä muodostettu matalimman arvostustason kvintiiliportfolio, joka tuotti riskikorjattuna tilastollisesti erittäin merkitsevästi positiivista alfaa matalalla riskitasolla.

Yllätys yritysjohdon ennusteissa: Vaikutus osakekurssiin

Tutkielman tavoitteena oli selvittää Suomen osakemarkkinoiden hinnoittamistehokkuutta johdon ennustepoikkeamien tapauksessa. Tarkastelu-ajanjakso on 1.1.2000–31.12.2006. Kiinnostuneita oltiin erityisesti keski-pitkän ja pitkän aikavälin (10 kaupankäyntivuorokautta ja 40 kaupankäyntivuorokautta) epänormaaleista tuotoista. Työn empiriaosuus suoritettiin tapahtumatutkimusmenetelmää hyväksikäyttäen. Empiriaosuudessa laskettiin ennustepoikkeaman aiheuttamat epänormaalit tuotot pienimmän neliösumman regressiota hyväksikäyttäen. Positiivisten poikkeamien aiheuttamat epänormaalit tuotot eivät poikenneet tilastollisesti markkinatuotoista millään tarkasteluvälillä. Negatiivisten epänormaalien tuottojen poikkeamaa havaittiin 10 kaupankäyntivuorokautta ennustepoikkeaman julkaisun jälkeen. Toimialakohtaisessa tarkastelussa parillisten otosten t-testissä havaittiin, että terveydenhuollon, rahoituksen ja informaatioteknologian epänormaalit tuotot poikkesivat markkinatuotoista. Yrityskohtaisia tekijöitä tutkittiin yksinkertaisella t-testillä. Näistä velkaisuusasteella, beetalla, päivätuottojen keskihajonnalla, päivittäisellä liikevaihdolla sekä P/E-luvulla havaittiin voi-tavan ennustaa mahdollisten ennustepoikkeamien esiintymistiheyttä. Sen sijaan markkina-arvolla ja P/B-luvulla ei havaittu yhteyttä ennustepoikkeamien esiintymistiheyteen. Tutkittaessa käyttäytymistieteellisen rahoituksen olettamaa kaupankäyntivolyymin kasvusta ennustepoikkeamaa ympäröivänä aikana ei tilastollista merkittävyyttä löydetty.