Rare and low-frequency coding variants alter human adult height

Height is a highly heritable, classic polygenic trait with ~700 common associated variants identified so far through genome - wide association studies . Here , we report 83 height - associated coding variants with lower minor allele frequenc ies ( range of 0.1 - 4.8% ) and effects of up to 2 16 cm /allele ( e.g. in IHH , STC2 , AR and CRISPLD2 ) , >10 times the average effect of common variants . In functional follow - up studies, rare height - increasing alleles of STC2 (+1 - 2 cm/allele) compromise d proteolytic inhibition of PAPP - A and increased cleavage of IGFBP - 4 in vitro , resulting in higher bioavailability of insulin - like growth factors . The se 83 height - associated variants overlap genes mutated in monogenic growth disorders and highlight new biological candidates ( e.g. ADAMTS3, IL11RA, NOX4 ) and pathways ( e.g . proteoglycan/ 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

Verdsettelse av Mowi ASA

Problemstillingen i denne oppgaven er hva er Mowi verdt per 31.12.2020? I løpet av dette semesteret har vi fått innblikk i hvordan et selskap av så stort omfang driftes, og hvilke muligheter og utfordringer som finnes. Ved å benytte års- og kvartalsrapporter, ulike artikler, dokumenter, pensumbøker og nyheter har vi klart å samle inn relevant data som er brukt til å analysere Mowi. Aksjeprisen som er fastsatt i oppgavens konklusjon er et resultat av innhentet data og prognoser mellom 2015-2025. Oppgavestrukturen er lagt opp slik at man først får ett innblikk i Mowi sin historie hvor de med stabil vekst og tilfredsstillende drift har opparbeidet seg en global markedsandel på hele 20% og dermed er ledende produsent av atlantisk laks. Videre har vi gjort en strategisk analyse av Mowi ved å benytte kjente strategiske verktøy som PESTEL , Porters 5 konkurransekrefter, VRIO og SWOT . I den oppsummerende SWOT analysen er det flere mikro- og makroøkonomiske faktorer som kan endre dagens bilde. Etter den strategiske analysen gjennomfører vi en regnskapsanalyse av selskapet. Fra analysen fremgår det at Mowi har en sunn kapitalstruktur med stabilitet i balansen mellom egenkapital og gjeld. Både selskapets likviditet og soliditet viser til stabile nivåer, selv om lønnsomheten har hatt en svak negativ trend i løpet av de siste fem årene. Videre i den finansielle analysen av oppgaven benytter vi den fundamentale Discounted Cash Flow-metoden og en komparativ multippel analyse. Ved å kombinere de to verdsettelsesmetodene estimerer vi en aksjekurs på 186,33. Tar vi utgangspunkt i den egentlige aksjekursen, som var på 190,72 per 31.12.2021 er konklusjonen at aksjen er overpriset. Avslutningsvis belyser vi noen kritikkverdige forhold ved verdsettelsen som kan ha påvirket validiteten til estimatet

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

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

[This corrects the article DOI: 10.1371/journal.pgen.1005378.].status: publishe

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

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

In the HTML version of this article initially published, the author groups ‘CHD Exome+ Consortium’, ‘EPIC-CVD Consortium’, ‘ExomeBP Consortium’, ‘Global Lipids Genetic Consortium’, ‘GoT2D Genes Consortium’, ‘EPIC InterAct Consortium’, ‘INTERVAL Study’, ‘ReproGen Consortium’, ‘T2D-Genes Consortium’, ‘The MAGIC Investigators’ and ‘Understanding Society Scientific Group’ appeared at the end of the author list but should have appeared earlier in the list, after author Krina T. Zondervan. The errors have been corrected in the HTML version of the article

Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure underpinning 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, non-coding variants from which pinpointing causal genes remains challenging. Here, we combined data from 718,734 individuals to discover rare and low-frequency (MAF<5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which eight in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2, ZNF169) newly implicated in human obesity, two (MC4R, KSR2) previously observed in extreme obesity, and two variants in GIPR. Effect sizes of rare variants are ~10 times larger than of common variants, with the largest effect observed in carriers of an MC4R stop-codon (p.Tyr35Ter, MAF=0.01%), weighing ~7kg more than non-carriers. Pathway analyses confirmed enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically-supported therapeutic targets to treat obesity