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.

A Gly98Val Mutation in the N-Myc Downstream Regulated Gene 1 (NDRG1) in Alaskan Malamutes with Polyneuropathy

Peer reviewe

A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

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

Sex-stratified Genome-wide Association Studies Including 270,000 Individuals Show Sexual Dimorphism in Genetic Loci for Anthropometric Traits

Peer reviewe

A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.Peer reviewe

Kränkande behandling ­ En studie av likabehandlingsplaner och förebyggande metoder och arbetssätt

Under vår verksamhetsförlagda utbildning väcktes vårt intresse för hur vi i vår kommande profession skulle bemöta både de verbala och fysiska kränkningar vi tyckte att eleverna ofta utsatte varandra för. Enligt styrdokumenten är kravet stort på att lärare ska kunna hantera dessa situationer i både förebyggande och motverkande syfte. Vi kom då speciellt att intressera oss för den i skolorna nyinrättande likabehandlingsplanen som regleras i Lagen om förbud mot diskriminering och annan kränkande behandling av barn och elever. Syftet med studien har varit att först undersöka huruvida våra VFU-skolors likabehandlingsplaner är formulerade utifrån Skolverkets allmänna råd. Därefter har vi studerat och beskrivit ett urval av arbetsmetoder som inriktar sig på förebyggande åtgärder mot kränkande behandling. Vårt examensarbete kom alltså att fokusera på två punkter. Vi har genom litteraturstudier försökt klargöra bakgrunden till den nya lagens tillkomst, vad begreppet kränkande behandling innebär, vilka kriterier som finns för likabehandlingsplanernas utformning och vilket utbud av förebyggande metoder som finns att tillgå. Vårt metodval har varit komparativa fallstudier och analys. Med intresse har vi jämfört hur likabehandlingsplanerna korrelerar med de krav som enligt Skolverket ställs på deras innehåll. Vi har även analyserat likheter och olikheter hos de förebyggande metoder och arbetssätt vi beskrivit, utan att ha för avsikt att avgöra vilka som är bäst. I resultatet synliggörs skolornas svårigheter att leva upp till de krav som ställs, både ifråga om dokumentupprättande och att aktivt och genomtänkt välja förebyggande metoder. Trots att likabehandlingsplanerna inte alltid är utförligt formulerade, kan förhoppningsvis kraven ändå praktiskt uppfyllas av de professionella lärarna i det vardagliga arbetet

Barn som anhöriga på en intensivvårdsavdelning : En litteraturstudie

Bakgrund: Barn som besökare på en intensivvårdsavdelning är ganska nytt förekommande, men har blivit mer vanligt. Många intensivvårdssjuksköterskor upplever dock att de saknar kompetens och stöd för att bemöta barn som anhöriga. Det finns också en osäkerhet bland hälso- och sjukvårdspersonal huruvida barn gynnas eller stressas av att se närstående vårdas i miljön på en intensivvårdsavdelning. Barn som inte tillåts vara delaktiga i vården av en närstående kan reagera med känslor av ensamhet, maktlöshet och övergivenhet. Syfte: Att beskriva barn som anhöriga på en intensivvårdsavdelning, ur barnets och intensivvårdssjuksköterskans perspektiv. Metod: En systematisk litteraturstudie med kvalitativ ansats baserad på vetenskapliga artiklar och ett induktivt förhållningssätt. Resultat: Resultatet visar att barn som anhöriga har behov av att se med egna ögon, behov av information och förberedelse samt behov av en normal vardag. Intensivvårdssjuksköterskorna beskriver att det finns ett behov av att stötta och motivera föräldrar, att vägleda det enskilda barnet men att det ofta saknas förutsättningar för att involvera barn som anhöriga. Slutsats: Det är viktigt att barn involveras i vården av en närstående på en intensivvårdsavdelning för att förhindra negativa konsekvenser nu, men även senare i livet. Det behövs stöd och förutsättningar med tydliga riktlinjer för intensivvårdssjuksköterskan att förhålla sig till när det gäller barn som anhöriga. Med en vårdande kommunikation kan intensivvårdssjuksköterskan lindra ett onödigt lidande och upprätta en gemenskap vilket gynnar alla inblandade. Background: Children as relatives in intensive care units are fairly new, but have become more common. Many intensive care nurses experience a lack of knowledge and support in order to care for children as relatives. There’s also an uncertainty among health care professionals whether children benefit or disadvantage by seeing relatives being cared for in the intensive care environment. Children who are not allowed to participate in the care of a loved one may react with feelings of loneliness, powerlessness and abandonment. Aim: To describe children as relatives in an intensive care unit, from the child and intensive care nurse perspective. Method: A systematic literature review with a qualitative approach based on scientific articles and an inductive approach. Result: The result shows that children as relatives have a need to see with their own eyes, a need for information and preparation and the need for a normal everyday life. The intensive care nurse describes that there’s a need to support and motivate parents, to guide the individual child but that there are often poor prerequisites for involving children as relatives. Conclusion: It is important that children are involved in the care of a close relative in an intensive care unit to prevent negative consequences now, but also later in life. The intensive care nurses need support and clear guidelines. With a caring communication the intensive care nurse can alleviate an unnecessary suffering and establish a communion which benefits everyone involved

Children who experience violence in a close relationship : A literature review with a focus on consequences

Bakgrund: Trots att barn har ett skyddsnät i form av lagar och riktlinjer har vart tionde barn iSverige någon gång upplevt våld i nära relation. Våldet kan ta sig i uttryck på olika sätt, till exempel fysiskt, psykiskt eller sexuellt. Barns utsatthet påverkades av flera olika faktorer blandannat personliga egenskaper, kultur och normer. Syfte: Studiens syfte var att utforska vilka konsekvenser som kan drabba barn som upplever våld inära relation, ur barnens perspektiv.  Metod: Metoden som tillämpades var en litteraturöversikt. Efter systematiska litteratursökningar inkluderades sju vetenskapliga artiklar i studien. Artiklarna kvalitetsgranskades, analyserades ochsammanställdes i kategorier. Resultat: Resultatet presenterades i två kategorier följt av fem subkategorier. I resultatetframgick det hur barn tänker, känner och agerar i våldsamma situationer. Det framgick även vilka konsekvenser våldet kunde föra med sig över tid. Konklusion: Barn uppgav att de vid den omedelbara våldssituationen att de hade flera olika tankar, känslor och beteenden. De kunde känna sig rädda, ledsna och arga. Våldet visade sig även föra med sig andra konsekvenser som utvecklades över tid till exempel emotionell och beteendemässig problematik, samt sämre prestation i skolan. De utvecklade även överlevnadsstrategier.Background: Even though children have a safety net in the form of laws and regulations, every tenth child in Sweden has at some point experienced intimate partner violence. The violence can manifest itself in various ways, for example physically, mentally, or sexually. Children's vulnerability is affected by several different factors, including personal characteristics, culture,and norms. Aim: The aim of the study was to explore the consequences that can affect children who experience intimate partner violence, from the children's perspective. Method: The method used was a literature review. After several systematic literature searches, seven scientific articles were included in the study. The articles were quality reviewed, analyzedand compiled into categories. Results: The results were presented in two categories followed by five subcategories. The results showed how children think, feel and act in violent situations. It was also clear what consequencesviolence could bring over time. Conclusion: Children stated that in the immediate situation of violence they had several different thoughts, feelings, and behaviors. They felt scared, sad and angry. The violence also turned out tohave other consequences that developed over time, such as emotional and behavioral problems aswell as poorer performance in school. They also developed survival strategies