Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension

High blood pressure is a major risk factor for cardiovascular disease and premature death. However, there is limited knowledge on specific causal genes and pathways. To better understand the genetics of blood pressure, we genotyped 242,296 rare, low-frequency and common genetic variants in up to ~192,000 individuals, and used ~155,063 samples for independent replication. We identified 31 novel blood pressure or hypertension associated genetic regions in the general population, including three rare missense variants in RBM47, COL21A1 and RRAS with larger effects (>1.5mmHg/allele) than common variants. Multiple rare, nonsense and missense variant associations were found in A2ML1 and a low-frequency nonsense variant in ENPEP was identified. Our data extend the spectrum of allelic variation underlying blood pressure traits and hypertension, provide new insights into the pathophysiology of hypertension and indicate new targets for clinical intervention

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

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

The trans-ancestral genomic architecture of glycemic traits

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 x 10(-8)), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution. A trans-ancestry meta-analysis of GWAS of glycemic traits in up to 281,416 individuals identifies 99 novel loci, of which one quarter was found due to the multi-ancestry approach, which also improves fine-mapping of credible variant sets.Peer reviewe

Maternal plasma levels of oxytocin during physiological childbirth - a systematic review with implications for uterine contractions and central actions of oxytocin

Oxytocin is a key hormone in childbirth, and synthetic oxytocin is widely administered to induce or speed labour. Due to lack of synthetized knowledge, we conducted a systematic review of maternal plasma levels of oxytocin during physiological childbirth, and in response to infusions of synthetic oxytocin, if reported in the included studies. An a priori protocol was designed and a systematic search was conducted in PubMed, CINAHL, and PsycINFO in October 2015. Search hits were screened on title and abstract after duplicates were removed (n = 4039), 69 articles were examined in full-text and 20 papers met inclusion criteria. As the articles differed in design and methodology used for analysis of oxytocin levels, a narrative synthesis was created and the material was categorised according to effects. Basal levels of oxytocin increased 3-4-fold during pregnancy. Pulses of oxytocin occurred with increasing frequency, duration, and amplitude, from late pregnancy through labour, reaching a maximum of 3 pulses/10 min towards the end of labour. There was a maximal 3- to 4-fold rise in oxytocin at birth. Oxytocin pulses also occurred in the third stage of labour associated with placental expulsion. Oxytocin peaks during labour did not correlate in time with individual uterine contractions, suggesting additional mechanisms in the control of contractions. Oxytocin levels were also raised in the cerebrospinal fluid during labour, indicating that oxytocin is released into the brain, as well as into the circulation. Oxytocin released into the brain induces beneficial adaptive effects during birth and postpartum. Oxytocin levels following infusion of synthetic oxytocin up to 10 mU/min were similar to oxytocin levels in physiological labour. Oxytocin levels doubled in response to doubling of the rate of infusion of synthetic oxytocin. Plasma oxytocin levels increase gradually during pregnancy, and during the first and second stages of labour, with increasing size and frequency of pulses of oxytocin. A large pulse of oxytocin occurs with birth. Oxytocin in the circulation stimulates uterine contractions and oxytocin released within the brain influences maternal physiology and behaviour during birth. Oxytocin given as an infusion does not cross into the mother's brain because of the blood brain barrier and does not influence brain function in the same way as oxytocin during normal labour does

Who influences you? : A study of how guidance counselors reason and relate to situations where thestudents' study and career choices are made collectively

Omgivningen påverkar alla människor i varierande utsträckning, inte minst när ett studie- ochyrkesval fattas. Den här undersökningens syfte är att synliggöra hur sex yrkesverksammastudie- och yrkesvägledare resonerar och förhåller sig i vägledning där elevens studie- ochyrkesval fattas kollektivt. Kunskap från denna undersökning skulle kunna bidra med insikteroch perspektiv på hur vägledarprofessionen kan stödja elever som befinner sig i en positiondär studie- och yrkesval fattas mer kollektivt än individualistiskt. Vår empiri belyser attföräldrar påverkar elevers studie- och yrkesval i störst utsträckning. Andra påverkansfaktorersom synliggörs i vår empiri är kompisar, lärare och sociala medier. Det framgår också attstatus har ett inflytande i val av yrke eller utbildning samt att vårdnadshavarna och elevernaibland har en bristande kunskap om hur det svenska skolsystemet fungerar, vilket kanresultera i mindre underbyggda karriärval. I under- sökningen använder vi oss av en kvalitativmetod med semistrukturerade intervjuer. Syftet med intervjumetoden är att följa upp medföljdfrågor där informanterna kan utveckla sina resonemang och vara mer utförlig i svaren.De teoretiska begrepp som används för att analysera empirin är handlingshorisont, habitus,socialt- och utbildningskapital

Barn som har Downs syndrom och deras skolgång : föräldrarnas möjlighet att välja skolform och hur de ser på sina barns skolgång

Sammanfattning Samarbetet med föräldrar är en viktig faktor för att barnens förskoletid och skolgång ska bli så bra som möjligt. Utifrån detta är syftet med vårt examensarbete att få en inblick i hur föräldrar till barn som har Downs syndrom ser på sina barns skolgång. Vår frågeställning lyder:  Vilken möjlighet att välja skolform för sina barn upplever de föräldrar som svarat på enkäten att de har?  Hur ser de föräldrar som svarat på enkäten på sina barns skolplacering?  Om de föräldrar som svarat på enkäten hade möjlighet att välja, vad avgjorde deras val?  Har barnens födelseår någon påverkan för hur föräldrarna har svarat? För att få svar på våra frågor valde vi att använda oss av en enkät. Enkäten lämnades ut till 32 stycken familjer och av dessa var det fem föräldrar som svarade. Bland de fem svar vi fick var det tre barn som var integrerade elever i grundskolan och två som gått inom träningsskolan. De föräldrar som haft sina barn inom träningsskolan gav svar som visade på ett totalt missnöje med barnens skolgång, medan de som hade barn inom grundskolan gav positiva svar. Barnens födelseår hade påverkan på föräldrarnas möjlighet att välja skolform.Abstract Cooperation with parents is an important factor to make the children’s preschool and schooling as good as possible. The purpose of our thesis is to gain an insight into how parents of children with Down syndrome see at their children's schooling. Our questions are: What possibilities for choice of school for their children perceive the parents who responded to the questionnaire that they have? How do these parents regard their child’s school allocation? If any of the parents had a say in the placing of their child what was the deciding factor for their choice? Has the children’s year of birth impact on how parents have responded? In order to get an answer to our questions, we chose to use a questionnaire. The questionnaire was sent out to thirty-two families and of these, there were five who answered. Among the five answers we received were three children who were integrated pupils in primary school and two who were enrolled in the training school. The parents who had their children in the training school gave answers that indicated a total dissatisfaction with their children’s schooling, while those who have children in elementary school gave a positive response. The children’s year of birth had impact at the parents’ opportunity of the selection of school form

Who influences you? : A study of how guidance counselors reason and relate to situations where thestudents' study and career choices are made collectively

Omgivningen påverkar alla människor i varierande utsträckning, inte minst när ett studie- ochyrkesval fattas. Den här undersökningens syfte är att synliggöra hur sex yrkesverksammastudie- och yrkesvägledare resonerar och förhåller sig i vägledning där elevens studie- ochyrkesval fattas kollektivt. Kunskap från denna undersökning skulle kunna bidra med insikteroch perspektiv på hur vägledarprofessionen kan stödja elever som befinner sig i en positiondär studie- och yrkesval fattas mer kollektivt än individualistiskt. Vår empiri belyser attföräldrar påverkar elevers studie- och yrkesval i störst utsträckning. Andra påverkansfaktorersom synliggörs i vår empiri är kompisar, lärare och sociala medier. Det framgår också attstatus har ett inflytande i val av yrke eller utbildning samt att vårdnadshavarna och elevernaibland har en bristande kunskap om hur det svenska skolsystemet fungerar, vilket kanresultera i mindre underbyggda karriärval. I under- sökningen använder vi oss av en kvalitativmetod med semistrukturerade intervjuer. Syftet med intervjumetoden är att följa upp medföljdfrågor där informanterna kan utveckla sina resonemang och vara mer utförlig i svaren.De teoretiska begrepp som används för att analysera empirin är handlingshorisont, habitus,socialt- och utbildningskapital