Integrated analyses of growth differentiation factor-15 concentration and cardiometabolic diseases in humans

Growth differentiation factor-15 (GDF15) is a stress response cytokine that is elevated in several cardiometabolic diseases and has attracted interest as a potential therapeutic target. To further explore the association of GDF15 with human disease, we conducted a broad study into the phenotypic and genetic correlates of GDF15 concentration in up to 14,099 individuals. Assessment of 772 traits across 6610 participants in FINRISK identified associations of GDF15 concentration with a range of phenotypes including all-cause mortality, cardiometabolic disease, respiratory diseases and psychiatric disorders, as well as inflammatory markers. A meta-analysis of genome-wide association studies (GWAS) of GDF15 concentration across three different assay platforms (n=14,099) confirmed significant heterogeneity due to a common missense variant (rs1058587; p.H202D) in GDF15, potentially due to epitope-binding artefacts. After conditioning on rs1058587, statistical fine mapping identified four independent putative causal signals at the locus. Mendelian randomisation (MR) analysis found evidence of a causal relationship between GDF15 concentration and high-density lipoprotein (HDL) but not body mass index (BMI). Using reverse MR, we identified a potential causal association of BMI on GDF15 (IVW p(FDR) = 0.0040). Taken together, our data derived from human population cohorts do not support a role for moderately elevated GDF15 concentrations as a causal factor in human cardiometabolic disease but support its role as a biomarker of metabolic stress.Peer reviewe

A large-scale genome-wide association study meta-analysis of cannabis use disorder

Summary Background Variation in liability to cannabis use disorder has a strong genetic component (estimated twin and family heritability about 50–70%) and is associated with negative outcomes, including increased risk of psychopathology. The aim of the study was to conduct a large genome-wide association study (GWAS) to identify novel genetic variants associated with cannabis use disorder. Methods To conduct this GWAS meta-analysis of cannabis use disorder and identify associations with genetic loci, we used samples from the Psychiatric Genomics Consortium Substance Use Disorders working group, iPSYCH, and deCODE (20 916 case samples, 363 116 control samples in total), contrasting cannabis use disorder cases with controls. To examine the genetic overlap between cannabis use disorder and 22 traits of interest (chosen because of previously published phenotypic correlations [eg, psychiatric disorders] or hypothesised associations [eg, chronotype] with cannabis use disorder), we used linkage disequilibrium score regression to calculate genetic correlations. Findings We identified two genome-wide significant loci: a novel chromosome 7 locus (FOXP2, lead single-nucleotide polymorphism [SNP] rs7783012; odds ratio [OR] 1·11, 95% CI 1·07–1·15, p=1·84 × 10−9) and the previously identified chromosome 8 locus (near CHRNA2 and EPHX2, lead SNP rs4732724; OR 0·89, 95% CI 0·86–0·93, p=6·46 × 10−9). Cannabis use disorder and cannabis use were genetically correlated (rg 0·50, p=1·50 × 10−21), but they showed significantly different genetic correlations with 12 of the 22 traits we tested, suggesting at least partially different genetic underpinnings of cannabis use and cannabis use disorder. Cannabis use disorder was positively genetically correlated with other psychopathology, including ADHD, major depression, and schizophrenia. Interpretation These findings support the theory that cannabis use disorder has shared genetic liability with other psychopathology, and there is a distinction between genetic liability to cannabis use and cannabis use disorder. Funding National Institute of Mental Health; National Institute on Alcohol Abuse and Alcoholism; National Institute on Drug Abuse; Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing; The European Commission, Horizon 2020; National Institute of Child Health and Human Development; Health Research Council of New Zealand; National Institute on Aging; Wellcome Trust Case Control Consortium; UK Research and Innovation Medical Research Council (UKRI MRC); The Brain & Behavior Research Foundation; National Institute on Deafness and Other Communication Disorders; Substance Abuse and Mental Health Services Administration (SAMHSA); National Institute of Biomedical Imaging and Bioengineering; National Health and Medical Research Council (NHMRC) Australia; Tobacco-Related Disease Research Program of the University of California; Families for Borderline Personality Disorder Research (Beth and Rob Elliott) 2018 NARSAD Young Investigator Grant; The National Child Health Research Foundation (Cure Kids); The Canterbury Medical Research Foundation; The New Zealand Lottery Grants Board; The University of Otago; The Carney Centre for Pharmacogenomics; The James Hume Bequest Fund; National Institutes of Health: Genes, Environment and Health Initiative; National Institutes of Health; National Cancer Institute; The William T Grant Foundation; Australian Research Council; The Virginia Tobacco Settlement Foundation; The VISN 1 and VISN 4 Mental Illness Research, Education, and Clinical Centers of the US Department of Veterans Affairs; The 5th Framework Programme (FP-5) GenomEUtwin Project; The Lundbeck Foundation; NIH-funded Shared Instrumentation Grant S10RR025141; Clinical Translational Sciences Award grants; National Institute of Neurological Disorders and Stroke; National Heart, Lung, and Blood Institute; National Institute of General Medical Sciences.Peer reviewe

Transancestral GWAS of alcohol dependence reveals common genetic underpinnings with psychiatric disorders

Liability to alcohol dependence (AD) is heritable, but little is known about its complex polygenic architecture or its genetic relationship with other disorders. To discover loci associated with AD and characterize the relationship between AD and other psychiatric and behavioral outcomes, we carried out the largest genome-wide association study to date of DSM-IV-diagnosed AD. Genome-wide data on 14,904 individuals with AD and 37,944 controls from 28 case-control and family-based studies were meta-analyzed, stratified by genetic ancestry (European, n = 46,568; African, n = 6,280). Independent, genome-wide significant effects of different ADH1B variants were identified in European (rs1229984; P = 9.8 x 10(-13)) and African ancestries (rs2066702; P = 2.2 x 10(-9)). Significant genetic correlations were observed with 17 phenotypes, including schizophrenia, attention deficit-hyperactivity disorder, depression, and use of cigarettes and cannabis. The genetic underpinnings of AD only partially overlap with those for alcohol consumption, underscoring the genetic distinction between pathological and nonpathological drinking behaviors.Peer reviewe

Verkkokoulutusmateriaali suorien vatsalihasten erkauman tunnistamisesta ja ohjausmenetelmistä

Vatsalihasten erkaantumassa suorat vatsalihakset erkaantuvat toisistaan vartalon keskilinjasta ja venyttävät valkoista jännesaumaa ja vatsalihasten lihaskalvoja. Vatsalihasten erkauma on yleinen raskaana olevilla ja synnyttäneillä naisilla, mutta sitä esiintyy myös miehillä ja lapsilla. Synnytyksen jälkeen erkauma palautuu useimmiten luonnollisesti parin kuukauden aikana. Osalla erkauma jää normaalia suuremmaksi ja kuntouttamiseen tarvitaan fysioterapian menetelmiä. Erkauma heikentää vatsanseinämän normaalia toimintaa ja voi johtaa lantiokorin -ja lantionpohjan toimintahäiriöihin. Selkärangan ja lantionkorin ylikuormittuminen voivat lisätä altistusta erilaisille tuki- ja liikuntaelin-vammoille. Kansainvälisesti aiheesta on julkaistu tutkimuksia yhä enemmän, mutta suomenkielistä tutkittua tietoa on hyvin vähän. Kliinisestä hoidosta ei ole vielä tehty yhtenäistä konservatiivista hoitolinjausta. Työn tavoitteena oli verkkokoulutusmateriaalin kautta lisätä tietoa suorien vatsalihasten erkaumasta, ennaltaehkäisemisestä, tunnistamisesta ja hoitokeinoista tuleville terveydenhoitajille. Tavoitteena oli koota tietoa keskeisistä asioista ja ohjaustavoista asiakasneuvontaa varten sekä lisätä moniammatillista yhteistyötä. Tiedon lisääntymisen myötä tavoitteena on ehkäistä tai vähentää erkauman aiheuttamia toimintahäiriöitä. Työ suunniteltiin esimateriaaliksi Saimaan ammattikorkeakoulun 4. lukuvuoden terveydenhoitajaopiskelijoiden Lasta odottavien ja lapsiperheiden terveydenhoitajatyön opintokokonaisuuden yhteyteen. Työ toteutettiin yhteistyössä Saimaan ammattikorkeakoulun kanssa. Tiedonhakuprosessissa tietoa haettiin tieteellisistä tutkimuksista, alaan liittyvästä kirjallisuudesta sekä asiantuntijahaastattelusta, joita hyödynnettiin koulutusmateriaalin sisällön suunnittelussa. Lisäksi Etelä-Karjalan sosiaali- ja terveyspiirin (Eksoten) terveydenhoitajille suunnattiin kyselytutkimus. Tutkimustulosten perusteella lisätietoa tarvittiin erkauman tunnistamisesta, ennaltaehkäisystä ja kuntouttavista harjoitteista. Koulutusmateriaali sisälsi taustatietoa suorien vatsalihasten erkaumasta ja anatomisista rakenteista. Tämän lisäksi materiaali sisälsi käytännön opastusta asiakkaan haastattelusta, erkauman tunnistamisesta, tutkimisesta ja ennaltaehkäisevistä neuvontakeinoista. Kokonaisuudet rakentuivat diasarjoista, kuvista, opastusvideoista ja kertaustehtävistä. Verkkokoulutusmateriaali julkaistiin Moodle- oppimisalustalla. Opinnäytetyöstä hyötyvät terveydenhoitoalalla työskentelevät henkilöt (fysioterapeutit, terveydenhoitajat, lääkärit, kätilöt, sairaanhoitajat). Työtä voidaan käyttää opetusmateriaalina kouluissa sekä fysioterapia- ja muissa terveydenhuollon laitoksissa