Is Brain-Derived Neurotrophic Factor Associated With Smoking Initiation? Replication Using a Large Finnish Population Sample : Replication Using a Large Finnish Population Sample

Introduction: Brain-derived neurotrophic factor (BDNF) is a growth factor in the central nervous system. There is evidence for the involvement of BDNF in addictions and mental disorders. We aimed to replicate the earlier reported association of a functional genetic variant of BDNF with smoking initiation (SI) using a large population-based sample and to test whether the association is independent of depression. Methods: Our sample was drawn from the Finnish population-based FINRISK surveys conducted in 1992, 1997, 2002, and 2007. We had nonmissing data on the genotype BDNF Val66Met (G/A) variant (rs6265) and self-reported never (n = 10 619) versus ever (n = 16 028) smoking among 26 647 adults aged 25-74 years. The association between BDNF Val66Met and SI was modeled using logistic regression adjusted for age and sex, and in secondary analyses also for depression. Depression was defined as self-reported depression diagnosed or treated by physician during the past year. Results:The sex- and age-adjusted analysis confirmed that the major (Val) allele increased the risk of being a lifetime ever smoker (per allele odds ratio [OR] = 1.07; 95% CI = 1.01 to 1.12; p =.01). When depression, which itself was significantly associated with SI (OR = 1.58; 95% CI = 1.37 to 1.82; p Conclusions: In a Finnish population sample, we replicated the earlier reported association of BDNF Val66Met with SI. Our data further suggest that this association is independent of depression.Peer reviewe

“Tuntuu, että mä rentoudun, kun saan keskittyä siihen ja unohtaa kaiken muun” : Nuorten kokemuksia käsityön tuottamasta hyvinvoinnista työpajatoiminnassa

Tutkimuksen tarkoituksena oli tarkastella ohjatun käsityötoiminnan tuottamaa hyvinvointia nuorten työpajan starttiosaston nuorten kokemuksien kautta. Teoriassa määrittelimme hyvinvointia käsitteenä psyykkisistä ja sosiaalisista näkökulmista, ja liitimme ne käsityön tuottamaan hyvinvointiin. Hyvinvoinnin kokemukset ovat yksilöllisiä, ja niihin liittyy elämän merkitykselliseksi kokeminen. Merkityksellisiä kokemuksia on mahdollista saada käsitöiden kautta. Käsitöiden tekemiseen liitetään kokemuksia itseilmaisusta, henkilökohtaisesta kasvusta, rentoutumisesta ja rauhoittumisesta. Ohjasimme nuorille käsityötoimintaa yhdentoista viikon ajan starttipajalla, joka toimi nuorten työpajan alaisena. Nuoret suunnittelivat painokuvioita, painoivat kangasta, tekivät kokeiluja ja valmistivat näistä itselleen tuotteita kuten laukkuja, tyynyjä ja pussilakanoita. Järjestimme ohjattua käsityötoimintaa starttipajalla siten, että otimme huomioon työpajan metodit ja osallistujien tarpeet. Keskityimme ohjauksessa erityisesti positiivisen palautteen antamiseen ja hyvään vuorovaikutukseen nuorten kanssa. Keräsimme aineiston havainnoimalla työskentelyä ja yleistä ilmapiiriä käsityötoiminnan aikana, minkä jälkeen haastattelimme nuoria. Keskustelimme nuorten kanssa käsityön tekemisen tuottamista tuntemuksista koko yhdentoista ohjauskerran ajan. Käytimme yksilöhaastatteluissa kysymysten pohjana teoriaa ja työskentelyn aikana nuorilta esiin tulleita teemoja. Aikaisempien tutkimusten perusteella sekä aineistosta nousseiden teemojen pohjalta päädyimme havainnoimaan kolmea osa-aluetta: käsityön tekemisen tuottamia tuntemuksia, käsityön tuottamaa hyvinvointia ja käsityön yhteyttä minäpystyvyyden tunteeseen. Haastatteluista ja havainnoista saamiemme tulosten mukaan nuoret kokivat hyvinvointia käsityöpajan aikana. He rauhoittuivat työskentelyn äärellä ja unohtivat muut murheensa. Vastauksissaan nuoret näkivät käsityön ensisijaisesti rentouttavana ja rauhoittavana toimintana. Hyvinvointia tuottavaan käsityöhön yhdistyi erityisesti itselle mieluisan työn tekeminen sekä rauhallinen ja työskentelyä tukeva ympäristö. Käsityön yhteys hyvinvointiin näyttäytyi suurelta osin samanlaisina kuin aiemmissa aihetta koskevissa tutkimuksissa, joissa käsityö tuotti hyvinvointia rentoutumisen, terapeuttisuuden, sosiaalisten suhteiden ja henkilökohtaisen kasvun muodossa. Tämän tutkimuksen nuorissa epävarmuutta aiheutti pelko epäonnistumisesta, mikä oli merkittävin ero muihin tutkimuksiin

High-resolution population-specific recombination rates and their effect on phasing and genotype imputation

Previous research has shown that using population-specific reference panels has a significant effect on downstream population genomic analyses like haplotype phasing, genotype imputation, and association, especially in the context of population isolates. Here, we developed a high-resolution recombination rate mapping at 10 and 50 kb scale using high-coverage (20-30x) whole-genome sequenced data of 55 family trios from Finland and compared it to recombination rates of non-Finnish Europeans (NFE). We tested the downstream effects of the population-specific recombination rates in statistical phasing and genotype imputation in Finns as compared to the same analyses performed by using the NFE-based recombination rates. We found that Finnish recombination rates have a moderately high correlation (Spearman's rho = 0.67-0.79) with NFE, although on average (across all autosomal chromosomes), Finnish rates (2.268 +/- 0.4209 cM/Mb) are 12-14% lower than NFE (2.641 +/- 0.5032 cM/Mb). Finnish recombination map was found to have no significant effect in haplotype phasing accuracy (switch error rates similar to 2%) and average imputation concordance rates (97-98% for common, 92-96% for low frequency and 78-90% for rare variants). Our results suggest that haplotype phasing and genotype imputation mostly depend on population-specific contexts like appropriate reference panels and their sample size, but not on population-specific recombination maps. Even though recombination rate estimates had some differences between the Finnish and NFE populations, haplotyping and imputation had not been noticeably affected by the recombination map used. Therefore, the currently available HapMap recombination maps seem robust for population-specific phasing and imputation pipelines, even in the context of relatively isolated populations like Finland.Peer reviewe

Bevasitsumabi ei-pienisoluisen keuhkosyövän hoidossa

Edenneen tai levinneen ei-pienisoluisen keuhkosyövän hoito nykyisillä solunsalpaajilla parhaimmillaan vain hidastaa taudin etenemistä, eikä parantavaa hoitoa tunneta. Uusien antiangiogeneettisten lääkkeiden, kuten bevasitsumabin, on odotettu muuttavan taudin hoitoa ja ennustetta. Bevasitsumabista on tehty kaksi satunnaistettua tutkimusta, joissa sen todettiin tehostavan hoitoa yhdistettynä platinasolunsalpaajayhdistelmään valikoidussa potilasryhmässä. Mielestämme nykyinen tutkimusnäyttö ei kuitenkaan puolla bevasitsumabin käyttöä keuhkosyövän standardihoitona. Haittavaikutukset on opittu hallitsemaan hyvin, mutta vielä tulisi pystyä määrittämään se ryhmä hoitoon soveltuvista potilaista, joka hyötyisi merkittävästi. Tämän ryhmän löytämiseksi tarvitaan kliinisten ennustetekijöiden ja mahdollisten biologisten merkkiaineiden tutkimusta. English summary: Bevasizumab in the treatment of non-small cell lung cancer Treatment of advanced or metastatic non-small cell lung cancer with current cytotoxic agents is at its best able to only slow down the progression of the disease, while no curative treatment is known. Novel antiangiogenetic agents such as Bevacizumab have been expected to bring about a change in the treatment and prognosis of this disease. Two randomized studies have been conducted with Bevacizumab, whereby it was observed to make the therapeutic results more effective when combined with a cytotoxic platinum agent in a selected patient group. In our opinion the current scientific evidence does not yet support the use of Bevacizumab as the standard therapy for lung cancer

Parempaa terveyttä ja ympäristöä

Ympäristöterveys.Luontoaskel terveyteen -ohjelma yhdistää Päijät-Hämeen terveys- ja ympäristötavoitteet. Ohjelmatyön taustalla on tieto siitä, että yleistyvät kansansairaudet kytkeytyvät ympäristö- ja elintapa¬muutoksiin

Landscape of multi-nucleotide variants in 125,748 human exomes and 15,708 genomes

Multi-nucleotide variants (MNVs), defined as two or more nearby variants existing on the same haplotype in an individual, are a clinically and biologically important class of genetic variation. However, existing tools typically do not accurately classify MNVs, and understanding of their mutational origins remains limited. Here, we systematically survey MNVs in 125,748 whole exomes and 15,708 whole genomes from the Genome Aggregation Database (gnomAD). We identify 1,792,248 MNVs across the genome with constituent variants falling within 2bp distance of one another, including 18,756 variants with a novel combined effect on protein sequence. Finally, we estimate the relative impact of known mutational mechanisms - CpG deamination, replication error by polymerase zeta, and polymerase slippage at repeat junctions - on the generation of MNVs. Our results demonstrate the value of haplotype-aware variant annotation, and refine our understanding of genome-wide mutational mechanisms of MNVs. Multi-nucleotide variants (MNV) are genetic variants in close proximity of each other on the same haplotype whose functional impact is difficult to predict if they reside in the same codon. Here, Wang et al. use the gnomAD dataset to assemble a catalogue of MNVs and estimate their global mutation rate.Peer reviewe

Characterising the loss-of-function impact of 5' untranslated region variants in 15,708 individuals

Upstream open reading frames (uORFs) are tissue-specific cis-regulators of protein translation. Isolated reports have shown that variants that create or disrupt uORFs can cause disease. Here, in a systematic genome-wide study using 15,708 whole genome sequences, we show that variants that create new upstream start codons, and variants disrupting stop sites of existing uORFs, are under strong negative selection. This selection signal is significantly stronger for variants arising upstream of genes intolerant to loss-of-function variants. Furthermore, variants creating uORFs that overlap the coding sequence show signals of selection equivalent to coding missense variants. Finally, we identify specific genes where modification of uORFs likely represents an important disease mechanism, and report a novel uORF frameshift variant upstream of NF2 in neurofibromatosis. Our results highlight uORF-perturbing variants as an under-recognised functional class that contribute to penetrant human disease, and demonstrate the power of large-scale population sequencing data in studying non-coding variant classes. Upstream open reading frames (uORFs), located in 5' untranslated regions, are regulators of downstream protein translation. Here, Whiffin et al. use the genomes of 15,708 individuals in the Genome Aggregation Database (gnomAD) to systematically assess the deleteriousness of variants creating or disrupting uORFs.Peer reviewe

Cross-trait analyses with migraine reveal widespread pleiotropy and suggest a vascular component to migraine headache

Background: Nearly a fifth of the world's population suffer from migraine headache, yet risk factors for this disease are poorly characterized. Methods: To further elucidate these factors, we conducted a genetic correlation analysis using cross-trait linkage disequilibrium (LD) score regression between migraine headache and 47 traits from the UK Biobank. We then tested for possible causality between these phenotypes and migraine, using Mendelian randomization. In addition, we attempted replication of our findings in an independent genome-wide association study (GWAS) when available. Results: We report multiple phenotypes with genetic correlation (P < 1.06 × 10-3) with migraine, including heart disease, type 2 diabetes, lipid levels, blood pressure, autoimmune and psychiatric phenotypes. In particular, we find evidence that blood pressure directly contributes to migraine and explains a previously suggested causal relationship between calcium and migraine. Conclusions: This is the largest genetic correlation analysis of migraine headache to date, both in terms of migraine GWAS sample size and the number of phenotypes tested. We find that migraine has a shared genetic basis with a large number of traits, indicating pervasive pleiotropy at migraine-associated loci.Peer reviewe

Common Variant Burden Contributes to the Familial Aggregation of Migraine in 1,589 Families

Complex traits, including migraine, often aggregate in families, but the underlying genetic architecture behind this is not well understood. The aggregation could be explained by rare, penetrant variants that segregate according to Mendelian inheritance or by the sufficient polygenic accumulation of common variants, each with an individually small effect, or a combination of the two hypotheses. In 8,319 individuals across 1,589 migraine families, we calculated migraine polygenic risk scores (PRS) and found a significantly higher common variant burden in familial cases (n = 5,317, OR = 1.76, 95% CI = 1.71-1.81, p = 1.7 × 10-109) compared to population cases from the FINRISK cohort (n = 1,101, OR = 1.32, 95% CI = 1.25-1.38, p = 7.2 × 10-17). The PRS explained 1.6% of the phenotypic variance in the population cases and 3.5% in the familial cases (including 2.9% for migraine without aura, 5.5% for migraine with typical aura, and 8.2% for hemiplegic migraine). The results demonstrate a significant contribution of common polygenic variation to the familial aggregation of migraine

Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.

We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease