Nicotine Dependence : Identifying the Contribution of Specific Genes

Cigarette smoking is a worldwide health burden causing several diseases. Chronic obstructive pulmonary disease, heart disease and several cancers remain the main avoidable causes for premature deaths. Among smokers, tobacco use is largely motivated by nicotine dependence (ND). Smoking is influenced by the complex interplay between genetic vulnerability, environmental risk factors and individual characteristics. Despite the high heritability estimates of ND, the underlying genetic factors remain largely unknown. This work aimed to identify the contribution of genes and specific genetic variants predisposing individuals to smoking behavior and ND, and to further assess their ability to explain other smoking-related comorbidities and traits, such as alcohol use. A Finnish twin family sample enriched for heavy smoking was used to map susceptibility genes for smoking-related phenotypes. Using a dense set of markers on chromosome 20, the previous linkage finding (Loukola et al., 2008) was replicated with an ND measure diagnosed by the Diagnostic and Statistical Manual of Mental Disorders (DSM), 4th edition (DSM-IV) criteria. The finding was extended using a larger sample. Sex-stratified analyses provided a clear distinction between genetic elements on chromosome 20 that influence ND in adult male and female smokers. This study highlights linkage between chromosome 20 and ND in Finnish adult smokers. The same Finnish twin family sample was used in a GWAS for smoking behavior. The data was imputed using the 1000 Genomes Phase I reference panel together with a whole genome sequence-based Finnish reference panel obtained from the Sequencing Initiative Suomi (SISu) project. The study yielded genome-wide significant association on 16p12.3 with smoking quantity defined as self-reported cigarettes smoked per day (CPD). Several highly correlating single nucleotide polymorphisms (SNPs) within the association region map to an intergenic locus near gene CLEC19A. In addition, association was detected on 11p15.5 with nicotine withdrawal symptoms assessed by the DSM-IV criteria. The finding pinpointed genes AP2A2 and MUC6. These findings on chromosomes 16 and 11 highlight the role of neurotrophin signaling pathway in smoking behavior. The most robust smoking behavior locus to date has been mapped to chromosome 15q24-q25, which harbors a gene cluster (CHRNA5-CHRNA3-CHRNB4) encoding nicotinic acetylcholine receptor (nAChR) subunits α5, α3 and β4. Three of the most intensively studied SNPs on the locus were analyzed by combining two large and individual Finnish population-based samples, The National FINRISK Study and The Health 2000 Survey, into one sample. The study replicated an earlier finding reporting association between three distinct loci on 15q25.1 and CPD (Saccone et al., 2010), and confirmed that the alleles at this strongest smoking behavior locus explain approximately 1% of the variance in CPD. Plausible pleiotropic effects of nAChRs were examined in two studies using SNPs tagging the robust smoking behavior locus on chromosome 15. First, we provided novel evidence of association between a genetic variant on 15q25.1 and alcohol use in the National FINRISK Study and the Health 2000 Survey. Second, we participated in an international collaboration work aiming to estimate the causality between smoking and body mass index (BMI). The National FINRISK study was included in the Mendelian Randomization meta-analyses, which demonstrated that variants on 15q25.1 may contribute to BMI: never smokers are associated with higher BMI, whereas current smokers are associated with lower BMI. Taken together, these results improve our knowledge of the genetic factors affecting smoking behavior and ND. They also provide further evidence on the pleiotropic effects of the nAChRs. However, bigger samples and large collaborations are needed to observe the many small effects of yet unidentified variants affecting complex traits.Tupakoinnin terveyshaitat luovat yhden suurimmista uhkakuvista kansanterveydelle maailmanlaajuisesti. Keuhkoahtaumatauti, sydänsairaudet sekä useat syövät muodostavat mittavan osuuden tupakoinnin aiheuttamista ennaltaehkäistävistä kuolemista. Tupakointi ja sitä ylläpitävä nikotiiniriippuvuus ovat monitekijäisiä ilmiasuja, joihin vaikuttavat niin ympäristö, perimä kuin henkilön yksilölliset ominaisuudet. Perinnölliset tekijät selittävät noin puolet nikotiiniriippuvuuden normaalivaihtelusta, miksi onkin olennaista kartoittaa ja ymmärtää sen geneettinen tausta. Yllättäen, koko perimänlaajuisissa assosiaatiotutkimuksissa tähän mennessä identifioidut riskivariantit selittävät vain pienen osan nikotiiniriippuvuuden vaihtelusta. Tässä väitöstutkimuksessa kartoitettiin perimänlaajuisesti geenien sekä kirjallisuuden pohjalta valikoitujen yhden emäksen variaatioiden yhteyksiä tupakointikäyttäytymiseen ja nikotiiniriippuvuuteen. Tavoitteena oli selvittää geenivarianttien kyky selittää ihmistenvälisiä eroja niin nikotiiniriippuvuudessa kuin alkoholinkäytössä. Aikaisempiin geneettisiin kytkentätutkimuksiin pohjautuen kromosomi 20 hienokartoitettiin mikrosatelliittigeenimerkkien avulla suomalaisessa kaksosperheaineistossa. Aikaisempi kytkös nikotiiniriippuvuuden ja kromosomin välillä vahvistettiin. Lisäksi sukupuolten välillä havaittiin selkeä ero nikotiiniriippuvuuteen vaikuttavissa geenimerkeissä. Samassa suomalaisessa kaksosperheaineistossa selvitettiin koko perimänlaajuisella assosiaatiotutkimuksella geenivarianttien yhteyttä tupakointikäyttäytymiseen, nikotiiniriipuvuuteen sekä nikotiinivieroitusoireisiin. Tutkimus osoitti selkeän yhteyden kromosomin 16 geenivarianttien ja päivittäisen tupakkamäärän välillä. Yhteys paikannettiin lähelle geeniä CLEC19A. Kromosomin 11 ja nikotiinivieroitusoireiden välillä havaittiin yhteys, joka paikannettiin geeneihin AP2A2 ja MUC6. Nämä tulokset korostavat hermostollisen kehityksen ja selviytymisen kannalta oleellisen neurotrofiinien viestintäketjun merkitystä tupakointikäyttäytymisen taustalla. Kromosomissa 15 sijaitsevien nikotiinireseptorigeenien CHRNA5, CHRNA3 ja CHRNB4 yhteyttä suomalaisten tupakointikäyttäytymiseen selvitettiin kolmen tunnetun geenivariantin avulla FINRISKI ja Terveys 2000 aineistoissa. Tutkimuksemme vahvisti aikaisemman havainnon kolmesta yhden emäksen variaatioista, joilla on itsenäinen yhteys päivättäiseen tupakkamäärään. Tutkimus varmisti vahvimman lokuksen selittävän noin yhden prosentin tupakkamäärässä havaitusta vaihtelusta. Tupakointiin ja tupakoinnista aiheutuviin terveyshaittoihin vahvasti yhdistetyn geenialueen mahdollisia monivaikutteisia ominaisuuksia määritettiin kahdessa eri tutkimuksessa niin ikään kromosomin 15 tunnettujen geenivarianttien avulla. Ensimmäisessä tutkimuksessa havaittiin uusi yhteys nikotiinireseptoreiden ja alkoholin käytön välillä. Toisessa tutkimuksessa arvioitiin tupakoinnin vaikutusta painoindeksiin. Kyseinen kausaalitutkimus oli osa laajempaa kansainvälistä konsortiotutkimusta. Osatyön mukaan tupakoimattomilla henkilöillä geenivariantti oli yhteydessä korkeampaan painoindeksiin, kun taas tupakoivilla henkilöillä sama geenimuunnos oli yhteydessä alhaisempaan painoindeksiin. Väitöstutkimuksessa havaittujen tulosten avulla olemme saaneet lisää tietoa tupakointikäyttäytymiseen ja nikotiiniriippuvuuteen vaikuttavasta geneettisestä muuntelusta. Havaitut geenimerkit kuitenkin lisäävät perimän osuutta nikotiiniriippuvuuden selittäjänä vain vähän. Lisäksi tulokset auttavat ymmärtämään geenien monivaikutteisia ominaisuuksia. Erityisesti nikotiinireseptoreiden genomitiedon kartoittaminen voisi antaa hyödyllistä lisätietoa eri riippuvuuksien hoidon suunnittelussa

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

The burden of chronic rhinosinusitis with nasal polyps and its relation to asthma in Finland

Background Chronic rhinosinusitis with nasal polyps (CRSwNP) is commonly associated with asthma. Treatment of CRSwNP includes intranasal and systemic corticosteroids, with non-responsive patients commonly considered for endoscopic sinus surgery (ESS). This nationwide register-based study evaluated the incidence, prevalence, and treatment burden of CRSwNP in Finland, and their association with the presence and severity of comorbid asthma. Methods Electronic health records of patients diagnosed with CRSwNP between 1.1.2012 and 31.12.2018 in Finnish specialty and primary care were included in the study. The patients were divided into subgroups based on presence, severity, and control of asthma: no asthma, mild to moderate asthma, severe controlled asthma, and severe uncontrolled asthma. A mean cumulative count of ESS was calculated over time per subgroup. Results The prevalence of CRSwNP increased from 602.2 to 856.7 patients per 100,000 population between years 2012 and 2019 (p < 0.001). A total of 18,563 patients (59.9% male) had incident CRSwNP between 2012 and 2019, with 27% having asthma, 6% having severe asthma, and 1.5% having severe uncontrolled asthma. In the no asthma, severe controlled asthma, and severe uncontrolled asthma subgroups, systemic corticosteroids were used by 54.1%, 94.9% and 99.3% (p < 0.001), respectively, while the ESS count 3 years post diagnosis was 0.49, 0.68 and 0.80, respectively. Conclusions The prevalence of CRSwNP showed a significant increase in the recent decade in Finland. Comorbid asthma, and in particular severe asthma, increased the probability of receiving systemic corticosteroids and undergoing ESS. Thus, improved management of CRSwNP in patients with comorbid asthma is urgently needed.Peer reviewe

Genome-wide association study in Finnish twins highlights the connection between nicotine addiction and neurotrophin signaling pathway

The heritability of nicotine dependence based on family studies is substantial. Nevertheless, knowledge of the underlying genetic architecture remains meager. Our aim was to identify novel genetic variants responsible for interindividual differences in smoking behavior. We performed a genome-wide association study on 1715 ever smokers ascertained from the population-based Finnish Twin Cohort enriched for heavy smoking. Data imputation used the 1000 Genomes Phase I reference panel together with a whole genome sequence-based Finnish reference panel. We analyzed three measures of nicotine addiction-smoking quantity, nicotine dependence and nicotine withdrawal. We annotated all genome-wide significant SNPs for their functional potential. First, we detected genome-wide significant association on 16p12 with smoking quantity (P = 8.5 x 10(-9)), near CLEC19A. The lead-SNP stands 22 kb from a binding site for NF-kappa B transcription factors, which play a role in the neurotrophin signaling pathway. However, the signal was not replicated in an independent Finnish population-based sample, FINRISK (n = 6763). Second, nicotine withdrawal showed association on 2q21 in an intron of TMEM163 (P = 2.1 x 10(-9)), and on 11p15 (P = 6.6 x 10(-8)) in an intron of AP2A2, and P = 4.2 x 10(-7) for a missense variant in MUC6, both involved in the neurotrophin signaling pathway). Third, association was detected on 3p22.3 for maximum number of cigarettes smoked per day (P = 3.1 x 10(-8)) near STAC. Associating CLEC19A and TMEM163 SNPs were annotated to influence gene expression or methylation. The neurotrophin signaling pathway has previously been associated with smoking behavior. Our findings further support the role in nicotine addiction.Peer reviewe

Scrutiny of the CHRNA5-CHRNA3-CHRNB4 smoking behavior locus reveals a novel association with alcohol use in a Finnish population based study

The CHRNA5-CHRNA3-CHRNB4 gene cluster on chromosome 15q25.1 encoding the cholinergic nicotinic receptor subunits is robustly associated with smoking behavior and nicotine dependence. Only a few studies to date have examined the locus with alcohol related traits and found evidence of association with alcohol abuse and dependence. Our main goal was to examine the role of three intensively studied single nucleotide polymorphisms, rs16969968, rs578776 and rs588765, tagging three distinct loci, in alcohol use. Our sample was drawn from two independent Finnish population-based surveys, the National FINRISK Study and the Health 2000 (Health Examination) Survey. The combined sample included a total of 32,592 adult Finns (54% women) of whom 8,356 were assessed for cigarettes per day (CPD). Data on alcohol use were available for 31,812 individuals. We detected a novel association between rs588765 and alcohol use defined as abstainers and low-frequency drinkers versus drinkers (OR=1.15, p=0.00007). Additionally, we provide precise estimates of strength of the association between the three loci and smoking quantity in a very large population based sample. As a conclusion, our results provide further evidence for the nicotine-specific role of rs16969968 (locus 1). Further, our data suggest that the effect of rs588765 (locus 3) may be specific to alcohol use as the effect is seen also in never smokers

Metabolomic Signature of Angiopoietin-Like Protein 3 Deficiency in Fasting and Postprandial State

Objective- Loss-of-function (LOF) variants in the ANGPTL3 (angiopoietin-like protein 3) have been associated with low levels of plasma lipoproteins and decreased coronary artery disease risk. We aimed to determine detailed metabolic effects of genetically induced ANGPTL3 deficiency in fasting and postprandial state. Approach and Results- We studied individuals carrying S17X LOF mutation in ANGPTL3 (6 homozygous and 32 heterozygous carriers) and 38 noncarriers. Nuclear magnetic resonance metabolomics was used to quantify 225 circulating metabolic measures. We compared metabolic differences between LOF carriers and noncarriers in fasting state and after a high-fat meal. In fasting, ANGPTL3 deficiency was characterized by similar extent of reductions in LDL (low-density lipoprotein) cholesterol (0.74 SD units lower concentration per LOF allele [95% CI, 0.42-1.06]) as observed for many TRL (triglyceride-rich lipoprotein) measures, including VLDL (very-low-density lipoprotein) cholesterol (0.75 [95% CI, 0.45-1.05]). Within most lipoprotein subclasses, absolute levels of cholesterol were decreased more than triglycerides, resulting in the relative proportion of cholesterol being reduced within TRLs and their remnants. Further, beta-hydroxybutyrate was elevated (0.55 [95% CI, 0.21-0.89]). Homozygous ANGPTL3 LOF carriers showed essentially no postprandial increase in TRLs and fatty acids, without evidence for adverse compensatory metabolic effects. Conclusions- In addition to overall triglyceride- and LDL cholesterol-lowering effects, ANGPTL3 deficiency results in reduction of cholesterol proportion within TRLs and their remnants. Further, ANGPTL3 LOF carriers had elevated ketone body production, suggesting enhanced hepatic fatty acid beta-oxidation. The detailed metabolic profile in human knockouts of ANGPTL3 reinforces inactivation of ANGPTL3 as a promising therapeutic target for decreasing cardiovascular risk.Peer reviewe

Ten principles for conservation translocations of threatened wood-inhabiting fungi

Unlike for many other organism groups, conservation translocations of fungi are still rare. Encouraged by recent successful translocations, there is a growing interest in applying this conservation tool to threatened wood-inhabiting fungi. When combined with other conservation or restoration measures, translocation can be an effective measure for preventing further population decline in the short term, and species extinctions in the long term. Translocations can be appropriate for rare and specialist fungal species that occur as small local populations in isolated patches across fragmented landscapes, where there is a low likelihood of successful dispersal between distant host trees that have special qualities and are situated in suitable conditions. As species translocations are a controversial topic, the pros and cons of translocation as a conservation tool for threatened fungi need careful consideration. We highlight the uncertainties and risks that are connected to fungal translocations, and propose ten principles adhering to the precautionary principle

Seurantakäsikirja Suomen merenhoitosuunnitelman seurantaohjelmaan vuosille 2020–2026

Tämä merenhoidon seurantakäsikirja käsittää merenhoitosuunnitelman seurantaohjelman kuvauksen kokonaisuudessaan. Se päivittää vuoden 2014–2020 seurantaohjelman ja sitä sovelletaan vuoden 2020 heinäkuusta vuoden 2026 heinäkuuhun. Seurantaohjelma on osa merenhoidon suunnittelua, jota tehdään vesienhoidon ja merenhoidon järjestämisestä annetun lain (272/2011) ja merenhoidon järjestämisestä annetun valtioneuvoston asetuksen (980/2011) toteuttamiseksi. Tämä laki ja asetus on annettu meristrategiadirektiivin (Euroopan parlamentin ja neuvoston direktiivi 2008/56/EY yhteisön meriympäristöpolitiikan puitteista) kansallista toimeenpanoa varten. Suomessa meristrategiadirektiivin mukaista meristrategiaa kutsutaan merenhoitosuunnitelmaksi. Suomen seurantaohjelma koostuu 13:sta ohjelmasta, joiden alla on yhteensä 44 alaohjelmaa. Tähän päivitettyyn seurantaohjelmaan lisättiin kuusi uutta alaohjelmaa ja useita alaohjelmia muokattiin joko muuttuneiden vaatimusten, kehittyneempien menetelmien tai muuttuneen toimintaympäristön takia. Merenhoidon uusia vaatimuksia ovat meristrategiadirektiivin liitteen 3 päivitys (EU/2017/845), Euroopan komission päätös EU/2017/848 merivesien hyvän ekologisen tilan vertailuperusteista ja menetelmästandardeista sekä seurantaa ja arviointia varten tarkoitetut täsmennykset standardoiduista menetelmistä. Seurantakäsikirja koostuu kolmesta osasta: seurantaohjelman tausta, varsinainen seurantaohjelma, ja kolmas osa, joka käsittelee seurannan kehitystarpeita, kustannuksia ja riittävyyttä. Seurantaohjelma kattaa ekosysteemilähestymistavan mukaisesti erilaisia muuttujia, jotka kuvaavat toisaalta veden ominaisuuksia ja laatua ja toisaalta ekosysteemin osia ja niiden tilaa sekä niihin kohdistuvia ihmisestä johtuvia paineita. Seurannan alaohjelmissa on kuvattu mitattavat meriympäristön ominaisuudet tai paineet, niiden seurantatiheys, indikaattorit, joihin seurantatietoa käytetään, seurannalla kootun tiedon hallinta ja yhteydet meristrategiadirektiivin hyvän tilan laadullisiin kuvaajiin ja kriteereihin

A novel earth observation based ecological indicator for cyanobacterial blooms

Highlights A novel Cyanobacterial Bloom Indicator (CyaBI) targeted for the ecosystem assessment of eutrophication in marine areas is presented. The indicator is presented applying seasonal algal bloom characteristics information derived from earth observation data. The CyaBI was found to pass the three critical factors set for marine indicator development. The Indicator measures the current status properly, the target setting is scientifically proven and it is connected to the ecosystem management

Manhattan plot of the GWAS meta-analysis results of the three Finnish cohorts. The horizontal line represents the genome-wide significance threshold (p<5E-08).

<p>Manhattan plot of the GWAS meta-analysis results of the three Finnish cohorts. The horizontal line represents the genome-wide significance threshold (p<5E-08).</p