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1. A Genome-Wide Association Study of a Biomarker of Nicotine Metabolism.

Author

Anu Loukola, Jadwiga Buchwald, Richa Gupta, Teemu Palviainen, Jenni Hällfors, Emmi Tikkanen, Tellervo Korhonen, Miina Ollikainen, Antti-Pekka Sarin, Samuli Ripatti, Terho Lehtimäki, Olli Raitakari, Veikko Salomaa, Richard J Rose, Rachel F Tyndale, and Jaakko Kaprio

Subjects
Genetics, QH426-470
Abstract

Individuals with fast nicotine metabolism typically smoke more and thus have a greater risk for smoking-induced diseases. Further, the efficacy of smoking cessation pharmacotherapy is dependent on the rate of nicotine metabolism. Our objective was to use nicotine metabolite ratio (NMR), an established biomarker of nicotine metabolism rate, in a genome-wide association study (GWAS) to identify novel genetic variants influencing nicotine metabolism. A heritability estimate of 0.81 (95% CI 0.70-0.88) was obtained for NMR using monozygotic and dizygotic twins of the FinnTwin cohort. We performed a GWAS in cotinine-verified current smokers of three Finnish cohorts (FinnTwin, Young Finns Study, FINRISK2007), followed by a meta-analysis of 1518 subjects, and annotated the genome-wide significant SNPs with methylation quantitative loci (meQTL) analyses. We detected association on 19q13 with 719 SNPs exceeding genome-wide significance within a 4.2 Mb region. The strongest evidence for association emerged for CYP2A6 (min p = 5.77E-86, in intron 4), the main metabolic enzyme for nicotine. Other interesting genes with genome-wide significant signals included CYP2B6, CYP2A7, EGLN2, and NUMBL. Conditional analyses revealed three independent signals on 19q13, all located within or in the immediate vicinity of CYP2A6. A genetic risk score constructed using the independent signals showed association with smoking quantity (p = 0.0019) in two independent Finnish samples. Our meQTL results showed that methylation values of 16 CpG sites within the region are affected by genotypes of the genome-wide significant SNPs, and according to causal inference test, for some of the SNPs the effect on NMR is mediated through methylation. To our knowledge, this is the first GWAS on NMR. Our results enclose three independent novel signals on 19q13.2. The detected CYP2A6 variants explain a strikingly large fraction of variance (up to 31%) in NMR in these study samples. Further, we provide evidence for plausible epigenetic mechanisms influencing NMR.

Published
2015
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2. The Older Finnish Twin Cohort : 45 Years of Follow-up

Author

Miina Ollikainen, Urho M. Kujala, Antti Latvala, Eija K. Laakkonen, Paula Iso-Markku, Maarit Piirtola, Vuokko Kovanen, Jadwiga Buchwald, Juha O. Rinne, Jaakko Kaprio, Noora Lindgren, Eero Vuoksimaa, Tuija Leskinen, Taina Rantanen, Sarianna Sipilä, Elina Sillanpää, Anne Viljanen, Tellervo Korhonen, Karri Silventoinen, Katja Waller, Sailalitha Bollepalli, Richard J. Rose, Institute for Molecular Medicine Finland, Department of Public Health, University of Helsinki, HUS Medical Imaging Center, Department of Diagnostics and Therapeutics, University Management, Staff Services, Helsinki Inequality Initiative (INEQ), Doctoral Programme in Social Sciences, Demography, Population Research Unit (PRU), Center for Population, Health and Society, Sociology, Epigenetics of Complex Diseases and Traits, Genetic Epidemiology, and Cognitive and Brain Aging

Subjects
0301 basic medicine, Male, Aging, HORMONE-REPLACEMENT THERAPY, physical activity, BLOOD-PRESSURE, Cohort Studies, 0302 clinical medicine, Surveys and Questionnaires, Twins, Dizygotic, kohonnut verenpaine, Medicine, kohorttitutkimus, Genetics (clinical), Finland, Biological Specimen Banks, Aged, 80 and over, alcohol, 1184 Genetics, developmental biology, physiology, Obstetrics and Gynecology, twins, Middle Aged, Biobank, POPULATION-BASED TWIN, epigenetiikka, DEPRESSIVE SYMPTOMS, Cohort, SKELETAL-MUSCLE, Female, fyysinen aktiivisuus, Cohort study, Adult, hypertension, Alcohol Drinking, longitudinal, Physical activity, review, PAIRS DISCORDANT, pitkittäistutkimus, smoking, ENVIRONMENTAL-INFLUENCES, 03 medical and health sciences, TIME PHYSICAL-ACTIVITY, tupakointi, Diseases in Twins, cohort study, Dementia, Humans, GENOME-WIDE ASSOCIATION, alkoholi (päihteet), Depressive symptoms, Questionnaire study, Aged, kaksostutkimus, epigenetics, business.industry, aging, Baseline survey, Twins, Monozygotic, medicine.disease, kaksoset, 030104 developmental biology, ikääntyminen, Pediatrics, Perinatology and Child Health, TELOMERE LENGTH, business, 030217 neurology & neurosurgery, Demography, Follow-Up Studies, dementia
Abstract

The older Finnish Twin Cohort (FTC) was established in 1974. The baseline survey was in 1975, with two follow-up health surveys in 1981 and 1990. The fourth wave of assessments was done in three parts, with a questionnaire study of twins born during 1945–1957 in 2011–2012, while older twins were interviewed and screened for dementia in two time periods, between 1999 and 2007 for twins born before 1938 and between 2013 and 2017 for twins born in 1938–1944. The content of these wave 4 assessments is described and some initial results are described. In addition, we have invited twin-pairs, based on response to the cohortwide surveys, to participate in detailed in-person studies; these are described briefly together with key results. We also review other projects based on the older FTC and provide information on the biobanking of biosamples and related phenotypes.

Published
2019

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

Author

Ida Surakka, Pekka Jousilahti, Jenni Hällfors, Anu Raevuori, Anu Loukola, Pamela A. F. Madden, Richa Gupta, Teemu Palviainen, Jadwiga Buchwald, Samuli Ripatti, Tellervo Korhonen, Jaakko Kaprio, University of Helsinki, Institute for Molecular Medicine Finland, University of Helsinki, Department of Public Health, University of Helsinki, Department of Public Health (-2009), Institute for Molecular Medicine Finland, University of Helsinki, Department of Public Health, Clinicum, Nuorisopsykiatria, Centre of Excellence in Complex Disease Genetics, Samuli Olli Ripatti / Principal Investigator, Biostatistics Helsinki, HUS Children and Adolescents, Complex Disease Genetics, and Genetic Epidemiology

Subjects
Male, NF-KAPPA-B, Medicine (miscellaneous), EFFICIENT, Genome-wide association study, VARIANTS, smoking behavior, Cohort Studies, Nicotine, 0302 clinical medicine, MIXED-MODEL, smoking quantity, DEPENDENCE, Finland, Genetics, education.field_of_study, Tobacco Use Disorder, Middle Aged, nicotine withdrawal, 3142 Public health care science, environmental and occupational health, Substance Withdrawal Syndrome, 3. Good health, Finnish population-based imputation reference panel, RECEPTORS, Psychiatry and Mental health, neurotrophin signaling pathway, Phenotype, Nicotine withdrawal, CLATHRIN, genome‐wide association analysis, Female, Original Article, Finnish population‐based imputation reference panel, Signal Transduction, medicine.drug, Genotype, Population, education, Single-nucleotide polymorphism, Locus (genetics), Biology, Human Epigenetic/Genetic Studies, nicotine addiction, 03 medical and health sciences, Tobacco Smoking, medicine, LINKAGE, LOCUS, Humans, Nerve Growth Factors, 1000 Genomes Project, Pharmacology, 3112 Neurosciences, CLUSTER, medicine.disease, 030227 psychiatry, genome-wide association analysis, 1182 Biochemistry, cell and molecular biology, 030217 neurology & neurosurgery, Imputation (genetics), Genome-Wide Association Study
Abstract

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.

Published
2018

4. An epigenome-wide association study of educational attainment (n = 10,767)

Author

George Davey Smith, Sara Hägg, Antti Latvala, Khadeeja Ismail, Cisca Wijmenga, Karen A. Mather, Laura Baglietto, Miina Ollikainen, Allison M. Hodge, Jari Lahti, Ian J. Deary, Andrew J Simpkin, Nicholas G. Martin, Ilkka Seppälä, Annette Peters, Silva Kasela, Riccardo E. Marioni, Mikko Hurme, Lisette Stolk, Pooja R. Mandaviya, Tõnu Esko, Kirsi Auro, Gianluca Severi, Jadwiga Buchwald, Silvia Polidoro, Yunzhang Wang, Neil M Davies, Pauliina Karell, Danielle Posthuma, Paolo Vineis, Roger L. Milne, Clemens Baumbach, Magnus Johannesson, Erdogan Taskesen, Richard Karlsson Linnér, Steve Horvath, Jaakko Kaprio, André G. Uitterlinden, Kyoko Watanabe, Christian Gieger, John M. Starr, Anni Joensuu, Melanie Waldenberger, Alison Pattie, Cornelius A. Rietveld, Pekka Jousilahti, Nicola J. Armstrong, Giovanni Fiorito, Sarah E. Medland, Lude Franke, Joyce B. C van Meurs, Graham G. Giles, Mika Kähönen, Andres Metspalu, Marc Jan Bonder, Lili Milani, Margaret J. Wright, Caroline L Relton, Terho Lehtimäki, Philipp Koellinger, Nancy L. Pedersen, Markus Perola, Elisabeth B. Binder, Allan F. McRae, Stella Iurato, Katri Räikkönen, Daniel J. Benjamin, Sarah E. Harris, Johan G. Eriksson, Perminder S. Sachdev, and Olli T. Raitakari

Subjects
Genetics, 0303 health sciences, Epigenome, Biology, Bioinformatics, Educational attainment, 03 medical and health sciences, 0302 clinical medicine, CpG site, DNA methylation, 030212 general & internal medicine, Epigenetics, Association (psychology), Body mass index, 030304 developmental biology, Cohort study
Abstract

The epigenome has been shown to be influenced by biological factors, such as disease status, and environmental factors, such as smoking, alcohol consumption, and body mass index. Although there is a widespread perception that environmental influences on the epigenome are pervasive and profound, there has been little evidence to date in humans with respect to environmental factors that are biologically distal. Here, we provide evidence on the associations between epigenetic modifications—in our case, CpG methylation—and educational attainment (EA), a biologically distal environmental factor that is arguably among of the most important life-shaping experiences for individuals. Specifically, we report the results of an epigenome-wide association study meta-analysis of EA based on data from 27 cohort studies with a total of 10,767 individuals. While we find that 9 CpG probes are significantly associated with EA, only two remain associated when we restrict the sample to never-smokers. These two are known to be strongly associated with maternal smoking during pregnancy, and thus their association with EA could be due to correlation between EA and maternal smoking. Moreover, their effect sizes on EA are far smaller than the known associations between CpG probes and biologically proximal environmental factors. Two analyses that combine the effects of many probes—polygenic methylation score and epigenetic-clock analyses—both suggest small associations with EA. If our findings regarding EA can be generalized to other biologically distal environmental factors, then they cast doubt on the hypothesis that such factors have large effects on the epigenome.

Published
2017
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5. Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses

Author

Sharon L.R. Kardia, Melinda Mills, Ian J. Deary, Sven Bergmann, Magnus Johannesson, Igor Rudan, Nicholas J. Timpson, Richa Gupta, Hester M. den Ruijter, Rico Rueedi, Lars Bertram, Juliette Harris, Jennifer A. Smith, Eero Kajantie, Jian Yang, David C. Liewald, Ronald de Vlaming, Anu Realo, Jessica D. Faul, Patrik K. E. Magnusson, Jadwiga Buchwald, Philip L. De Jager, Rajesh Rawal, Marisa Koini, K. Petrovic, Unnur Thorsteinsdottir, Pedro Marques-Vidal, Roy Thurik, Evie Stergiakouli, Ivana Kolcic, William G. Iacono, Laura D. Kubzansky, Jaakko Kaprio, Behrooz Z. Alizadeh, Samantha Cherney, Reinhold Schmidt, Vilmundur Gudnason, Nicholas A. Furlotte, Nicholas G. Martin, Delilah Zabaneh, Rebecca T. Emeny, Eco J. C. de Geus, Klaus Berger, Lude Franke, Sven J. van der Lee, S. Fleur W. Meddens, Bart M. L. Baselmans, Dalton Conley, Jouke-Jan Hottenga, David A. Bennett, Saskia Haitjema, Jun Ding, Elina Hyppönen, Kari Stefansson, Henning Tiemeier, Grant W. Montgomery, Michelle N. Meyer, James J. Lee, Aysu Okbay, Lei Yu, Gyda Bjornsdottir, Marie Henrike Geisel, Albertine J. Oldehinkel, Liisa Keltikangas-Järvinen, George Davey Smith, Harold Snieder, Juho Wedenoja, Frits R. Rosendaal, Michel G. Nivard, Simon R. Cox, Christine Power, Dorret I. Boomsma, Börge Schmidt, David A. Hinds, Philipp Koellinger, Harm-Jan Westra, Terho Lehtimäki, Alison Pattie, Jan-Emmanuel De Neve, Torben Hansen, John M. Starr, Albert V. Smith, Antonio Terracciano, Juergen Wellmann, Albert Hofman, Katri Räikkönen, Patrick Turley, Andrew Steptoe, Jimmy Z. Liu, Evelin Mihailov, Jari Lahti, Marika Kaakinen, David R. Weir, Cornelia M. van Duijn, Maciej Trzaskowski, David Cesarini, Najaf Amin, Lydia Quaye, Sara M. Willems, Ghazaleh Fatemifar, Christopher Oldmeadow, Ville Karhunen, Alana Cavadino, Juan R. González, Caroline Hayward, Penelope A. Lind, Tamara B. Harris, Jaime Derringer, Camelia C. Minică, Jacob Gratten, Patrick J. F. Groenen, Ozren Polasek, Anu Loukola, Peter Vollenweider, Christian Gieger, Rodney J. Scott, Lindsay K. Matteson, Meike Bartels, Andrew Bakshi, David Laibson, Andrew C. Heath, Daniel J. Benjamin, Stephen S. Rich, Claire M. A. Haworth, C.A. Hartman, Angelina R. Sutin, Tian Liu, Johan G. Eriksson, Robert Plomin, Francesco Cucca, John Attia, Tarunveer S. Ahluwalia, Andreas J. Forstner, Gudmar Thorleifsson, Rauli Svento, Ute Bültmann, Olli T. Raitakari, Karl-Heinz Jöckel, Mark Alan Fontana, Oliver S. P. Davis, Yong Qian, Anna A. E. Vinkhuyzen, Wei Zhao, Elizabeth G. Holliday, Andres Metspalu, Alexis C. Frazier-Wood, Meena Kumari, Nese Direk, Miriam A. Mosing, Ilja M. Nolte, Sander W. van der Laan, Matt McGue, Tim D. Spector, Marjo-Riitta Järvelin, Peter Eibich, Nancy L. Pedersen, David Schlessinger, Toshiko Tanaka, Dennis O. Mook-Kanamori, Luigi Ferrucci, Gerard Pasterkamp, Jonathan P. Beauchamp, Robert Karlsson, Lenore J. Launer, Helena Schmidt, Renée de Mutsert, Gert G. Wagner, Peter Kraft, Joseph K. Pickrell, Thorkild I. A. Sørensen, André G. Uitterlinden, Patricia A. Boyle, Cornelius A. Rietveld, Robert F. Krueger, Karl-Heinz Ladwig, Michael B. Miller, Sarah E. Medland, Tõnu Esko, Kent D. Taylor, Lavinia Paternoster, Peter J. van der Most, Richard Karlsson Linnér, Laura Pulkki-Råback, Gail Davies, Victoria Garfield, Shun-Chiao Chang, Ruifang Li-Gao, Applied Economics, Pathology, Epidemiology, Public Health, Child and Adolescent Psychiatry / Psychology, Psychiatry, Internal Medicine, Ophthalmology, Social Science Genetic Association Consortium (SSGAC), CHARGE Consortium, Okbay, Aysu, Baselmans, Bart ML, De Neve, Jan-Emmanuel, Turley, Patrick, Hyppönen, Elina, Cesarini, David, EMGO+ - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Complex Trait Genetics, Biological Psychology, Functional Genomics, Economics, Amsterdam Neuroscience - Complex Trait Genetics, Queensland Institute of Medical Research, Massachusetts General Hospital [Boston], University of Queensland [Brisbane], Center for Research in Environmental Epidemiology (CREAL), Universitat Pompeu Fabra [Barcelona] (UPF)-Catalunya ministerio de salud, Universitat Pompeu Fabra [Barcelona] (UPF), CIBER de Epidemiología y Salud Pública (CIBERESP), Institut des Sciences Moléculaires (ISM), Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Université Sciences et Technologies - Bordeaux 1-Université Montesquieu - Bordeaux 4-Institut de Chimie du CNRS (INC), Tampere University Hospital, University of Turku, King‘s College London, University of Helsinki, AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Lausanne (UNIL), Birmingham City University (BCU), Helmholtz-Zentrum München (HZM), Department of Epidemiology and Public Health, University College of London [London] (UCL), Donders Institute for Brain, Cognition and Behaviour, Radboud university [Nijmegen], University of Edinburgh, Florida State University [Tallahassee] (FSU), Wuhan University [China], Rush University Medical Center [Chicago], Department of Epidemiology [Rotterdam], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Erasmus University Rotterdam, National Institute for Health and Welfare [Helsinki], Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], Dpt of Pharmacology and Personalised Medicine [Maastricht], Maastricht University [Maastricht], Montpellier Research in Management (MRM), Université Montpellier 1 (UM1)-Groupe Sup de Co Montpellier (GSCM) - Montpellier Business School-Université Paul-Valéry - Montpellier 3 (UPVM)-Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Perpignan Via Domitia (UPVD), Université Montesquieu - Bordeaux 4-Université Sciences et Technologies - Bordeaux 1-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Université Paul-Valéry - Montpellier 3 (UPVM)-Université de Perpignan Via Domitia (UPVD)-Groupe Sup de Co Montpellier (GSCM) - Montpellier Business School-Université de Montpellier (UM), Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Public Health Research (PHR), Sociology/ICS, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Stem Cell Aging Leukemia and Lymphoma (SALL), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), and LifeLines Cohort Study

Subjects
0301 basic medicine, Netherlands Twin Register (NTR), Medizin, Genome-wide association study, Disease, Genome-wide association studies, DISEASE, 0302 clinical medicine, well-being, neuroticism, Anxiety Disorders/genetics, Bayes Theorem, Depression/genetics, Genome-Wide Association Study, Humans, Phenotype, Polymorphism, Single Nucleotide, Genetics & Heredity, RISK, Genetics, PERSONALITY, [QFIN]Quantitative Finance [q-fin], Depression, HERITABILITY, COMMON VARIANTS, 11 Medical And Health Sciences, Anxiety Disorders, Neuroticism, depression, Behavioural genetics, Life Sciences & Biomedicine, Biology, personality, genetic, epidemiology, ta3111, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, RESOURCE, Journal Article, Human height, Subjective well-being, behavioural genetics, METAANALYSIS, Genetic association, HAPPINESS, Science & Technology, MAJOR DEPRESSION, 06 Biological Sciences, Heritability, 030104 developmental biology, genome-wide association studies, HUMAN HEIGHT, 030217 neurology & neurosurgery, LifeLines Cohort Study, Developmental Biology, genome-wide analysis
Abstract

Very few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data. We conducted genome-wide association studies of three phenotypes: subjective well-being (n = 298,420), depressive symptoms (n = 161,460), and neuroticism (n = 170,911). We identify 3 variants associated with subjective well-being, 2 variants associated with depressive symptoms, and 11 variants associated with neuroticism, including 2 inversion polymorphisms. The two loci associated with depressive symptoms replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (vertical bar(p) over cap vertical bar approximate to 0.8) strengthen the overall credibility of the findings and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal or pancreas tissues are strongly enriched for association.

Published
2016

6. A Genome-Wide Association Study of a Biomarker of Nicotine Metabolism

Author

Olli T. Raitakari, Jadwiga Buchwald, Jaakko Kaprio, Rachel F. Tyndale, Samuli Ripatti, Teemu Palviainen, Terho Lehtimäki, Anu Loukola, Antti-Pekka Sarin, Veikko Salomaa, Emmi Tikkanen, Jenni Hällfors, Richa Gupta, Miina Ollikainen, Richard J. Rose, Tellervo Korhonen, Lääketieteen yksikkö - School of Medicine, University of Tampere, Clinicum, Department of Public Health, Institute for Molecular Medicine Finland, Samuli Olli Ripatti / Principal Investigator, Jaakko Kaprio / Principal Investigator, Biostatistics Helsinki, Complex Disease Genetics, and Genetic Epidemiology

Subjects
Male, Cancer Research, CYP2B6, medicine.medical_treatment, Genome-wide association study, PLACEBO-CONTROLLED TRIAL, Epigenesis, Genetic, Cytochrome P-450 CYP2A6, Nicotine, 0302 clinical medicine, Polymorphism (computer science), Twins, Dizygotic, CYP2A6, DNA METHYLATION, Genetics (clinical), Genetics, 0303 health sciences, CARDIOVASCULAR RISK, DISPOSITION KINETICS, Smoking, Tobacco Use Disorder, 3142 Public health care science, environmental and occupational health, 3. Good health, TRANSDERMAL NICOTINE, DNA methylation, Female, Research Article, medicine.drug, Genotype, lcsh:QH426-470, Biolääketieteet - Biomedicine, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, LUNG-CANCER, RATIO, medicine, Humans, Molecular Biology, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, SMOKING-CESSATION, ta3121, lcsh:Genetics, Smoking cessation, Smoking Cessation, CIGARETTE-SMOKING, 3111 Biomedicine, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Individuals with fast nicotine metabolism typically smoke more and thus have a greater risk for smoking-induced diseases. Further, the efficacy of smoking cessation pharmacotherapy is dependent on the rate of nicotine metabolism. Our objective was to use nicotine metabolite ratio (NMR), an established biomarker of nicotine metabolism rate, in a genome-wide association study (GWAS) to identify novel genetic variants influencing nicotine metabolism. A heritability estimate of 0.81 (95% CI 0.70–0.88) was obtained for NMR using monozygotic and dizygotic twins of the FinnTwin cohort. We performed a GWAS in cotinine-verified current smokers of three Finnish cohorts (FinnTwin, Young Finns Study, FINRISK2007), followed by a meta-analysis of 1518 subjects, and annotated the genome-wide significant SNPs with methylation quantitative loci (meQTL) analyses. We detected association on 19q13 with 719 SNPs exceeding genome-wide significance within a 4.2 Mb region. The strongest evidence for association emerged for CYP2A6 (min p = 5.77E-86, in intron 4), the main metabolic enzyme for nicotine. Other interesting genes with genome-wide significant signals included CYP2B6, CYP2A7, EGLN2, and NUMBL. Conditional analyses revealed three independent signals on 19q13, all located within or in the immediate vicinity of CYP2A6. A genetic risk score constructed using the independent signals showed association with smoking quantity (p = 0.0019) in two independent Finnish samples. Our meQTL results showed that methylation values of 16 CpG sites within the region are affected by genotypes of the genome-wide significant SNPs, and according to causal inference test, for some of the SNPs the effect on NMR is mediated through methylation. To our knowledge, this is the first GWAS on NMR. Our results enclose three independent novel signals on 19q13.2. The detected CYP2A6 variants explain a strikingly large fraction of variance (up to 31%) in NMR in these study samples. Further, we provide evidence for plausible epigenetic mechanisms influencing NMR., Author Summary Nicotine metabolism rate significantly varies between individuals and affects smoking behavior. Individuals with fast nicotine metabolism typically smoke more and thus have a greater risk for smoking-induced diseases. Further, the efficacy of smoking cessation pharmacotherapy is dependent on nicotine metabolism rate. Twin and family studies have shown that genes influence nicotine metabolism; however, only a minor fraction of variance in inter-individual differences in nicotine metabolism is accounted for by known reduced activity variants in CYP2A6, the main metabolic enzyme for nicotine. Here we utilized a biomarker of nicotine metabolism (nicotine metabolite ratio, NMR) in a genome-wide association study of three Finnish cohorts to identify novel genetic variants influencing nicotine metabolism rate. Our results enclose three independent novel signals in CYP2A6. The detected variants explain a strikingly large fraction of variance (up to 31%) in NMR in the study samples. A genetic risk score constructed using the independent signals predicts smoking quantity in two independent Finnish samples. Further, we enclose evidence for plausible epigenetic mechanisms influencing NMR. With the advent of other nicotine delivery devices than tobacco, such as e-cigarettes, the need to understand the long-term consequences and action mechanisms of nicotine and its metabolism are of high public health relevance.

Published
2015

7. Correction: Corrigendum: Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses

Author

Nicholas A. Furlotte, S. Fleur W. Meddens, Ronald de Vlaming, Anu Realo, Bart M. L. Baselmans, Patrick Turley, Jacob Gratten, Jan-Emmanuel De Neve, Melinda Mills, Alexis C. Frazier-Wood, Marie Henrike Geisel, Peter J. van der Most, Richard Karlsson Linnér, Saskia Haitjema, Tian Liu, Yong Qian, Juan R. González, Ilja M. Nolte, Sven J. van der Lee, Harm-Jan Westra, Jaime Derringer, Mark Alan Fontana, Behrooz Z. Alizadeh, Jimmy Z. Liu, Meena Kumari, Evelin Mihailov, Tarunveer S. Ahluwalia, Jadwiga Buchwald, Alana Cavadino, Penelope A. Lind, Aysu Okbay, Christopher Oldmeadow, Harold Snieder, Michael B. Miller, Albertine J. Oldehinkel, Sander W. van der Laan, Camelia C. Minică, Michel G. Nivard, Dennis O. Mook-Kanamori, Victoria Garfield, Karl-Heinz Ladwig, Lindsay K. Matteson, James J. Lee, Ute Bültmann, Olli T. Raitakari, Robert Karlsson, Lude Franke, Rajesh Rawal, Cornelius A. Rietveld, and Jari Lahti

Subjects
0301 basic medicine, medicine.medical_specialty, Public health, Genetic variants, Biology, Neuroticism, Genome, 03 medical and health sciences, 030104 developmental biology, Genetics, medicine, Subjective well-being, Depressive symptoms, Clinical psychology
Abstract

In the version of this article initially published, one of the affiliations listed for author Maciej Trzaskowski, to the Department of Public Health, Faculty of Medicine, University of Split, Split, Croatia, was included in error. The correct affiliation for this author is the Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia. The error has been corrected in the HTML and PDF versions of the article.

Published
2016

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