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1. Evidence for a shared genetic contribution to loneliness and borderline personality disorder

Author

Anna Schulze, Fabian Streit, Lea Zillich, Swapnil Awasthi, Alisha S. M. Hall, Martin Jungkunz, Nikolaus Kleindienst, Josef Frank, Cornelia E. Schwarze, Norbert Dahmen, Björn H. Schott, Markus Nöthen, Arian Mobascher, Dan Rujescu, Klaus Lieb, Stefan Roepke, Sabine C. Herpertz, Christian Schmahl, Martin Bohus, Stephan Ripke, Marcella Rietschel, Stefanie Lis, and Stephanie Witt

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Abstract Loneliness, influenced by genetic and environmental factors such as childhood maltreatment, is one aspect of interpersonal dysfunction in Borderline Personality Disorder (BPD). Numerous studies link loneliness and BPD and twin studies indicate a genetic contribution to this association. The aim of our study was to investigate whether genetic predisposition for loneliness and BPD risk overlap and whether genetic risk for loneliness contributes to higher loneliness reported by BPD patients, using genome-wide genotype data. We assessed the genetic correlation of genome-wide association studies (GWAS) of loneliness and BPD using linkage disequilibrium score regression and tested whether a polygenic score for loneliness (loneliness-PGS) was associated with case-control status in two independent genotyped samples of BPD patients and healthy controls (HC; Witt2017-sample: 998 BPD, 1545 HC; KFO-sample: 187 BPD, 261 HC). In the KFO-sample, we examined associations of loneliness-PGS with reported loneliness, and whether the loneliness-PGS influenced the association between childhood maltreatment and loneliness. We found a genetic correlation between the GWAS of loneliness and BPD in the Witt2017-sample (rg = 0.23, p = 0.015), a positive association of loneliness-PGS with BPD case-control status (Witt2017-sample: NkR² = 2.3%, p = 2.7*10–12; KFO-sample: NkR² = 6.6%, p = 4.4*10–6), and a positive association between loneliness-PGS and loneliness across patient and control groups in the KFO-sample (β = 0.186, p = 0.002). The loneliness-PGS did not moderate the association between childhood maltreatment and loneliness in BPD. Our study is the first to use genome-wide genotype data to show that the genetic factors underlying variation in loneliness in the general population and the risk for BPD overlap. The loneliness-PGS was associated with reported loneliness. Further research is needed to investigate which genetic mechanisms and pathways are involved in this association and whether a genetic predisposition for loneliness contributes to BPD risk.

Published
2023
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2. Borderline personality disorder and the big five: molecular genetic analyses indicate shared genetic architecture with neuroticism and openness

Author

Fabian Streit, Stephanie H. Witt, Swapnil Awasthi, Jerome C. Foo, Martin Jungkunz, Josef Frank, Lucía Colodro-Conde, Guy Hindley, Olav B. Smeland, Tolou Maslahati, Cornelia E. Schwarze, Norbert Dahmen, Björn H. Schott, Nikolaus Kleindienst, Annette Hartmann, Ina Giegling, Lea Zillich, Lea Sirignano, Eric Poisel, Chi-Hua Chen, Markus M. Nöthen, Arian Mobascher, Dan Rujescu, Klaus Lieb, Stefan Roepke, Christian Schmahl, Martin Bohus, Stephan Ripke, Marcella Rietschel, and Ole A. Andreassen

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Abstract Both environmental (e.g. interpersonal traumatization during childhood and adolescence) and genetic factors may contribute to the development of Borderline Personality Disorder (BPD). Twin studies assessing borderline personality symptoms/features in the general population indicate that genetic factors underlying these symptoms/features are shared in part with the personality traits of the Five Factor Model (FFM) of personality—the “Big Five”. In the present study, the genetic overlap of BPD with the Big Five -Openness to Experience, Conscientiousness, Extraversion, Agreeableness, and Neuroticism- was assessed. Linkage disequilibrium score regression was used to calculate genetic correlations between a genome-wide association study (GWAS) in central European populations on BPD (N = 2543) and GWAS on the Big Five (N = 76,551–122,886, Neuroticism N = 390,278). Polygenic scores (PGS) were calculated to test the association of the genetic disposition for the personality traits with BPD case-control status. Significant positive genetic correlations of BPD were found with Neuroticism (rg = 0.34, p = 6.3*10−5) and Openness (rg = 0.24, p = 0.036), but not with the other personality traits (all | rg | 0.30). A cluster and item-level analysis showed positive genetic correlations of BPD with the Neuroticism clusters “Depressed Affect” and “Worry”, and with a broad range of Neuroticism items (N = 348,219–376,352). PGS analyses confirmed the genetic correlations, and found an independent contribution of the personality traits to BPD risk. The observed associations indicate a partially shared genetic background of BPD and the personality traits Neuroticism and Openness. Larger GWAS of BPD and the “Big Five” are needed to further explore the role of personality traits in the etiology of BPD.

Published
2022
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3. Prevalence of eating disorders and eating attacks in narcolepsy

Author

Norbert Dahmen, Julia Becht, Alice Engel, Monika Thommes, and Peter Tonn

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract

Norbert Dahmen, Julia Becht, Alice Engel, Monika Thommes, Peter TonnPsychiatry Department, University of Mainz, GermanyAbstract: Narcoleptic patients suffer frequently from obesity and type II diabetes. Most patients show a deficit in the energy balance regulating orexinergic system. Nevertheless, it is not known, why narcoleptic patients tend to be obese. We examined 116 narcoleptic patients and 80 controls with the structured interview for anorectic and bulimic eating disorders (SIAB) to test the hypothesis that typical or atypical eating attacks or eating disorders may be more frequent in narcoleptic patients. No difference in the current prevalence of eating disorders bulimia nervosa, binge eating disorder, or anorexia nervosa was found, nor was the frequency of eating attacks higher in the narcolepsy group. We conclude that present eating disorders and eating attacks as defined in DSM IV are not the reason for the observed differences in body composition. Additional factors, such as basal metabolic rates and lifestyle factors need to be considered.Keywords: narcolepsy, eating disorder, SIAB, bulimia, anorexia, eating attack

Published
2008

4. Differences between human plasma and serum metabolite profiles.

Author

Zhonghao Yu, Gabi Kastenmüller, Ying He, Petra Belcredi, Gabriele Möller, Cornelia Prehn, Joaquim Mendes, Simone Wahl, Werner Roemisch-Margl, Uta Ceglarek, Alexey Polonikov, Norbert Dahmen, Holger Prokisch, Lu Xie, Yixue Li, H-Erich Wichmann, Annette Peters, Florian Kronenberg, Karsten Suhre, Jerzy Adamski, Thomas Illig, and Rui Wang-Sattler

Subjects
Medicine, Science
Abstract

BackgroundHuman plasma and serum are widely used matrices in clinical and biological studies. However, different collecting procedures and the coagulation cascade influence concentrations of both proteins and metabolites in these matrices. The effects on metabolite concentration profiles have not been fully characterized.Methodology/principal findingsWe analyzed the concentrations of 163 metabolites in plasma and serum samples collected simultaneously from 377 fasting individuals. To ensure data quality, 41 metabolites with low measurement stability were excluded from further analysis. In addition, plasma and corresponding serum samples from 83 individuals were re-measured in the same plates and mean correlation coefficients (r) of all metabolites between the duplicates were 0.83 and 0.80 in plasma and serum, respectively, indicating significantly better stability of plasma compared to serum (p = 0.01). Metabolite profiles from plasma and serum were clearly distinct with 104 metabolites showing significantly higher concentrations in serum. In particular, 9 metabolites showed relative concentration differences larger than 20%. Despite differences in absolute concentration between the two matrices, for most metabolites the overall correlation was high (mean r = 0.81±0.10), which reflects a proportional change in concentration. Furthermore, when two groups of individuals with different phenotypes were compared with each other using both matrices, more metabolites with significantly different concentrations could be identified in serum than in plasma. For example, when 51 type 2 diabetes (T2D) patients were compared with 326 non-T2D individuals, 15 more significantly different metabolites were found in serum, in addition to the 25 common to both matrices.Conclusions/significanceOur study shows that reproducibility was good in both plasma and serum, and better in plasma. Furthermore, as long as the same blood preparation procedure is used, either matrix should generate similar results in clinical and biological studies. The higher metabolite concentrations in serum, however, make it possible to provide more sensitive results in biomarker detection.

Published
2011
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5. Elevated peripheral visfatin levels in narcoleptic patients.

Author

Norbert Dahmen, Nina Manderscheid, Jana Helfrich, Petra B Musholt, Thomas Forst, Andreas Pfützner, and Alice Engel

Subjects
Medicine, Science
Abstract

OBJECTIVE: Narcolepsy is a severe sleep disorder that is characterized by excessive daytime sleepiness, cataplexies and a tendency towards obesity. Recent discoveries indicate that the major pathophysiology is a loss of hypocretin (orexin) producing neurons due to immunologically mediated degeneration. Visfatin is a recently described proinflammatory adipokine. It is identical to the immune modulating pre-B-cell colony enhancing factor (PBEF). Our study examines the hypothesis that visfatin levels are altered in narcoleptic patients. METHODS: For the analysis, a total of n = 54 patients (n = 18 males and n = 36 females) with the diagnosis of narcolepsy according to DSM-IV and the International Classification of Sleep Disorders were examined (BMI mean 30.3+/-5.5, age mean 52.5+/-16.1 years). As a control group 39 unrelated (n = 12 males and n = 27 females) healthy volunteers with no sleep disorder according to DSM-IV were included (BMI mean 28.5+/-4.6, age mean 51.1+/-13.6 years). Peripheral visfatin levels were measured using a commercial enzyme immunoassay kit with a measurement range from 0.1-1000 ng/ml. Narcolepsy symptoms, severity and frequency of symptoms as well as the total duration of various aspects of the symptomatology were assessed by unstructured and structured clinical interviews in including the Stanford Center for Narcolepsy Sleep Inventory. RESULTS: Circulating visfatin was found to be significantly increased in HLA DR2 positive narcoleptic patients compared to controls. CONCLUSION: Taken together, our results add to the evidence of disturbed immunological regulation in patients with narcolepsy.

Published
2008
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6. Metabolic profiling reveals distinct variations linked to nicotine consumption in humans--first results from the KORA study.

Author

Rui Wang-Sattler, Yao Yu, Kirstin Mittelstrass, Eva Lattka, Elisabeth Altmaier, Christian Gieger, Karl H Ladwig, Norbert Dahmen, Klaus M Weinberger, Pei Hao, Lei Liu, Yixue Li, H-Erich Wichmann, Jerzy Adamski, Karsten Suhre, and Thomas Illig

Subjects
Medicine, Science
Abstract

Exposure to nicotine during smoking causes a multitude of metabolic changes that are poorly understood. We quantified and analyzed 198 metabolites in 283 serum samples from the human cohort KORA (Cooperative Health Research in the Region of Augsburg). Multivariate analysis of metabolic profiles revealed that the group of smokers could be clearly differentiated from the groups of former smokers and non-smokers. Moreover, 23 lipid metabolites were identified as nicotine-dependent biomarkers. The levels of these biomarkers are all up-regulated in smokers compared to those in former and non-smokers, except for three acyl-alkyl-phosphatidylcholines (e.g. plasmalogens). Consistently significant results were further found for the ratios of plasmalogens to diacyl-phosphatidylcolines, which are reduced in smokers and regulated by the enzyme alkylglycerone phosphate synthase (alkyl-DHAP) in both ether lipid and glycerophospholipid pathways. Notably, our metabolite profiles are consistent with the strong down-regulation of the gene for alkyl-DHAP (AGPS) in smokers that has been found in a study analyzing gene expression in human lung tissues. Our data suggest that smoking is associated with plasmalogen-deficiency disorders, caused by reduced or lack of activity of the peroxisomal enzyme alkyl-DHAP. Our findings provide new insight into the pathophysiology of smoking addiction. Activation of the enzyme alkyl-DHAP by small molecules may provide novel routes for therapy.

Published
2008
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7. Data from A Genome-wide Association Study of Early-Onset Breast Cancer Identifies PFKM as a Novel Breast Cancer Gene and Supports a Common Genetic Spectrum for Breast Cancer at Any Age

Author

Alice S. Whittemore, Nancy J. Cox, Douglas F. Easton, Dan Nicolae, Fernando Rivadeneira, Andre G. Uitterlinden, Hanne Meijers-Heijboer, Quinten Waisfisz, Paul Pharoah, Alison M. Dunning, Clare Turnbull, Nazneen Rahman, Jianjun Liu, Astrid Irwanto, Kamila Czene, Per Hall, Carl Blomqvist, Kristiina Aittomäki, Heli Nevanlinna, Norbert Dahmen, Dieter Flesch-Janys, Jennifer Stone, Quang Minh Bui, Daniel F. Schmidt, Enes Makalic, Rebecca Hein, Lars Beckmann, Magdalena Lochmann, Bertram Müller-Myhsok, Rita K. Schmutzler, Alfons Meindl, Stephen J. Chanock, David J. Hunter, Mark Lathrop, Isabel dos Santos Silva, Olivia Fletcher, Julian Peto, Daniel J. Park, Carmel Apicella, Kyriaki Michailidou, Polly Newcomb, Noralane M. Lindor, Mark Jenkins, Robert Haile, Steve Gallinger, David Duggan, David Conti, Eunjung Lee, Regina M. Santella, Graham G. Giles, Melissa C. Southey, Julia A. Knight, Graham Casey, Daniela Seminara, Duncan C. Thomas, Marilie D. Gammon, Giske Ursin, Kathi Malone, Esther M. John, John L. Hopper, Irene Andrulis, Jenny Chang-Claude, Stephanie Melkonian, Maria Argos, Rachelle Brutus, Shantanu Roy, Farzana Jasmine, Jianxin Shi, Anna Felberg, Valerie McGuire, Eric Gamazon, Lin Tong, Brandon L. Pierce, Muhammad G. Kibriya, Jerry Halpern, and Habibul Ahsan

Abstract

Early-onset breast cancer (EOBC) causes substantial loss of life and productivity, creating a major burden among women worldwide. We analyzed 1,265,548 Hapmap3 single-nucleotide polymorphisms (SNP) among a discovery set of 3,523 EOBC incident cases and 2,702 population control women ages ≤ 51 years. The SNPs with smallest P values were examined in a replication set of 3,470 EOBC cases and 5,475 control women. We also tested EOBC association with 19,684 genes by annotating each gene with putative functional SNPs, and then combining their P values to obtain a gene-based P value. We examined the gene with smallest P value for replication in 1,145 breast cancer cases and 1,142 control women. The combined discovery and replication sets identified 72 new SNPs associated with EOBC (P < 4 × 10−8) located in six genomic regions previously reported to contain SNPs associated largely with later-onset breast cancer (LOBC). SNP rs2229882 and 10 other SNPs on chromosome 5q11.2 remained associated (P < 6 × 10−4) after adjustment for the strongest published SNPs in the region. Thirty-two of the 82 currently known LOBC SNPs were associated with EOBC (P < 0.05). Low power is likely responsible for the remaining 50 unassociated known LOBC SNPs. The gene-based analysis identified an association between breast cancer and the phosphofructokinase-muscle (PFKM) gene on chromosome 12q13.11 that met the genome-wide gene-based threshold of 2.5 × 10−6. In conclusion, EOBC and LOBC seem to have similar genetic etiologies; the 5q11.2 region may contain multiple distinct breast cancer loci; and the PFKM gene region is worthy of further investigation. These findings should enhance our understanding of the etiology of breast cancer. Cancer Epidemiol Biomarkers Prev; 23(4); 658–69. ©2014 AACR.

Published
2023
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8. Supplementary Methods, Tables 1 - 6 from A Genome-wide Association Study of Early-Onset Breast Cancer Identifies PFKM as a Novel Breast Cancer Gene and Supports a Common Genetic Spectrum for Breast Cancer at Any Age

Author

Alice S. Whittemore, Nancy J. Cox, Douglas F. Easton, Dan Nicolae, Fernando Rivadeneira, Andre G. Uitterlinden, Hanne Meijers-Heijboer, Quinten Waisfisz, Paul Pharoah, Alison M. Dunning, Clare Turnbull, Nazneen Rahman, Jianjun Liu, Astrid Irwanto, Kamila Czene, Per Hall, Carl Blomqvist, Kristiina Aittomäki, Heli Nevanlinna, Norbert Dahmen, Dieter Flesch-Janys, Jennifer Stone, Quang Minh Bui, Daniel F. Schmidt, Enes Makalic, Rebecca Hein, Lars Beckmann, Magdalena Lochmann, Bertram Müller-Myhsok, Rita K. Schmutzler, Alfons Meindl, Stephen J. Chanock, David J. Hunter, Mark Lathrop, Isabel dos Santos Silva, Olivia Fletcher, Julian Peto, Daniel J. Park, Carmel Apicella, Kyriaki Michailidou, Polly Newcomb, Noralane M. Lindor, Mark Jenkins, Robert Haile, Steve Gallinger, David Duggan, David Conti, Eunjung Lee, Regina M. Santella, Graham G. Giles, Melissa C. Southey, Julia A. Knight, Graham Casey, Daniela Seminara, Duncan C. Thomas, Marilie D. Gammon, Giske Ursin, Kathi Malone, Esther M. John, John L. Hopper, Irene Andrulis, Jenny Chang-Claude, Stephanie Melkonian, Maria Argos, Rachelle Brutus, Shantanu Roy, Farzana Jasmine, Jianxin Shi, Anna Felberg, Valerie McGuire, Eric Gamazon, Lin Tong, Brandon L. Pierce, Muhammad G. Kibriya, Jerry Halpern, and Habibul Ahsan

Abstract

PDF file - 197K, Table S1. Discovery set study populations. Table S2. Distribution of discovery set subjects by site, case-control status and chip. Table S3. Discovery set quality control summary. Table S4. SNPs with score-based P-values < 4 X 10-8 among 58016 SNPs for which Plink aborted the logistic regressions. Table S5. Replication set study populations. Table S6. Distribution of replication set subjects by site, case-control status and

Published
2023
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9. A large-scale genome-wide association study meta-analysis of cannabis use disorder

Author

Emma C Johnson, Ditte Demontis, Thorgeir E Thorgeirsson, Raymond K Walters, Renato Polimanti, Alexander S Hatoum, Sandra Sanchez-Roige, Sarah E Paul, Frank R Wendt, Toni-Kim Clarke, Dongbing Lai, Gunnar W Reginsson, Hang Zhou, June He, David A A Baranger, Daniel F Gudbjartsson, Robbee Wedow, Daniel E Adkins, Amy E Adkins, Jeffry Alexander, Silviu-Alin Bacanu, Tim B Bigdeli, Joseph Boden, Sandra A Brown, Kathleen K Bucholz, Jonas Bybjerg-Grauholm, Robin P Corley, Louisa Degenhardt, Danielle M Dick, Benjamin W Domingue, Louis Fox, Alison M Goate, Scott D Gordon, Laura M Hack, Dana B Hancock, Sarah M Hartz, Ian B Hickie, David M Hougaard, Kenneth Krauter, Penelope A Lind, Jeanette N McClintick, Matthew B McQueen, Jacquelyn L Meyers, Grant W Montgomery, Ole Mors, Preben B Mortensen, Merete Nordentoft, John F Pearson, Roseann E Peterson, Maureen D Reynolds, John P Rice, Valgerdur Runarsdottir, Nancy L Saccone, Richard Sherva, Judy L Silberg, Ralph E Tarter, Thorarinn Tyrfingsson, Tamara L Wall, Bradley T Webb, Thomas Werge, Leah Wetherill, Margaret J Wright, Stephanie Zellers, Mark J Adams, Laura J Bierut, Jason D Boardman, William E Copeland, Lindsay A Farrer, Tatiana M Foroud, Nathan A Gillespie, Richard A Grucza, Kathleen Mullan Harris, Andrew C Heath, Victor Hesselbrock, John K Hewitt, Christian J Hopfer, John Horwood, William G Iacono, Eric O Johnson, Kenneth S Kendler, Martin A Kennedy, Henry R Kranzler, Pamela A F Madden, Hermine H Maes, Brion S Maher, Nicholas G Martin, Matthew McGue, Andrew M McIntosh, Sarah E Medland, Elliot C Nelson, Bernice Porjesz, Brien P Riley, Michael C Stallings, Michael M Vanyukov, Scott Vrieze, Lea K Davis, Ryan Bogdan, Joel Gelernter, Howard J Edenberg, Kari Stefansson, Anders D Børglum, Arpana Agrawal, Raymond Walters, Emma Johnson, Jeanette McClintick, Alexander Hatoum, Frank Wendt, Mark Adams, Amy Adkins, Fazil Aliev, Anthony Batzler, Sarah Bertelsen, Joanna Biernacka, Tim Bigdeli, Li-Shiun Chen, Yi-Ling Chou, Franziska Degenhardt, Anna Docherty, Alexis Edwards, Pierre Fontanillas, Jerome Foo, Josef Frank, Ina Giegling, Scott Gordon, Laura Hack, Annette Hartmann, Sarah Hartz, Stefanie Heilmann-Heimbach, Stefan Herms, Colin Hodgkinson, Per Hoffman, Jouke Hottenga, Martin Kennedy, Mervi Alanne-Kinnunen, Bettina Konte, Jari Lahti, Marius Lahti-Pulkkinen, Lannie Ligthart, Anu Loukola, Brion Maher, Hamdi Mbarek, Andrew McIntosh, Matthew McQueen, Jacquelyn Meyers, Yuri Milaneschi, Teemu Palviainen, John Pearson, Roseann Peterson, Samuli Ripatti, Euijung Ryu, Nancy Saccone, Jessica Salvatore, Melanie Schwandt, Fabian Streit, Jana Strohmaier, Nathaniel Thomas, Jen-Chyong Wang, Bradley Webb, Amanda Wills, Jason Boardman, Danfeng Chen, Doo-Sup Choi, William Copeland, Robert Culverhouse, Norbert Dahmen, Benjamin Domingue, Sarah Elson, Mark Frye, Wolfgang Gäbel, Caroline Hayward, Marcus Ising, Margaret Keyes, Falk Kiefer, John Kramer, Samuel Kuperman, Susanne Lucae, Michael Lynskey, Wolfgang Maier, Karl Mann, Satu Männistö, Bertram Müller-Myhsok, Alison Murray, John Nurnberger, Aarno Palotie, Ulrich Preuss, Katri Räikkönen, Maureen Reynolds, Monika Ridinger, Norbert Scherbaum, Marc Schuckit, Michael Soyka, Jens Treutlein, Stephanie Witt, Norbert Wodarz, Peter Zill, Daniel Adkins, Dorret Boomsma, Laura Bierut, Sandra Brown, Kathleen Bucholz, Sven Cichon, E. Jane Costello, Harriet de Wit, Nancy Diazgranados, Danielle Dick, Johan Eriksson, Lindsay Farrer, Tatiana Foroud, Nathan Gillespie, Alison Goate, David Goldman, Richard Grucza, Dana Hancock, Andrew Heath, John Hewitt, Christian Hopfer, William Iacono, Eric Johnson, Jaakko Kaprio, Victor Karpyak, Kenneth Kendler, Henry Kranzler, Paul Lichtenstein, Penelope Lind, Matt McGue, James MacKillop, Pamela Madden, Hermine Maes, Patrik Magnusson, Nicholas Martin, Sarah Medland, Grant Montgomery, Elliot Nelson, Markus Nöthen, Abraham Palmer, Nancy Pederson, Brenda Penninx, John Rice, Marcella Rietschel, Brien Riley, Richard Rose, Dan Rujescu, Pei-Hong Shen, Judy Silberg, Michael Stallings, Ralph Tarter, Michael Vanyukov, Tamara Wall, John Whitfield, Hongyu Zhao, Benjamin Neale, Howard Edenberg, Technology Centre, Department of Psychology and Logopedics, Developmental Psychology Research Group, University Management, HUSLAB, Genetic Epidemiology, Institute for Molecular Medicine Finland, Department of Public Health, Centre of Excellence in Complex Disease Genetics, Samuli Olli Ripatti / Principal Investigator, Complex Disease Genetics, Biostatistics Helsinki, Faculty of Arts, Research Programme of Molecular Medicine, Aarno Palotie / Principal Investigator, Genomics of Neurological and Neuropsychiatric Disorders, Research Programs Unit, Diabetes and Obesity Research Program, Department of General Practice and Primary Health Care, Johan Eriksson / Principal Investigator, Clinicum, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, APH - Digital Health, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, and APH - Methodology

Subjects
Risk, Marijuana Abuse, medicine.medical_specialty, Alcohol abuse, Disease, Polymorphism, Single Nucleotide, 3124 Neurology and psychiatry, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, medicine, Humans, 030212 general & internal medicine, Psychiatry, Borderline personality disorder, Biological Psychiatry, business.industry, Articles, Mental illness, medicine.disease, Mental health, 030227 psychiatry, 3. Good health, Substance abuse, Psychiatry and Mental health, Translational science, business, Genome-Wide Association Study, Psychopathology
Abstract

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 (r g 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.

Published
2020
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10. Sensitive determination of ethyl glucuronide in serum and whole blood: detection time after alcohol exposure compared with urine

Author

Anders Helander, Olof Beck, Norbert Dahmen, Jasna Neumann, and Michael Böttcher

Subjects
Chromatography, Chemistry, 010401 analytical chemistry, Biochemistry (medical), Clinical Biochemistry, Urine, Alcohol exposure, 01 natural sciences, urine, 0104 chemical sciences, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Ethyl glucuronide, alcohol biomarker, blood, ethyl glucuronide, Lc ms ms, Medical technology, Discrete Mathematics and Combinatorics, 030216 legal & forensic medicine, lc-ms/ms, R855-855.5, serum, Whole blood
Abstract

Objectives Ethyl glucuronide (EtG) is a conjugated, minor ethanol metabolite used as a biomarker for recent alcohol intake. EtG is commonly measured in urine as part of a drug testing service but has also attracted attention for measurement in blood. However, due to lower EtG concentrations in blood, the detection time is expected to be shorter. The present work aimed to improve the analytical sensitivity of EtG in blood, to prolong the detection time. Methods A liquid chromatography-tandem mass spectrometry method was developed for EtG in whole blood and serum, using protein precipitation with methanol, a deuterated internal standard, and selected reaction monitoring mode with negative electrospray ionization. No significant matrix effect was observed. The method generated linear results in the measuring range 1.0–50 μg/L, the accuracy was within ±10% and the imprecision Results In 46 patients followed with daily blood and urine sampling during alcohol detoxification, the mean (median) time to first negative serum EtG sample was 112 (111) h. This was slightly longer than for EtG in urine, using 100 μg/L as cutoff. The detection rate was 76% for serum EtG and 68% for urine EtG. In cases where serum EtG was positive but urine EtG negative, the urine samples tended to be more dilute as indicated by lower creatinine concentrations. On admission to hospital, the whole-blood and serum EtG concentrations correlated with the breath ethanol concentration (p = 0.012 and p = 0.027, respectively). In 100 patients sampled at admission to hospital for other reasons than substance abuse and with no ethanol detected in breath, 40% tested positive for EtG in serum and 43% in urine. In 79 paired urine and serum EtG measurements, the median urine/serum concentration ratio was 155. Conclusions A sensitive method was developed for EtG measurement in whole-blood and serum specimens, offering similar detection time for recent alcohol exposure compared with routine EtG measurement in urine.

Published
2020

13. Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Author

Niamh Mullins, JooEun Kang, Adrian I. Campos, Jonathan R.I. Coleman, Alexis C. Edwards, Hanga Galfalvy, Daniel F. Levey, Adriana Lori, Andrey Shabalin, Anna Starnawska, Mei-Hsin Su, Hunna J. Watson, Mark Adams, Swapnil Awasthi, Michael Gandal, Jonathan D. Hafferty, Akitoyo Hishimoto, Minsoo Kim, Satoshi Okazaki, Ikuo Otsuka, Stephan Ripke, Erin B. Ware, Andrew W. Bergen, Wade H. Berrettini, Martin Bohus, Harry Brandt, Xiao Chang, Wei J. Chen, Hsi-Chung Chen, Steven Crawford, Scott Crow, Emily DiBlasi, Philibert Duriez, Fernando Fernández-Aranda, Manfred M. Fichter, Steven Gallinger, Stephen J. Glatt, Philip Gorwood, Yiran Guo, Hakon Hakonarson, Katherine A. Halmi, Hai-Gwo Hwu, Sonia Jain, Stéphane Jamain, Susana Jiménez-Murcia, Craig Johnson, Allan S. Kaplan, Walter H. Kaye, Pamela K. Keel, James L. Kennedy, Kelly L. Klump, Dong Li, Shih-Cheng Liao, Klaus Lieb, Lisa Lilenfeld, Chih-Min Liu, Pierre J. Magistretti, Christian R. Marshall, James E. Mitchell, Eric T. Monson, Richard M. Myers, Dalila Pinto, Abigail Powers, Nicolas Ramoz, Stefan Roepke, Vsevolod Rozanov, Stephen W. Scherer, Christian Schmahl, Marcus Sokolowski, Michael Strober, Laura M. Thornton, Janet Treasure, Ming T. Tsuang, Stephanie H. Witt, D. Blake Woodside, Zeynep Yilmaz, Lea Zillich, Rolf Adolfsson, Ingrid Agartz, Tracy M. Air, Martin Alda, Lars Alfredsson, Ole A. Andreassen, Adebayo Anjorin, Vivek Appadurai, María Soler Artigas, Sandra Van der Auwera, M. Helena Azevedo, Nicholas Bass, Claiton H.D. Bau, Bernhard T. Baune, Frank Bellivier, Klaus Berger, Joanna M. Biernacka, Tim B. Bigdeli, Elisabeth B. Binder, Michael Boehnke, Marco P. Boks, Rosa Bosch, David L. Braff, Richard Bryant, Monika Budde, Enda M. Byrne, Wiepke Cahn, Miguel Casas, Enrique Castelao, Jorge A. Cervilla, Boris Chaumette, Sven Cichon, Aiden Corvin, Nicholas Craddock, David Craig, Franziska Degenhardt, Srdjan Djurovic, Howard J. Edenberg, Ayman H. Fanous, Jerome C. Foo, Andreas J. Forstner, Mark Frye, Janice M. Fullerton, Justine M. Gatt, Pablo V. Gejman, Ina Giegling, Hans J. Grabe, Melissa J. Green, Eugenio H. Grevet, Maria Grigoroiu-Serbanescu, Blanca Gutierrez, Jose Guzman-Parra, Steven P. Hamilton, Marian L. Hamshere, Annette Hartmann, Joanna Hauser, Stefanie Heilmann-Heimbach, Per Hoffmann, Marcus Ising, Ian Jones, Lisa A. Jones, Lina Jonsson, René S. Kahn, John R. Kelsoe, Kenneth S. Kendler, Stefan Kloiber, Karestan C. Koenen, Manolis Kogevinas, Bettina Konte, Marie-Odile Krebs, Mikael Landén, Jacob Lawrence, Marion Leboyer, Phil H. Lee, Douglas F. Levinson, Calwing Liao, Jolanta Lissowska, Susanne Lucae, Fermin Mayoral, Susan L. McElroy, Patrick McGrath, Peter McGuffin, Andrew McQuillin, Sarah E. Medland, Divya Mehta, Ingrid Melle, Yuri Milaneschi, Philip B. Mitchell, Esther Molina, Gunnar Morken, Preben Bo Mortensen, Bertram Müller-Myhsok, Caroline Nievergelt, Vishwajit Nimgaonkar, Markus M. Nöthen, Michael C. O’Donovan, Roel A. Ophoff, Michael J. Owen, Carlos Pato, Michele T. Pato, Brenda W.J.H. Penninx, Jonathan Pimm, Giorgio Pistis, James B. Potash, Robert A. Power, Martin Preisig, Digby Quested, Josep Antoni Ramos-Quiroga, Andreas Reif, Marta Ribasés, Vanesa Richarte, Marcella Rietschel, Margarita Rivera, Andrea Roberts, Gloria Roberts, Guy A. Rouleau, Diego L. Rovaris, Dan Rujescu, Cristina Sánchez-Mora, Alan R. Sanders, Peter R. Schofield, Thomas G. Schulze, Laura J. Scott, Alessandro Serretti, Jianxin Shi, Stanley I. Shyn, Lea Sirignano, Pamela Sklar, Olav B. Smeland, Jordan W. Smoller, Edmund J.S. Sonuga-Barke, Gianfranco Spalletta, John S. Strauss, Beata Świątkowska, Maciej Trzaskowski, Gustavo Turecki, Laura Vilar-Ribó, John B. Vincent, Henry Völzke, James T.R. Walters, Cynthia Shannon Weickert, Thomas W. Weickert, Myrna M. Weissman, Leanne M. Williams, Naomi R. Wray, Clement C. Zai, Allison E. Ashley-Koch, Jean C. Beckham, Elizabeth R. Hauser, Michael A. Hauser, Nathan A. Kimbrel, Jennifer H. Lindquist, Benjamin McMahon, David W. Oslin, Xuejun Qin, Esben Agerbo, Anders D. Børglum, Gerome Breen, Annette Erlangsen, Tõnu Esko, Joel Gelernter, David M. Hougaard, Ronald C. Kessler, Henry R. Kranzler, Qingqin S. Li, Nicholas G. Martin, Andrew M. McIntosh, Ole Mors, Merete Nordentoft, Catherine M. Olsen, David Porteous, Robert J. Ursano, Danuta Wasserman, Thomas Werge, David C. Whiteman, Cynthia M. Bulik, Hilary Coon, Ditte Demontis, Anna R. Docherty, Po-Hsiu Kuo, Cathryn M. Lewis, J. John Mann, Miguel E. Rentería, Daniel J. Smith, Eli A. Stahl, Murray B. Stein, Fabian Streit, Virginia Willour, Douglas M. Ruderfer, Manuel Mattheisen, Abdel Abdellaoui, Mark J. Adams, Till F.M. Andlauer, Silviu-Alin Bacanu, Marie Bækvad-Hansen, Aartjan T.F. Beekman, Julien Bryois, Henriette N. Buttenschøn, Jonas Bybjerg-Grauholm, Na Cai, Jane Hvarregaard Christensen, Toni-Kim Clarke, Lucía Colodro-Conde, Baptiste Couvy-Duchesne, Nick Craddock, Gregory E. Crawford, Gail Davies, Eske M. Derks, Nese Direk, Conor V. Dolan, Erin C. Dunn, Thalia C. Eley, Valentina Escott-Price, Farnush Farhadi Hassan Kiadeh, Hilary K. Finucane, Josef Frank, Héléna A. Gaspar, Michael Gill, Fernando S. Goes, Scott D. Gordon, Shantel Marie Weinsheimer, Jürgen Wellmann, Gonneke Willemsen, Yang Wu, Hualin S. Xi, Jian Yang, Futao Zhang, Volker Arolt, Dorret I. Boomsma, Udo Dannlowski, E.J.C. de Geus, J. Raymond Depaulo, Enrico Domenici, Katharina Domschke, Jakob Grove, Lynsey S. Hall, Christine Søholm Hansen, Thomas F. Hansen, Stefan Herms, Ian B. Hickie, Georg Homuth, Carsten Horn, Jouke-Jan Hottenga, David M. Howard, Rick Jansen, Eric Jorgenson, James A. Knowles, Isaac S. Kohane, Julia Kraft, Warren W. Kretzschmar, Zoltán Kutalik, Yihan Li, Penelope A. Lind, Donald J. MacIntyre, Dean F. MacKinnon, Robert M. Maier, Wolfgang Maier, Jonathan Marchini, Hamdi Mbarek, Christel M. Middeldorp, Evelin Mihailov, Lili Milani, Francis M. Mondimore, Grant W. Montgomery, Sara Mostafavi, Matthias Nauck, Bernard Ng, Michel G. Nivard, Dale R. Nyholt, Paul F. O’Reilly, Hogni Oskarsson, Caroline Hayward, Andrew C. Heath, Glyn Lewis, Pamela A.F. Madden, Patrik K. Magnusson, Andres Metspalu, Sara A. Paciga, Nancy L. Pedersen, Jodie N. Painter, Carsten Bøcker Pedersen, Marianne Giørtz Pedersen, Roseann E. Peterson, Wouter J. Peyrot, Danielle Posthuma, Jorge A. Quiroz, Per Qvist, John P. Rice, Brien P. Riley, Saira Saeed Mirza, Robert Schoevers, Eva C. Schulte, Ling Shen, Engilbert Sigurdsson, Grant C.B. Sinnamon, Johannes H. Smit, Hreinn Stefansson, Stacy Steinberg, Jana Strohmaier, Katherine E. Tansey, Henning Teismann, Alexander Teumer, Wesley Thompson, Pippa A. Thomson, Thorgeir E. Thorgeirsson, Matthew Traylor, Jens Treutlein, Vassily Trubetskoy, André G. Uitterlinden, Daniel Umbricht, Albert M. van Hemert, Alexander Viktorin, Peter M. Visscher, Yunpeng Wang, Bradley T. Webb, Roy H. Perlis, David J. Porteous, Catherine Schaefer, Kari Stefansson, Henning Tiemeier, Rudolf Uher, Patrick F. Sullivan, Kevin S. O’Connell, Brandon Coombes, Zhen Qiao, Thomas D. Als, Sigrid Børte, Alexander W. Charney, Ole Kristian Drange, Michael J. Gandal, Saskia P. Hagenaars, Masashi Ikeda, Nolan Kamitaki, Kristi Krebs, Georgia Panagiotaropoulou, Brian M. Schilder, Laura G. Sloofman, Bendik S. Winsvold, Hong-Hee Won, Liliya Abramova, Kristina Adorjan, Mariam Al Eissa, Diego Albani, Ney Alliey-Rodriguez, Verneri Antilla, Anastasia Antoniou, Ji Hyun Baek, Michael Bauer, Eva C. Beins, Sarah E. Bergen, Armin Birner, Erlend Bøen, Murielle Brum, Ben M. Brumpton, Nathalie Brunkhorst-Kanaan, William Byerley, Murray Cairns, Miquel Casas, Pablo Cervantes, Cristiana Cruceanu, Alfredo Cuellar-Barboza, Julie Cunningham, David Curtis, Piotr M. Czerski, Anders M. Dale, Nina Dalkner, Friederike S. David, Amanda L. Dobbyn, Athanassios Douzenis, Torbjørn Elvsåshagen, I. Nicol Ferrier, Alessia Fiorentino, Tatiana M. Foroud, Liz Forty, Oleksandr Frei, Nelson B. Freimer, Louise Frisén, Katrin Gade, Julie Garnham, Ian R. Gizer, Katherine Gordon-Smith, Tiffany A. Greenwood, José Guzman-Parra, Kyooseob Ha, Magnus Haraldsson, Martin Hautzinger, Urs Heilbronner, Dennis Hellgren, Peter A. Holmans, Laura Huckins, Jessica S. Johnson, Janos L. Kalman, Yoichiro Kamatani, Sarah Kittel-Schneider, Maria Koromina, Thorsten M. Kranz, Michiaki Kubo, Ralph Kupka, Steven A. Kushner, Catharina Lavebratt, Markus Leber, Heon-Jeong Lee, Shawn E. Levy, Catrin Lewis, Martin Lundberg, Sigurdur H. Magnusson, Adam Maihofer, Dolores Malaspina, Eirini Maratou, Lina Martinsson, Nathaniel W. McGregor, James D. McKay, Helena Medeiros, Vincent Millischer, Jennifer L. Moran, Derek W. Morris, Thomas W. Mühleisen, Niamh O’Brien, Claire O’Donovan, Loes M. Olde Loohuis, Lilijana Oruc, Sergi Papiol, Antonio F. Pardiñas, Amy Perry, Andrea Pfennig, Evgenia Porichi, Towfique Raj, Mark H. Rapaport, J. Raymond DePaulo, Eline J. Regeer, Fabio Rivas, Julian Roth, Panos Roussos, Fanny Senner, Sally Sharp, Paul D. Shilling, Claire Slaney, Janet L. Sobell, Maria Soler Artigas, Anne T. Spijker, Dan J. Stein, Chikashi Terao, Claudio Toma, Paul Tooney, Evangelia-Eirini Tsermpini, Marquis P. Vawter, Helmut Vedder, Simon Xi, Wei Xu, Jessica Mei Kay Yang, Allan H. Young, Hannah Young, Peter P. Zandi, Hang Zhou, null HUNT All-In Psychiatry, Gulja Babadjanova, Lena Backlund, Susanne Bengesser, Douglas H.R. Blackwood, Vaughan J. Carr, Stanley Catts, Dimitris Dikeos, Bruno Etain, Panagiotis Ferentinos, Micha Gawlik, Elliot S. Gershon, Frans Henskens, Jan Hillert, Kyung Sue Hong, Christina M. Hultman, Kristian Hveem, Nakao Iwata, Assen V. Jablensky, George Kirov, Christine Lochner, Carmel Loughland, Carol A. Mathews, Francis J. McMahon, Patricia Michie, Bryan Mowry, Benjamin M. Neale, Caroline M. Nievergelt, Ketil J. Oedegaard, Tomas Olsson, Chris Pantelis, George P. Patrinos, Eva Z. Reininghaus, Takeo Saito, Ulrich Schall, Martin Schalling, Rodney J. Scott, Eystein Stordal, Arne E. Vaaler, Eduard Vieta, Irwin D. Waldman, John-Anker Zwart, John I. Nurnberger, Arianna Di Florio, Roger A.H. Adan, Tetsuya Ando, Harald Aschauer, Jessica H. Baker, Vladimir Bencko, Andreas Birgegård, Joseph M. Boden, Ilka Boehm, Claudette Boni, Vesna Boraska Perica, Katharina Buehren, Roland Burghardt, Laura Carlberg, Matteo Cassina, Maurizio Clementi, Roger D. Cone, Philippe Courtet, James J. Crowley, Unna N. Danner, Oliver S.P. Davis, Martina de Zwaan, George Dedoussis, Daniela Degortes, Janiece E. DeSocio, Danielle M. Dick, Christian Dina, Monika Dmitrzak-Weglarz, Elisa Docampo Martinez, Laramie E. Duncan, Karin Egberts, Morten Mattingsdal, Sara McDevitt, Ingrid Meulenbelt, Nadia Micali, James Mitchell, Karen Mitchell, Palmiero Monteleone, Alessio Maria Monteleone, Melissa A. Munn-Chernoff, Benedetta Nacmias, Marie Navratilova, Ioanna Ntalla, Julie K. O’Toole, Leonid Padyukov, Aarno Palotie, Jacques Pantel, Hana Papezova, Richard Parker, John F. Pearson, Stefan Ehrlich, Geòrgia Escaramís, Thomas Espeseth, Xavier Estivill, Anne Farmer, Angela Favaro, Krista Fischer, James A.B. Floyd, Manuel Föcker, Lenka Foretova, Monica Forzan, Christopher S. Franklin, Giovanni Gambaro, Johanna Giuranna, Paola Giusti-Rodríquez, Fragiskos Gonidakis, Scott Gordon, Monica Gratacos Mayora, Sébastien Guillaume, Ken B. Hanscombe, Konstantinos Hatzikotoulas, Johannes Hebebrand, Sietske G. Helder, Anjali K. Henders, Beate Herpertz-Dahlmann, Wolfgang Herzog, Anke Hinney, L. John Horwood, Christopher Hübel, Liselotte V. Petersen, Kirstin L. Purves, Anu Raevuori, Ted Reichborn-Kjennerud, Valdo Ricca, Samuli Ripatti, Franziska Ritschel, Marion Roberts, Filip Rybakowski, Paolo Santonastaso, André Scherag, Ulrike Schmidt, Nicholas J. Schork, Alexandra Schosser, Jochen Seitz, Lenka Slachtova, P. Eline Slagboom, Margarita C.T. Slof-Op ‘t Landt, Agnieszka Slopien, Nicole Soranzo, Sandro Sorbi, Lorraine Southam, Vidar W. Steen, Laura M. Huckins, James I. Hudson, Hartmut Imgart, Hidetoshi Inoko, Vladimir Janout, Jennifer Jordan, Antonio Julià, Gursharan Kalsi, Deborah Kaminská, Jaakko Kaprio, Leila Karhunen, Andreas Karwautz, Martien J.H. Kas, Martin A. Kennedy, Anna Keski-Rahkonen, Kirsty Kiezebrink, Youl-Ri Kim, Katherine M. Kirk, Lars Klareskog, Gun Peggy S. Knudsen, Janne T. Larsen, Stephanie Le Hellard, Virpi M. Leppä, Paul Lichtenstein, Bochao Danae Lin, Astri Lundervold, Jurjen Luykx, Mario Maj, Katrin Mannik, Sara Marsal, Garret D. Stuber, Jin P. Szatkiewicz, Ioanna Tachmazidou, Elena Tenconi, Alfonso Tortorella, Federica Tozzi, Artemis Tsitsika, Marta Tyszkiewicz-Nwafor, Konstantinos Tziouvas, Annemarie A. van Elburg, Eric F. van Furth, Tracey D. Wade, Gudrun Wagner, Esther Walton, H. Erich Wichmann, Elisabeth Widen, Shuyang Yao, Eleftheria Zeggini, Stephanie Zerwas, Stephan Zipfel, Martin Jungkunz, Lydie Dietl, Cornelia E. Schwarze, Norbert Dahmen, Björn H. Schott, Arian Mobascher, Silvia Crivelli, Michelle F. Dennis, Phillip D. Harvey, Bruce W. Carter, Jennifer E. Huffman, Daniel Jacobson, Ravi Madduri, Maren K. Olsen, John Pestian, J. Michael Gaziano, Sumitra Muralidhar, Rachel Ramoni, Jean Beckham, Kyong-Mi Chang, Christopher J. O’Donnell, Philip S. Tsao, James Breeling, Grant Huang, J.P. Casas Romero, Jennifer Moser, Stacey B. Whitbourne, Jessica V. Brewer, Mihaela Aslan, Todd Connor, Dean P. Argyres, Brady Stephens, Mary T. Brophy, Donald E. Humphries, Luis E. Selva, Nhan Do, Shahpoor Shayan, Kelly Cho, Saiju Pyarajan, Elizabeth Hauser, Yan Sun, Hongyu Zhao, Peter Wilson, Rachel McArdle, Louis Dellitalia, Kristin Mattocks, John Harley, Clement J. Zablocki, Jeffrey Whittle, Frank Jacono, Salvador Gutierrez, Gretchen Gibson, Kimberly Hammer, Laurence Kaminsky, Gerardo Villareal, Scott Kinlay, Junzhe Xu, Mark Hamner, Roy Mathew, Sujata Bhushan, Pran Iruvanti, Michael Godschalk, Zuhair Ballas, Douglas Ivins, Stephen Mastorides, Jonathan Moorman, Saib Gappy, Jon Klein, Nora Ratcliffe, Hermes Florez, Olaoluwa Okusaga, Maureen Murdoch, Peruvemba Sriram, Shing Shing Yeh, Neeraj Tandon, Darshana Jhala, Samuel Aguayo, David Cohen, Satish Sharma, Suthat Liangpunsakul, Kris Ann Oursler, Mary Whooley, Sunil Ahuja, Joseph Constans, Paul Meyer, Jennifer Greco, Michael Rauchman, Richard Servatius, Melinda Gaddy, Agnes Wallbom, Timothy Morgan, Todd Stapley, Scott Sherman, George Ross, Philip Tsao, Patrick Strollo, Edward Boyko, Laurence Meyer, Samir Gupta, Mostaqul Huq, Joseph Fayad, Adriana Hung, Jack Lichy, Robin Hurley, Brooks Robey, Robert Striker, Dietl, Lydie, Schwarze, Cornelia E., Dahmen, Norbert, Schott, Björn H., Nöthen, Markus M., Ripke, Stephan, Mobascher, Arian, Rujescu, Dan, Lieb, Klaus, Roepke, Stefan, Schmahl, Christian, Bohus, Martin, Rietschel, Marcella, Crivelli, Silvia, Dennis, Michelle F., Harvey, Phillip D., Carter, Bruce W., Huffman, Jennifer E., Jacobson, Daniel, Madduri, Ravi, Olsen, Maren K., Pestian, John, Gaziano, J. Michael, Muralidhar, Sumitra, Ramoni, Rachel, Beckham, Jean, Chang, Kyong-Mi, O'Donnell, Christopher J., Tsao, Philip S., Breeling, James, Huang, Grant, Romero, J. P. Casas, Moser, Jennifer, Whitbourne, Stacey B., Brewer, Jessica V., Aslan, Mihaela, Connor, Todd, Argyres, Dean P., Stephens, Brady, Brophy, Mary T., Humphries, Donald E., Selva, Luis E., Do, Nhan, Shayan, Shahpoor, Cho, Kelly, Pyarajan, Saiju, Hauser, Elizabeth, Sun, Yan, Zhao, Hongyu, Wilson, Peter, McArdle, Rachel, Dellitalia, Louis, Mattocks, Kristin, Harley, John, Zablocki, Clement J., Whittle, Jeffrey, Jacono, Frank, Gutierrez, Salvador, Gibson, Gretchen, Hammer, Kimberly, Kaminsky, Laurence, Villareal, Gerardo, Kinlay, Scott, Xu, Junzhe, Hamner, Mark, Mathew, Roy, Bhushan, Sujata, Iruvanti, Pran, Godschalk, Michael, Ballas, Zuhair, Ivins, Douglas, Mastorides, Stephen, Moorman, Jonathan, Gappy, Saib, Klein, Jon, Ratcliffe, Nora, Florez, Hermes, Okusaga, Olaoluwa, Murdoch, Maureen, Sriram, Peruvemba, Yeh, Shing Shing, Tandon, Neeraj, Jhala, Darshana, Aguayo, Samuel, Cohen, David, Sharma, Satish, Liangpunsakul, Suthat, Oursler, Kris Ann, Whooley, Mary, Ahuja, Sunil, Constans, Joseph, Meyer, Paul, Greco, Jennifer, Rauchman, Michael, Servatius, Richard, Gaddy, Melinda, Wallbom, Agnes, Morgan, Timothy, Stapley, Todd, Sherman, Scott, Ross, George, Tsao, Philip, Strollo, Patrick, Boyko, Edward, Meyer, Laurence, Gupta, Samir, Huq, Mostaqul, Fayad, Joseph, Hung, Adriana, Lichy, Jack, Hurley, Robin, Robey, Brooks, Striker, Robert, Wray, Naomi R., Mattheisen, Manuel, Trzaskowski, Maciej, Byrne, Enda M., Abdellaoui, Abdel, Adams, Mark J., Agerbo, Esben, Air, Tracy M., Andlauer, Till F. M., Bacanu, Silviu-Alin, Bækvad-Hansen, Marie, Beekman, Aartjan T. F., Bigdeli, Tim B., Binder, Elisabeth B., Bryois, Julien, Buttenschøn, Henriette N., Bybjerg-Grauholm, Jonas, Cai, Na, Castelao, Enrique, Christensen, Jane Hvarregaard, Clarke, Toni-Kim, Coleman, Jonathan R. I., Colodro-Conde, Lucía, Couvy-Duchesne, Baptiste, Craddock, Nick, Crawford, Gregory E., Davies, Gail, Degenhardt, Franziska, Derks, Eske M., Direk, Nese, Dolan, Conor V., Dunn, Erin C., Eley, Thalia C., Escott-Price, Valentina, Hassan Kiadeh, Farnush Farhadi, Finucane, Hilary K., Foo, Jerome C., Forstner, Andreas J., Frank, Josef, Gaspar, Héléna A., Gill, Michael, Goes, Fernando S., Gordon, Scott D., Weinsheimer, Shantel Marie, Wellmann, Jürgen, Willemsen, Gonneke, Witt, Stephanie H., Wu, Yang, Xi, Hualin S., Yang, Jian, Zhang, Futao, Arolt, Volker, Baune, Bernhard T., Berger, Klaus, Boomsma, Dorret I., Cichon, Sven, Dannlowski, Udo, de Geus, E. J. C., DePaulo, J. Raymond, Domenici, Enrico, Domschke, Katharina, Esko, Tõnu, Grabe, Hans J., Hamilton, Steven P., Grove, Jakob, Hall, Lynsey S., Hansen, Christine Søholm, Hansen, Thomas F., Herms, Stefan, Hickie, Ian B., Hoffmann, Per, Homuth, Georg, Horn, Carsten, Hottenga, Jouke-Jan, Hougaard, David M., Howard, David M., Ising, Marcus, Jansen, Rick, Jones, Ian, Jones, Lisa A., Jorgenson, Eric, Knowles, James A., Kohane, Isaac S., Kraft, Julia, Kretzschmar, Warren W., Kutalik, Zoltán, Li, Yihan, Lind, Penelope A., MacIntyre, Donald J., MacKinnon, Dean F., Maier, Robert M., Maier, Wolfgang, Marchini, Jonathan, Mbarek, Hamdi, McGrath, Patrick, McGuffin, Peter, Medland, Sarah E., Mehta, Divya, Middeldorp, Christel M., Mihailov, Evelin, Milaneschi, Yuri, Milani, Lili, Mondimore, Francis M., Montgomery, Grant W., Mostafavi, Sara, Mullins, Niamh, Nauck, Matthias, Ng, Bernard, Nivard, Michel G., Nyholt, Dale R., O'Reilly, Paul F., Oskarsson, Hogni, Hayward, Caroline, Heath, Andrew C., Kendler, Kenneth S., Kloiber, Stefan, Lewis, Glyn, Li, Qingqin S., Lucae, Susanne, Madden, Pamela A. F., Magnusson, Patrik K., Martin, Nicholas G., McIntosh, Andrew M., Metspalu, Andres, Mors, Ole, Mortensen, Preben Bo, Müller-Myhsok, Bertram, Nordentoft, Merete, O'Donovan, Michael C., Paciga, Sara A., Pedersen, Nancy L., Owen, Michael J., Painter, Jodie N., Pedersen, Carsten Bøcker, Pedersen, Marianne Giørtz, Peterson, Roseann E., Peyrot, Wouter J., Pistis, Giorgio, Posthuma, Danielle, Quiroz, Jorge A., Qvist, Per, Rice, John P., Riley, Brien P., Rivera, Margarita, Mirza, Saira Saeed, Schoevers, Robert, Schulte, Eva C., Shen, Ling, Shi, Jianxin, Shyn, Stanley I., Sigurdsson, Engilbert, Sinnamon, Grant C. B., Smit, Johannes H., Smith, Daniel J., Stefansson, Hreinn, Steinberg, Stacy, Streit, Fabian, Strohmaier, Jana, Tansey, Katherine E., Teismann, Henning, Teumer, Alexander, Thompson, Wesley, Thomson, Pippa A., Thorgeirsson, Thorgeir E., Traylor, Matthew, Treutlein, Jens, Trubetskoy, Vassily, Uitterlinden, André G., Umbricht, Daniel, Van der Auwera, Sandra, van Hemert, Albert M., Viktorin, Alexander, Visscher, Peter M., Wang, Yunpeng, Webb, Bradley T., Penninx, Brenda W. J. H., Perlis, Roy H., Porteous, David J., Potash, James B., Preisig, Martin, Schaefer, Catherine, Schulze, Thomas G., Smoller, Jordan W., Stefansson, Kari, Tiemeier, Henning, Uher, Rudolf, Völzke, Henry, Weissman, Myrna M., Werge, Thomas, Lewis, Cathryn M., Levinson, Douglas F., Breen, Gerome, Børglum, Anders D., Sullivan, Patrick F., O'Connell, Kevin S., Coombes, Brandon, Qiao, Zhen, Als, Thomas D., Børte, Sigrid, Charney, Alexander W., Drange, Ole Kristian, Gandal, Michael J., Hagenaars, Saskia P., Ikeda, Masashi, Kamitaki, Nolan, Kim, Minsoo, Krebs, Kristi, Panagiotaropoulou, Georgia, Schilder, Brian M., Sloofman, Laura G., Winsvold, Bendik S., Won, Hong-Hee, Abramova, Liliya, Adorjan, Kristina, Al Eissa, Mariam, Albani, Diego, Alliey-Rodriguez, Ney, Anjorin, Adebayo, Antilla, Verneri, Antoniou, Anastasia, Awasthi, Swapnil, Baek, Ji Hyun, Bass, Nicholas, Bauer, Michael, Beins, Eva C., Bergen, Sarah E., Birner, Armin, Bøen, Erlend, Boks, Marco P., Bosch, Rosa, Brum, Murielle, Brumpton, Ben M., Brunkhorst-Kanaan, Nathalie, Budde, Monika, Byerley, William, Cairns, Murray, Casas, Miquel, Cervantes, Pablo, Cruceanu, Cristiana, Cuellar-Barboza, Alfredo, Cunningham, Julie, Curtis, David, Czerski, Piotr M., Dale, Anders M., Dalkner, Nina, David, Friederike S., Djurovic, Srdjan, Dobbyn, Amanda L., Douzenis, Athanassios, Elvsåshagen, Torbjørn, Ferrier, I. Nicol, Fiorentino, Alessia, Foroud, Tatiana M., Forty, Liz, Frei, Oleksandr, Freimer, Nelson B., Frisén, Louise, Gade, Katrin, Garnham, Julie, Gelernter, Joel, Gizer, Ian R., Gordon-Smith, Katherine, Greenwood, Tiffany A., Guzman-Parra, José, Ha, Kyooseob, Haraldsson, Magnus, Hautzinger, Martin, Heilbronner, Urs, Hellgren, Dennis, Holmans, Peter A., Huckins, Laura, Jamain, Stéphane, Johnson, Jessica S., Kalman, Janos L., Kamatani, Yoichiro, Kennedy, James L., Kittel-Schneider, Sarah, Kogevinas, Manolis, Koromina, Maria, Kranz, Thorsten M., Kranzler, Henry R., Kubo, Michiaki, Kupka, Ralph, Kushner, Steven A., Lavebratt, Catharina, Lawrence, Jacob, Leber, Markus, Lee, Heon-Jeong, Lee, Phil H., Levy, Shawn E., Lewis, Catrin, Liao, Calwing, Lundberg, Martin, Magnusson, Sigurdur H., Maihofer, Adam, Malaspina, Dolores, Maratou, Eirini, Martinsson, Lina, McGregor, Nathaniel W., McKay, James D., Medeiros, Helena, Millischer, Vincent, Moran, Jennifer L., Morris, Derek W., Mühleisen, Thomas W., O'Brien, Niamh, O'Donovan, Claire, Olde Loohuis, Loes M., Oruc, Lilijana, Papiol, Sergi, Pardiñas, Antonio F., Perry, Amy, Pfennig, Andrea, Porichi, Evgenia, Quested, Digby, Raj, Towfique, Rapaport, Mark H., Regeer, Eline J., Rivas, Fabio, Roth, Julian, Roussos, Panos, Ruderfer, Douglas M., Sánchez-Mora, Cristina, Senner, Fanny, Sharp, Sally, Shilling, Paul D., Sirignano, Lea, Slaney, Claire, Smeland, Olav B., Sobell, Janet L., Artigas, Maria Soler, Spijker, Anne T., Stein, Dan J., Strauss, John S., Świątkowska, Beata, Terao, Chikashi, Toma, Claudio, Tooney, Paul, Tsermpini, Evangelia-Eirini, Vawter, Marquis P., Vedder, Helmut, Walters, James T. 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Nyholt D.R., O'Reilly P.F., Oskarsson H., Hayward C., Heath A.C., Lewis G., Li Q.S., Madden P.A.F., Magnusson P.K., Martin N.G., McIntosh A.M., Metspalu A., Mors O., Nordentoft M., Paciga S.A., Pedersen N.L., Painter J.N., Pedersen C.B., Pedersen M.G., Peterson R.E., Peyrot W.J., Posthuma D., Quiroz J.A., Qvist P., Rice J.P., Riley B.P., Mirza S.S., Schoevers R., Schulte E.C., Shen L., Sigurdsson E., Sinnamon G.C.B., Smit J.H., Smith D.J., Stefansson H., Steinberg S., Streit F., Strohmaier J., Tansey K.E., Teismann H., Teumer A., Thompson W., Thomson P.A., Thorgeirsson T.E., Traylor M., Treutlein J., Trubetskoy V., Uitterlinden A.G., Umbricht D., der Auwera S.V., van Hemert A.M., Viktorin A., Visscher P.M., Wang Y., Webb B.T., Perlis R.H., Porteous D.J., Schaefer C., Stefansson K., Tiemeier H., Uher R., Werge T., Lewis C.M., Breen G., Borglum A.D., Sullivan P.F., O'Connell K.S., Coombes B., Qiao Z., Als T.D., Borte S., Charney A.W., Drange O.K., Gandal M.J., Hagenaars S.P., Ikeda M., Kamitaki N., Krebs K., Panagiotaropoulou G., Schilder B.M., Sloofman L.G., Winsvold B.S., Won H.-H., Abramova L., Adorjan K., Al Eissa M., Albani D., Alliey-Rodriguez N., Antilla V., Antoniou A., Baek J.H., Bauer M., Beins E.C., Bergen S.E., Birner A., Boen E., Brum M., Brumpton B.M., Brunkhorst-Kanaan N., Byerley W., Cairns M., Cervantes P., Cruceanu C., Cuellar-Barboza A., Cunningham J., Curtis D., Czerski P.M., Dale A.M., Dalkner N., David F.S., Dobbyn A.L., Douzenis A., Elvsashagen T., Ferrier I.N., Fiorentino A., Foroud T.M., Forty L., Frei O., Freimer N.B., Frisen L., Gade K., Garnham J., Gelernter J., Gizer I.R., Gordon-Smith K., Greenwood T.A., Ha K., Haraldsson M., Hautzinger M., Heilbronner U., Hellgren D., Holmans P.A., Huckins L., Johnson J.S., Kalman J.L., Kamatani Y., Kittel-Schneider S., Koromina M., Kranz T.M., Kranzler H.R., Kubo M., Kupka R., Kushner S.A., Lavebratt C., Leber M., Lee H.-J., Levy S.E., Lewis C., Lundberg M., Magnusson S.H., Maihofer A., Malaspina D., Maratou E., Martinsson L., McGregor N.W., McKay J.D., Medeiros H., Millischer V., Moran J.L., Morris D.W., Muhleisen T.W., O'Brien N., O'Donovan C., Olde Loohuis L.M., Oruc L., Papiol S., Pardinas A.F., Perry A., Pfennig A., Porichi E., Raj T., Rapaport M.H., Regeer E.J., Rivas F., Roth J., Roussos P., Ruderfer D.M., Senner F., Sharp S., Shilling P.D., Slaney C., Sobell J.L., Artigas M.S., Spijker A.T., Stein D.J., Terao C., Toma C., Tooney P., Tsermpini E.-E., Vawter M.P., Vedder H., Xi S., Xu W., Kay Yang J.M., Young A.H., Young H., Zandi P.P., Zhou H., HUNT All-In Psychiatry, Babadjanova G., Backlund L., Bengesser S., Blackwood D.H.R., Carr V.J., Catts S., Dikeos D., Etain B., Ferentinos P., Gawlik M., Gershon E.S., Henskens F., Hillert J., Hong K.S., Hultman C.M., Hveem K., Iwata N., Jablensky A.V., Kirov G., Lochner C., Loughland C., Mathews C.A., McMahon F.J., Michie P., Mowry B., Neale B.M., Nievergelt C.M., Oedegaard K.J., Olsson T., Pantelis C., Patrinos G.P., Reininghaus E.Z., Saito T., Schall U., Schalling M., Scott R.J., Weickert C.S., Stordal E., Vaaler A.E., Vieta E., Waldman I.D., Zwart J.-A., Nurnberger J.I., Stahl E.A., Di Florio A., Adan R.A.H., Ando T., Aschauer H., Baker J.H., Bencko V., Birgegard A., Boden J.M., Boehm I., Boni C., Perica V.B., Buehren K., Bulik C.M., Burghardt R., Carlberg L., Cassina M., Clementi M., Cone R.D., Courtet P., Crowley J.J., Danner U.N., Davis O.S.P., de Zwaan M., Dedoussis G., Degortes D., DeSocio J.E., Dick D.M., Dina C., Dmitrzak-Weglarz M., Martinez E.D., Duncan L.E., Egberts K., Mattingsdal M., McDevitt S., Meulenbelt I., Micali N., Mitchell J., Mitchell K., Monteleone P., Monteleone A.M., Munn-Chernoff M.A., Nacmias B., Navratilova M., Ntalla I., Olsen C.M., O'Toole J.K., Padyukov L., Palotie A., Pantel J., Papezova H., Parker R., Pearson J.F., Ehrlich S., Escaramis G., Espeseth T., Estivill X., Farmer A., Favaro A., Fischer K., Floyd J.A.B., Focker M., Foretova L., Forzan M., Franklin C.S., Gambaro G., 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F., Tsitsika A., Tyszkiewicz-Nwafor M., Tziouvas K., van Elburg A.A., van Furth E.F., Wade T.D., Wagner G., Walton E., Whiteman D.C., Wichmann H.E., Widen E., Yao S., Zeggini E., Zerwas S., Zipfel S., Jungkunz M., Dietl L., Schwarze C.E., Dahmen N., Schott B.H., Mobascher A., Crivelli S., Dennis M.F., Harvey P.D., Carter B.W., Huffman J.E., Jacobson D., Madduri R., Olsen M.K., Pestian J., Gaziano J.M., Muralidhar S., Ramoni R., Beckham J., Chang K.-M., O'Donnell C.J., Tsao P.S., Breeling J., Huang G., Romero J.P.C., Moser J., Whitbourne S.B., Brewer J.V., Aslan M., Connor T., Argyres D.P., Stephens B., Brophy M.T., Humphries D.E., Selva L.E., Do N., Shayan S., Cho K., Pyarajan S., Hauser E., Sun Y., Zhao H., Wilson P., McArdle R., Dellitalia L., Mattocks K., Harley J., Zablocki C.J., Whittle J., Jacono F., Gutierrez S., Gibson G., Hammer K., Kaminsky L., Villareal G., Kinlay S., Xu J., Hamner M., Mathew R., Bhushan S., Iruvanti P., Godschalk M., Ballas Z., Ivins D., Mastorides S., Moorman J., Gappy S., Klein J., Ratcliffe N., Florez H., Okusaga O., Murdoch M., Sriram P., Yeh S.S., Tandon N., Jhala D., Aguayo S., Cohen D., Sharma S., Liangpunsakul S., Oursler K.A., Whooley M., Ahuja S., Constans J., Meyer P., Greco J., Rauchman M., Servatius R., Gaddy M., Wallbom A., Morgan T., Stapley T., Sherman S., Ross G., Tsao P., Strollo P., Boyko E., Meyer L., Gupta S., Huq M., Fayad J., Hung A., Lichy J., Hurley R., Robey B., Striker R., Erlangsen A., Kessler R.C., Porteous D., Ursano R.J., Wasserman D., Coon H., Demontis D., Docherty A.R., Kuo P.-H., Mann J.J., Renteria M.E., Stein M.B., and Willour V.

Subjects
LD SCORE REGRESSION, Genome-wide association study, Suicide, Attempted, 3124 Neurology and psychiatry, 0302 clinical medicine, Risk Factors, Insomnia, Suicide attempt, GWAS, Suïcidi, Depression (differential diagnoses), Cause of death, Psychiatry, 0303 health sciences, Factors de risc en les malalties, Mental Disorders, Genetic Correlation, Genome-wide Association Study, Pleiotropy, Polygenicity, Suicide, Suicide Attempt, DEPRESSION, 3. Good health, Genetic correlation, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Depressive Disorder, Major, Mental illness, Cohort, SEX, medicine.symptom, Human, medicine.medical_specialty, Risk factors in diseases, BF, Locus (genetics), BEHAVIORS, Psykiatri, EVENTS, 03 medical and health sciences, SDG 3 - Good Health and Well-being, medicine, ddc:610, GENOME-WIDE ASSOCIATION, IDEATION, Socioeconomic status, METAANALYSIS, Biological Psychiatry, 030304 developmental biology, business.industry, Risk Factor, Genetic architecture, THOUGHTS, RC0321, business, Malalties mentals, 030217 neurology & neurosurgery
Abstract

Statistical analyses were carried out on the NL Genetic Cluster Computer (http://www.geneticcluster.org) hosted by SURFsara and the Mount Sinai high performance computing cluster (http://hpc.mssm.edu), which is supported by the Office of Research Infrastructure of the National Institutes of Health (Grant Nos. S10OD018522 and S10OD026880). This work was conducted in part using the resources of the Advanced Computing Center for Research and Education at Vanderbilt University, Nashville, TN. This work was funded by the National Institutes of Health (Grant Nos. R01MH116269 and R01MH121455 [to DMR]), NIGMS of the National Institutes of Health (Grant No. T32GM007347 [to JK]), and the Brain & Behavior Research Foundation (NARSAD Young Investigator Award No. 29551 [to NM])., BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders., Office of Research Infrastructure of the National Institutes of Health S10OD018522 S10OD026880, United States Department of Health & Human Services, National Institutes of Health (NIH) - USA R01MH116269 R01MH121455, NIH National Institute of General Medical Sciences (NIGMS) T32GM007347 NARSAD 29551

Published
2022
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14. Borderline Personality Disorder and the Big Five: Molecular Genetic Analyses Indicate Shared Genetic Architecture with Neuroticism and Openness

Author

Eric Poisel, Ole A. Andreassen, Tolou Maslahati, Stephan Ripke, Lucía Colodro-Conde, Norbert Dahmen, Olav B. Smeland, Guy Hindley, Marcella Rietschel, Björn H. Schott, Stefan Roepke, Jerome C. Foo, Cornelia E. Schwarze, Arian Mobascher, Josef Frank, Markus M. Nöthen, Christian Schmahl, Martin Jungkunz, Fabian Streit, Chi-Hua Chen, Ina Giegling, Lea Sirignano, Dan Rujescu, Annette M. Hartmann, Martin Bohus, Lea Zillich, Klaus Lieb, Swapnil Awasthi, and Stephanie H. Witt

Subjects
medicine, Openness to experience, Psychology, medicine.disease, Neuroticism, Borderline personality disorder, Genetic architecture, Clinical psychology
Abstract

Both environmental (e.g. interpersonal traumatization during childhood and adolescence) and genetic factors may contribute to the development of Borderline Personality Disorder (BPD). Twin studies assessing borderline personality symptoms/features in the general population indicate that genetic factors underlying these symptoms/features are shared in part with the personality traits of the Five Factor Model (FFM) of personality – the “Big Five". In the present study, the genetic overlap of BPD with the Big Five -Openness to Experience, Conscientiousness, Extraversion, Agreeableness and Neuroticism- was assessed. Linkage disequilibrium score regression was used to calculate genetic correlations between a genome-wide association study (GWAS) in central European populations on BPD (N = 2,543) and GWAS on the “Big Five” (N = 76,551–122,886, Neuroticism N = 390,278). Significant positive genetic correlations were found between BPD and the traits Neuroticism (rg=.34, p=6.3*10−5) and Openness (rg=.24, p=.036), but not between BPD and the other personality traits (all |rg|p>.30). A cluster and item-level analysis showed positive correlations with the Neuroticism clusters “Depressed Affect” and “Worry”, and with a broad range of Neuroticism items (N = 348,219 – 376,352). The observed associations indicate a partially shared genetic background of BPD and the personality traits Neuroticism and Openness. Larger GWAS of BPD and the “Big Five” are needed to further explore the role of personality traits in the etiology of this disorder.

Published
2021
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15. Elimination Characteristics of the Alcohol Biomarker Phosphatidylethanol (PEth) in Blood during Alcohol Detoxification

Author

Olof Beck, Anders Helander, Norbert Dahmen, and Michael Böttcher

Subjects
Adult, Male, medicine.medical_treatment, Physiology, Alcohol, Original Manuscript, Glucuronates, Urine, Glycerophospholipids, Sulfuric Acid Esters, 01 natural sciences, Ethyl sulfate, Drug/alcohol abstinence, 03 medical and health sciences, chemistry.chemical_compound, Young Adult, 0302 clinical medicine, Ethyl glucuronide, mental disorders, Medicine, Humans, Aged, business.industry, Alcohol Abstinence, 010401 analytical chemistry, Alcohol detoxification, General Medicine, Middle Aged, 0104 chemical sciences, Substance Abuse Detection, chemistry, Breath Tests, Phosphatidylethanol, Female, business, 030217 neurology & neurosurgery, Biomarkers, Half-Life
Abstract

Heavy drinkers admitted for alcohol detoxification at hospital tested positive for PEth in blood. During abstinence, a steady, first-order elimination of PEth homologs from blood was demonstrated over a 2-week period. The elimination rates did not differ significantly between men and women, but differed between individuals and between PEth homologs., Aims The study documented elimination characteristics of three phosphatidylethanol (PEth) homologs in serially collected blood samples from 47 heavy drinkers during ~2 weeks of alcohol detoxification at hospital. Methods Venous whole blood and urine samples were collected every 1–2 days during treatment. Concentrations of PEth, and of urinary ethyl glucuronide (EtG) and ethyl sulfate (EtS) to detect relapse drinking, were measured using liquid chromatography-tandem mass spectrometry. Results When included in the study, negative or decreasing breath ethanol concentrations demonstrated that the patients were in the elimination phase. The EtG and EtS measurements further confirmed alcohol abstinence during the study, with three exceptions. On admission, all patients tested positive for PEth, the total concentration ranging 0.82–11.7 (mean 6.35, median 5.88) μmol/l. PEth 16:0/18:1, 16:0/18:2 and 16:0/20:4 accounted for on average ~42%, ~26% and ~9%, respectively, of total PEth in these samples. There were good correlations between total PEth and individual homologs (P < 0.0001). There was no significant difference in PEth values between male and female subjects. During abstinence, the elimination half-life values ranged 3.5–9.8 days for total PEth, 3.7–10.4 days for PEth 16:0/18:1, 2.7–8.5 days for PEth 16:0/18:2 and 2.3–8.4 days for PEth 16:0/20:4. Conclusions The results demonstrated a very high sensitivity (100%) of PEth as alcohol biomarker for recent heavy drinking, but considerable differences in the elimination rates between individuals and between different PEth forms. This indicates that it is possible to make only approximate estimates of the quantity and recency of alcohol intake based on a single PEth value.

Published
2019

16. Shared genetic risk between eating disorder- and substance-use-related phenotypes: Evidence from genome-wide association studies

Author

Samuel Kuperman, Leila Karhunen, Geòrgia Escaramís, Sébastien Guillaume, Kelly L. Klump, David C. Whiteman, Colin A. Hodgkinson, Stephanie H. Witt, Artemis Tsitsika, Hana Papezova, Renato Polimanti, P. Eline Slagboom, Peter Zill, Jakob Grove, Toni-Kim Clarke, Michael Soyka, Jennifer Jordan, Steven Gallinger, Philip Gorwood, Preben Bo Mortensen, Yuri Milaneschi, Ingrid Meulenbelt, Jen Chyong Wang, Markus M. Nöthen, Katrin Männik, Henry R. Kranzler, Michael M. Vanyukov, Anna Keski-Rahkonen, William G. Iacono, Raymond K. Walters, Stephanie Le Hellard, Bochao Danae Lin, Vesna Boraska Perica, Marion Roberts, Patrick F. Sullivan, Steven Crawford, Mark A. Frye, Melissa A. Munn-Chernoff, Hakon Hakonarson, Andreas Birgegård, Robert Culverhouse, Alexis C. Edwards, Jerome C. Foo, Alessandro Rotondo, Brenda W.J.H. Penninx, Laura M. Hack, Michael T. Lynskey, Mario Maj, Alessio Maria Monteleone, Ted Reichborn-Kjennerud, Julie K. O'Toole, Marta Tyszkiewicz-Nwafor, Matt McGue, Julien Bryois, Martina de Zwaan, Norbert Dahmen, Stefanie Heilmann-Heimbach, Deborah Kaminská, Benedetta Nacmias, Nicholas G. Martin, Anna R. Docherty, Christopher Hübel, Nancy L. Pedersen, Janet Treasure, William E. Copeland, Roger A.H. Adan, Jaakko Kaprio, Aarno Palotie, L. John Horwood, Maria La Via, Philippe Courtet, Virpi M. Leppä, Judy L. Silberg, Jason D. Boardman, Fazil Aliev, Wade H. Berrettini, Doo Sup Choi, Youl-Ri Kim, Konstantinos Hatzikotoulas, Harriet de Wit, Sandra A. Brown, Elisabeth Widen, Caroline Hayward, Nicholas J. Schork, Penelope A. Lind, Ralph E. Tarter, Jana Strohmaier, Allan S. Kaplan, Richard A. Grucza, Bradley T. Webb, Angela Favaro, Dalila Pinto, Helena Gaspar, Andrew W. Bergen, Beate Herpertz-Dahlmann, Robert Levitan, Wolfgang Gäbel, Xavier Estivill, Emma C. Johnson, Konstantinos Tziouvas, Lindsay A. Farrer, Lenka Foretova, Marc A. Schuckit, Joanna M. Biernacka, André Scherag, Robbee Wedow, Abraham A. Palmer, Amy E. Adkins, Franziska Degenhardt, Louisa Degenhardt, Jurjen J. Luykx, Marius Lahti-Pulkkinen, Brien P. Riley, Monika Ridinger, Matteo Cassina, Harry Brandt, Yiran Guo, Stephan Ripke, Palmiero Monteleone, Katri Räikkönen, Jonathan R. I. Coleman, Martin A. Kennedy, Stephen W. Scherer, Ioanna Tachmazidou, Catherine M. Olsen, Bernice Porjesz, Esther Walton, Yi-Ling Chou, Nicolas Ramoz, Tetsuya Ando, Andres Metspalu, Bertram Müller-Myhsok, Brion S. Maher, Sarah Bertelsen, Melanie L. Schwandt, Janiece E. DeSocio, Margaret Keyes, John F. Pearson, Dongbing Lai, Paul Lichtenstein, James MacKillop, George Dedoussis, Jari Lahti, Ulrike Schmidt, Stefan Ehrlich, Amanda G. Wills, Teemu Palviainen, David Goldman, Elena Tenconi, Dimitris Dikeos, Scott I. Vrieze, Sietske G. Helder, Katharina Buehren, Hongyu Zhao, Sara McDevitt, Jolanta Lissowska, Joseph M. Boden, Li-Shiun Chen, Susanne Lucae, Sara Marsal, Dan Rujescu, Claes Norring, Howard J. Edenberg, Victor M. Karpyak, Fragiskos Gonidakis, Per Hoffmann, Christopher S. Franklin, Karin Egberts, Johanna Giuranna, Stefan Herms, Leah Wetherill, Stephanie Zerwas, Anthony Batzler, Elliot C. Nelson, Jouke-Jan Hottenga, Marcella Rietschel, Ioanna Ntalla, Victor Hesselbrock, Sarah M. Hartz, Marie Navratilova, Falk Kiefer, Martien J H Kas, Richard J. Rose, Andrew C. Heath, Jin P. Szatkiewicz, Lenka Slachtova, Lisa Lilenfeld, Katherine A. Halmi, John P. Rice, Anjali K. Henders, Christian Dina, Norbert Wodarz, Satu Männistö, Hamdi Mbarek, Shuyang Yao, Vladimir Janout, Alison Goate, Bettina Konte, Alexandra Schosser, Danfeng Chen, Kirsty Kiezebrink, Euijung Ryu, Dana B. Hancock, James Mitchell, Sarah E. Medland, Ina Giegling, Valdo Ricca, Scott D. Gordon, Gabrielle Koller, Samuli Ripatti, Laura M. Thornton, Alison D. Murray, Morten Mattingsdal, Zeynep Yilmaz, Jens Treutlein, Kathleen K. Bucholz, Tim B. Bigdeli, Eric F. van Furth, Hermine H. Maes, Ken B. Hanscombe, Sandra Sanchez-Roige, Daniela Degortes, Monica Forzan, Manuel Mattheisen, Richard Sherva, Scott J. Crow, Mikael Landén, Wolfgang Herzog, Jeanette N. McClintick, Tõnu Esko, Louis Fox, Wolfgang Maier, Liselotte Petersen, Laura J. Bierut, Roseann E. Peterson, Gursharan Kalsi, Kathleen Mullan Harris, Margarita C T Slof-Op 't Landt, Tamara L. Wall, Patrik K. E. Magnusson, Unna N. Danner, Stephan Zipfel, Ulrich W. Preuss, Elisa Docampo, D. Blake Woodside, Alfonso Tortorella, Benjamin W. Domingue, Franziska Ritschel, Johan G. Eriksson, Anu Raevuori, Benjamin M. Neale, Marcus Ising, Annemarie A. van Elburg, Filip Rybakowski, Maureen Reynolds, Tracey D. Wade, Manfred M. Fichter, Monica Gratacos Mayora, Claudette Boni, Andreas J. Forstner, John Whitfield, Silviu Alin Bacanu, Matthew B. McQueen, Andrew M. McIntosh, Norbert Scherbaum, Tatiana Foroud, Gun Peggy Knudsen, Sven Cichon, Christian J. Hopfer, Josef Frank, Eleftheria Zeggini, Federica Tozzi, Nadia Micali, Danielle M. Dick, Pamela A. F. Madden, Christian R. Marshall, Johannes Hebebrand, Fernando Fernández-Aranda, Roel A. Ophoff, Roland Burghardt, Nathaniel Thomas, Leonid Padyukov, Nancy L. Saccone, Anu Loukola, Fabian Streit, James L. Kennedy, Jessica H. Baker, Peter McGuffin, Walter H. Kaye, Pei Hong Shen, Anne Farmer, Roger D. Cone, Ilka Boehm, Jacquelyn L. Meyers, Paolo Santonastaso, Maurizio Clementi, Susana Jiménez-Murcia, Gudrun Wagner, Anke Hinney, Richard Parker, James I. Hudson, Nathan A. Gillespie, Michael Strober, John I. Nurnberger, Sandro Sorbi, Dorret I. Boomsma, Beata Świątkowska, Janne Tidselbak Larsen, Kenneth S. Kendler, Hidetoshi Inoko, Jessica E. Salvatore, Hunna J. Watson, Jochen Seitz, Jacques Pantel, Karl Mann, Hang Zhou, Antonio Julià, Oliver S. P. Davis, Nancy Diazgranados, Krista Fischer, John K. Hewitt, Karen S. Mitchell, Joanna Hauser, Eric O. Johnson, Craig Johnson, E. Jane Costello, Agnieszka Słopień, Dong Li, Laramie E. Duncan, Arpana Agrawal, Grant W. Montgomery, Manuel Föcker, Thomas Werge, Lannie Ligthart, Andreas Karwautz, Raquel Rabionet, Kenneth Krauter, Joel Gelernter, James J. Crowley, Cynthia M. Bulik, Paola Giusti-Rodríguez, Laura M. Huckins, Gerome Breen, Michael C. Stallings, Daniel E. Adkins, Pierre J. Magistretti, John Kramer, Lars Alfredsson, Hartmut Imgart, Annette M. Hartmann, Ole A. Andreassen, Monika Dmitrzak-Weglarz, Psychiatry, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), Department Psychiatry [Chapel Hill], University of North Carolina System (UNC)-University of North Carolina System (UNC), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Institute of Psychiatry, Psychology & Neuroscience, King's College London, King‘s College London, Harvard Medical School [Boston] (HMS), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], QIMR Berghofer Medical Research Institute, Karolinska Institutet [Stockholm], University Children's Hospital of Essen [Essen, Germany], University of Duisburg-Essen, Aarhus University [Aarhus], Stockholm County Council, University of Würzburg, Guy's Hospital [London], University Medical Center [Utrecht], University of Gothenburg (GU), Altrecht Center for Eating Disorders Rintveld [Zeist, The Netherlands] (Mental Health Institute), National Institute of Mental Health [Tokyo, Japan] (NIMH), National Center of Neurology and Psychiatry [Tokyo, Japan], University of Oslo (UiO), Norwegian Centre for Mental Disorders Research [Oslo] (NORMENT), University of Oslo (UiO)-Haukeland University Hospital, University of Bergen (UiB)-University of Bergen (UiB)-Oslo University Hospital [Oslo], Department of Psychiatry [Philadelphia], University of Pennsylvania [Philadelphia], Perelman School of Medicine, Technische Universität Dresden = Dresden University of Technology (TU Dresden), Institut de psychiatrie et neurosciences (U894 / UMS 1266), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Split, The Wellcome Trust Sanger Institute [Cambridge], RWTH Aachen University, Universitätsklinikum Frankfurt, Universita degli Studi di Padova, University Hospital Basel [Basel], Jülich Supercomputing Centre (JSC), Forschungszentrum Jülich GmbH | Centre de recherche de Juliers, Helmholtz-Gemeinschaft = Helmholtz Association-Helmholtz-Gemeinschaft = Helmholtz Association, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Minnesota System, University of Bristol [Bristol], Hannover Medical School [Hannover] (MHH), Harokopio University of Athens, Seattle University [Seattle], Virginia Commonwealth University (VCU), University of Athens Medical School [Athens], unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Poznan University of Medical Sciences [Poland] (PUMS), Institute of Environmental Science and Technology [Barcelona] (ICTA), Universitat Autònoma de Barcelona (UAB), Massachusetts General Hospital [Boston], Stanford University, MetaGenoPolis (MGP (US 1367)), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Estonian Genome and Medicine, University of Tartu, Universitat Pompeu Fabra [Barcelona] (UPF), MRC Social, Genetic and Developmental Psychiatry Centre (SGDP), The Institute of Psychiatry-King‘s College London, Department of Psychiatry (IDIBELL), CIBERobn Fisiopatología de la Obesidad y Nutrición-University Hospital of Bellvitge, Ludwig-Maximilians-Universität München (LMU), Infectious diseases division, Department of internal medicine, University of Münster, Masaryk Memorial Cancer Institute, Masaryk Memorial Cancer Institute (RECAMO), Universitätsklinikum Bonn (UKB), Familial Gastrointestinal Cancer Registry, Mount Sinai Hospital [Toronto, Canada] (MSH), Medstar Research Institute, Universität Duisburg-Essen [Essen], National and Kapodistrian University of Athens (NKUA), Children’s Hospital of Philadelphia (CHOP ), The Center for Applied Genomics, Psychiatric Genetic Unit, Poznan University of Medical Sciences, Department of Child and Adolescent Psychiatry and Psychotherapy, LVR-Klinikum Essen, Centre for Epidemiology and Biostatistics, Faculty of Medicine and Health Leeds, University of Leeds, Rheinisch-Westfälische Technische Hochschule Aachen (RWTH), Heidelberg University Hospital [Heidelberg], Icahn School of Medicine at Mount Sinai [New York] (MSSM), School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, 4072, Australia., Parkland-Klinik [Bad Wildungen-Reinhardshausen, Germany], Tokai University, Department of Epidemiology and Public Health [university of Ostrava], Lékařská fakulta / Faculty of Medicine [University of Ostrava], Ostravská univerzita / University of Ostrava-Ostravská univerzita / University of Ostrava, Vall d'Hebron University Hospital [Barcelona], Charles University [Prague] (CU), University of Eastern Finland, Medizinische Universität Wien = Medical University of Vienna, Centre de toxicomanie et de santé mentale [Toronto, ON, Canada], University of Helsinki, University of Aberdeen, Faculty of Science, J.E. Purkinje University, J. E. Purkinje University, Michigan State University System, Norwegian Institute of Public Health [Oslo] (NIPH), Haukeland University Hospital, University of Bergen (UiB), Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), The Chicago School of Professional Psychology [Washington, District of Columbia, USA] (Washington DC Campus), Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Brain and Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Department of Psychiatry, University of Napoli, Center for Integrative Genomics - Institute of Bioinformatics, Génopode (CIG), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne (UNIL)-Université de Lausanne (UNIL), Program in Genetics and Genomic Biology, Hospital for Sick Children-University of Toronto McLaughlin Centre, KG Jebsen Centre for Psychosis Research, University of Oslo (UiO)-Institute of Clinical Medicine-Oslo University Hospital [Oslo], University College Cork (UCC), Section Molecular Epidemiology, Leiden University Medical Center (LUMC), Institute of Psychiatry, King's College, VA Boston Healthcare System, Università degli studi della Campania 'Luigi Vanvitelli', Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Kartini Clinic [Portland, Oregon, USA], University Medical Center [Utrecht]-Brain Center Rudolf Magnus, Head of Medical Sequencing, Vanderbilt University School of Medicine [Nashville], The Hospital for sick children [Toronto] (SickKids), Center for Genomic Regulation (CRG-UPF), CIBER de Epidemiología y Salud Pública (CIBERESP), Department of Medical Epidemiology and Biostatistics (MEB), University of Pisa - Università di Pisa, Division of Psychiatric Genomics, Institute of Medical Informatics, Biometry and Epidemiology, Department of Molecular and Experimental Medicine, The Scripps Research Institute, The Scripps Research Institute, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University-Medical Research Council, Leiden University Medical Center (LUMC), Center for Eating Disorders Ursula [Leiden, The Netherlands] (Rivierduinen), Medical University of Łódź (MUL), The Jackson Laboratory [Bar Harbor] (JAX), Neurosciences Centre of Excellence in Drug Discovery, GlaxoSmithKline Research and Development, Utrecht University [Utrecht], SURFACES, Institut de recherches sur la catalyse et l'environnement de Lyon (IRCELYON), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre épigénétique et destin cellulaire (EDC (UMR_7216)), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Human Genetics, Internal Medicine [Tuebingen, Germany], Tuebingen University [Germany], Oregon Research Institute (ORI), University of Otago [Dunedin, Nouvelle-Zélande], The Center for Eating Disorders at Sheppard Pratt [Baltimore, MD, USA], Weill Medical College of Cornell University [New York], Eating Recovery Center [Denver, CO, USA], Centre for Addiction and Mental Health [Toronto, ON, Canada], University of California [San Diego] (UC San Diego), University of California, Jet Propulsion Laboratory (JPL), NASA-California Institute of Technology (CALTECH), David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California-University of California, Center for Genomic Medicine, Copenhagen University Hospital-Rigshospitalet [Copenhagen], Copenhagen University Hospital, Institute of Medical Science [Toronto], University of Toronto, Department of Psychiatry [Pittsburgh], University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Génétique des maladies multifactorielles (GMM), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Sahlgrenska Academy at University of Gothenburg [Göteborg], Department of Genomics, Yale University School of Medicine, Indiana University School of Medicine, Indiana University System, Mayo Clinic [Rochester], Mayo Clinic, SUNY Downstate Medical Center, State University of New York (SUNY), University of Edinburgh, Department of Genomics, Life and Brain Center, University of Bonn, University of Utah School of Medicine [Salt Lake City], University of Heidelberg, Medical Faculty, Department of Psychiatry and Behavioral Sciences, Howard University College of Medicine, Department of Genomics [Bonn, Germany] (Institute of Human Genetics), University of Bonn-Institute of Human Genetics [Bonn, Germany], National Institutes of Health [Bethesda] (NIH), National Institute on Alcohol Abuse and Alcoholism [Bethesda, MD, USA] (NIAAA), Martin-Luther-University Halle-Wittenberg, Helsinki Institute of Life Science (HiLIFE), Johns Hopkins Bloomberg School of Public Health [Baltimore], Johns Hopkins University (JHU), Vrije Universiteit Amsterdam [Amsterdam] (VU), Mathematical Sciences Institute (MSI), Australian National University (ANU), University of Colorado [Boulder], VU University Medical Center [Amsterdam], Boston University School of Medicine (BUSM), Boston University [Boston] (BU), Universität Heidelberg [Heidelberg], Department of Genetic Epidemiology in Psychiatry [Mannhein], Universität Heidelberg [Heidelberg]-Central Institute of Mental Health Mannheim, Harvard University [Cambridge], University of Colorado Anschutz [Aurora], University of Vermont [Burlington], University of New South Wales [Sydney] (UNSW), University of Dusseldorf, Genetics and Pathology, Center for Human Genetic Research, Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Heidelberg University, University of Iowa [Iowa City], Vienna University of Technology (TU Wien), Max Planck Institute of Psychiatry, Max-Planck-Gesellschaft, Department of Psychiatry and Psychotherapy, Rheinische Friedrich-Wilhelms-Universität Bonn, Chronic Disease Epidemiology and Prevention Unit, National Institute for Health and Welfare [Helsinki], Translational Centre for Regenerative Medicine (TRM), Department of Cell Therapy, Universität Leipzig [Leipzig]-Universität Leipzig [Leipzig], Indiana University System-Indiana University System, University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), University of Regensburg, Rush University Medical Center [Chicago], University of Utah, Duke University Medical Center, University of Illinois [Chicago] (UIC), University of Illinois System, Department of Medical and Molecular Genetics, Dpt of Neuroscience [New York], Laboratory of Neurogenetics, National Institutes of Health [Bethesda] (NIH)-National Institute on Alcohol Abuse and Alcoholism, Department of Health and Human Services, University of Connecticut (UCONN), University of Colorado [Denver], Research Triangle Institute International (RTI International), McMaster University [Hamilton, Ontario], CLinical Psychology, Department of Electrical and Computer Engineering [Montréal], McGill University = Université McGill [Montréal, Canada], Yale School of Public Health (YSPH), Analytic and Translational Genetics Unit, Flinders University [Adelaide, Australia], Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), Department of Public Health, Indiana University - Purdue University Indianapolis (IUPUI), National Institute of Mental Health (NIMH), University of Pennsylvania, Rheinisch-Westfälische Technische Hochschule Aachen University (RWTH), Università degli Studi di Padova = University of Padua (Unipd), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), King‘s College London-The Institute of Psychiatry, Westfälische Wilhelms-Universität Münster = University of Münster (WWU), Masaryk Memorial Cancer Institute (MMCI), Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Université de Lausanne = University of Lausanne (UNIL)-Université de Lausanne = University of Lausanne (UNIL), Università degli studi della Campania 'Luigi Vanvitelli' = University of the Study of Campania Luigi Vanvitelli, Università degli Studi di Firenze = University of Florence (UniFI), Department of Molecular Medicine [Scripps Research Institute], The Scripps Research Institute [La Jolla, San Diego], Medical Research Council-Cardiff University, Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), University of California (UC), University of California (UC)-University of California (UC), Yale School of Medicine [New Haven, Connecticut] (YSM), Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Martinez Rico, Clara, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, APH - Mental Health, APH - Methodology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Amsterdam Neuroscience - Complex Trait Genetics, APH - Digital Health, Kas lab, Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL), Munn-Chernoff, M. A., Johnson, E. C., Chou, Y. -L., Coleman, J. R. I., Thornton, L. M., Walters, R. K., Yilmaz, Z., Baker, J. H., Hubel, C., Gordon, S., Medland, S. E., Watson, H. J., Gaspar, H. A., Bryois, J., Hinney, A., Leppa, V. M., Mattheisen, M., Ripke, S., Yao, S., Giusti-Rodriguez, P., Hanscombe, K. B., Adan, R. A. H., Alfredsson, L., Ando, T., Andreassen, O. A., Berrettini, W. H., Boehm, I., Boni, C., Boraska Perica, V., Buehren, K., Burghardt, R., Cassina, M., Cichon, S., Clementi, M., Cone, R. D., Courtet, P., Crow, S., Crowley, J. J., Danner, U. N., Davis, O. S. P., de Zwaan, M., Dedoussis, G., Degortes, D., Desocio, J. E., Dick, D. M., Dikeos, D., Dina, C., Dmitrzak-Weglarz, M., Docampo, E., Duncan, L. E., Egberts, K., Ehrlich, S., Escaramis, G., Esko, T., Estivill, X., Farmer, A., Favaro, A., Fernandez-Aranda, F., Fichter, M. M., Fischer, K., Focker, M., Foretova, L., Forstner, A. J., Forzan, M., Franklin, C. S., Gallinger, S., Giegling, I., Giuranna, J., Gonidakis, F., Gorwood, P., Gratacos Mayora, M., Guillaume, S., Guo, Y., Hakonarson, H., Hatzikotoulas, K., Hauser, J., Hebebrand, J., Helder, S. G., Herms, S., Herpertz-Dahlmann, B., Herzog, W., Huckins, L. M., Hudson, J. I., Imgart, H., Inoko, H., Janout, V., Jimenez-Murcia, S., Julia, A., Kalsi, G., Kaminska, D., Karhunen, L., Karwautz, A., Kas, M. J. H., Kennedy, J. L., Keski-Rahkonen, A., Kiezebrink, K., Kim, Y. -R., Klump, K. L., Knudsen, G. P. S., La Via, M. C., Le Hellard, S., Levitan, R. D., Li, D., Lilenfeld, L., Lin, B. D., Lissowska, J., Luykx, J., Magistretti, P. J., Maj, M., Mannik, K., Marsal, S., Marshall, C. R., Mattingsdal, M., Mcdevitt, S., Mcguffin, P., Metspalu, A., Meulenbelt, I., Micali, N., Mitchell, K., Monteleone, A. M., Monteleone, P., Nacmias, B., Navratilova, M., Ntalla, I., O'Toole, J. K., Ophoff, R. A., Padyukov, L., Palotie, A., Pantel, J., Papezova, H., Pinto, D., Rabionet, R., Raevuori, A., Ramoz, N., Reichborn-Kjennerud, T., Ricca, V., Ripatti, S., Ritschel, F., Roberts, M., Rotondo, A., Rujescu, D., Rybakowski, F., Santonastaso, P., Scherag, A., Scherer, S. W., Schmidt, U., Schork, N. J., Schosser, A., Seitz, J., Slachtova, L., Slagboom, P. E., Slof-Op't Landt, M. C. T., Slopien, A., Sorbi, S., Swiatkowska, B., Szatkiewicz, J. P., Tachmazidou, I., Tenconi, E., Tortorella, A., Tozzi, F., Treasure, J., Tsitsika, A., Tyszkiewicz-Nwafor, M., Tziouvas, K., van Elburg, A. A., van Furth, E. F., Wagner, G., Walton, E., Widen, E., Zeggini, E., Zerwas, S., Zipfel, S., Bergen, A. W., Boden, J. M., Brandt, H., Crawford, S., Halmi, K. A., Horwood, L. J., Johnson, C., Kaplan, A. S., Kaye, W. H., Mitchell, J., Olsen, C. M., Pearson, J. F., Pedersen, N. L., Strober, M., Werge, T., Whiteman, D. C., Woodside, D. B., Grove, J., Henders, A. K., Larsen, J. T., Parker, R., Petersen, L. V., Jordan, J., Kennedy, M. A., Birgegard, A., Lichtenstein, P., Norring, C., Landen, M., Mortensen, P. B., Polimanti, R., Mcclintick, J. N., Adkins, A. E., Aliev, F., Bacanu, S. -A., Batzler, A., Bertelsen, S., Biernacka, J. M., Bigdeli, T. B., Chen, L. -S., Clarke, T. -K., Degenhardt, F., Docherty, A. R., Edwards, A. C., Foo, J. C., Fox, L., Frank, J., Hack, L. M., Hartmann, A. M., Hartz, S. M., Heilmann-Heimbach, S., Hodgkinson, C., Hoffmann, P., Hottenga, J. -J., Konte, B., Lahti, J., Lahti-Pulkkinen, M., Lai, D., Ligthart, L., Loukola, A., Maher, B. S., Mbarek, H., Mcintosh, A. M., Mcqueen, M. B., Meyers, J. L., Milaneschi, Y., Palviainen, T., Peterson, R. E., Ryu, E., Saccone, N. L., Salvatore, J. E., Sanchez-Roige, S., Schwandt, M., Sherva, R., Streit, F., Strohmaier, J., Thomas, N., Wang, J. -C., Webb, B. T., Wedow, R., Wetherill, L., Wills, A. G., Zhou, H., Boardman, J. D., Chen, D., Choi, D. -S., Copeland, W. E., Culverhouse, R. C., Dahmen, N., Degenhardt, L., Domingue, B. W., Frye, M. A., Gaebel, W., Hayward, C., Ising, M., Keyes, M., Kiefer, F., Koller, G., Kramer, J., Kuperman, S., Lucae, S., Lynskey, M. T., Maier, W., Mann, K., Mannisto, S., Muller-Myhsok, B., Murray, A. D., Nurnberger, J. I., Preuss, U., Raikkonen, K., Reynolds, M. D., Ridinger, M., Scherbaum, N., Schuckit, M. A., Soyka, M., Treutlein, J., Witt, S. H., Wodarz, N., Zill, P., Adkins, D. E., Boomsma, D. I., Bierut, L. J., Brown, S. A., Bucholz, K. K., Costello, E. J., de Wit, H., Diazgranados, N., Eriksson, J. G., Farrer, L. A., Foroud, T. M., Gillespie, N. A., Goate, A. M., Goldman, D., Grucza, R. A., Hancock, D. B., Harris, K. M., Hesselbrock, V., Hewitt, J. K., Hopfer, C. J., Iacono, W. G., Johnson, E. O., Karpyak, V. M., Kendler, K. S., Kranzler, H. R., Krauter, K., Lind, P. A., Mcgue, M., Mackillop, J., Madden, P. A. F., Maes, H. H., Magnusson, P. K. E., Nelson, E. C., Nothen, M. M., Palmer, A. A., Penninx, B. W. J. H., Porjesz, B., Rice, J. P., Rietschel, M., Riley, B. P., Rose, R. J., Shen, P. -H., Silberg, J., Stallings, M. C., Tarter, R. E., Vanyukov, M. M., Vrieze, S., Wall, T. L., Whitfield, J. B., Zhao, H., Neale, B. M., Wade, T. D., Heath, A. C., Montgomery, G. W., Martin, N. G., Sullivan, P. F., Kaprio, J., Breen, G., Gelernter, J., Edenberg, H. J., Bulik, C. M., and Agrawal, A.

Subjects
Netherlands Twin Register (NTR), Alcoholism/genetics, Schizophrenia/genetics, [SDV]Life Sciences [q-bio], [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Medizin, Medicine (miscellaneous), Genome-wide association study, Alcohol use disorder, Anorexia nervosa, Linkage Disequilibrium, ddc:616.89, [SCCO]Cognitive science, 0302 clinical medicine, Risk Factors, Tobacco Use Disorder/genetics, Substance-Related Disorders/genetics, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Factors de risc en les malalties, Bulimia nervosa, Feeding and Eating Disorders/genetics, eating disorders, genetic correlation, substance use, Tobacco Use Disorder, 3. Good health, Fenotip, [SDV] Life Sciences [q-bio], Psychiatry and Mental health, Alcoholism, Eating disorders, Phenotype, Schizophrenia, Drinking of alcoholic beverages, eating disorder, Consum d'alcohol, Major depressive disorder, medicine.symptom, Depressive Disorder, Major/genetics, eating disorders, genetic correlation, substance use, Clinical psychology, Substance abuse, Risk factors in diseases, Substance-Related Disorders, Polymorphism, Single Nucleotide, Article, Feeding and Eating Disorders, 03 medical and health sciences, SDG 3 - Good Health and Well-being, mental disorders, Genetics, medicine, Humans, Trastorns de la conducta alimentària, 030304 developmental biology, Genetic association, Pharmacology, Depressive Disorder, Major, Binge eating, business.industry, [SCCO.NEUR]Cognitive science/Neuroscience, [SCCO.NEUR] Cognitive science/Neuroscience, [SCCO] Cognitive science, medicine.disease, Comorbidity, Twin study, 030227 psychiatry, Abús de substàncies, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, business, Genètica, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Genome-Wide Association Study
Abstract

Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa (BN) and problem alcohol use (genetic correlation [rg], twin-based=0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge-eating, AN without binge-eating, and a BN factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder (MDD). Total sample sizes per phenotype ranged from ~2,400 to ~537,000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (rg=0.18; false discovery rate q=0.0006), cannabis initiation and AN (rg=0.23; qwith binge-eating (rg=0.27; q=0.0016). Conversely, significant negative genetic correlations were observed between three non-diagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge-eating (rgs=-0.19 to −0.23; qs

Published
2021
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17. Transancestral GWAS of alcohol dependence reveals common genetic underpinnings with psychiatric disorders

Author

Sarah L. Elson, Brion S. Maher, Samuel Kuperman, Raymond K. Walters, Ulrich W. Preuss, Fazil Aliev, Josef Frank, Annette M. Hartmann, Anu Loukola, Roseann E. Peterson, Tamara L. Wall, Norbert Dahmen, Lindsay A. Farrer, John Kramer, Wolfgang Gäbel, Yuri Milaneschi, Doo Sup Choi, Kenneth Krauter, Marc A. Schuckit, Bradley T. Webb, Louisa Degenhardt, Hermine H. Maes, Susanne Lucae, Renato Polimanti, Danielle M. Dick, Li-Shiun Chen, Sarah E. Medland, Louis Fox, Martin A. Kennedy, Dorret I. Boomsma, Margaret Keyes, John I. Nurnberger, Melanie L. Schwandt, Joel Gelernter, John P. Rice, Jeanette N. McClintick, Michael Soyka, Jacquelyn L. Meyers, Harriet de Wit, Marcus Ising, Richard Sherva, Danfeng Chen, Scott I. Vrieze, John F. Pearson, Dan Rujescu, Paul Lichtenstein, Hongyu Zhao, Jana Strohmaier, Monika Ridinger, Dongbing Lai, Kenneth S. Kendler, Teemu Palviainen, Stefan Herms, Silviu-Alin Bacanu, Kathleen Mullan Harris, Sven Cichon, Anna R. Docherty, Norbert Wodarz, Jaakko Kaprio, Sandra Sanchez-Roige, Pei-Hong Shen, Falk Kiefer, Katri Räikkönen, Victor Hesselbrock, Sarah M. Hartz, Peter Zill, Jason D. Boardman, Bernice Porjesz, Tim B. Bigdeli, Per Hoffmann, Bertram Müller-Myhsok, Jens Treutlein, James MacKillop, Matthew B. McQueen, Elliot C. Nelson, Mark A. Frye, Nathan A. Gillespie, Victor M. Karpyak, Marcella Rietschel, Howard J. Edenberg, Mark Adams, Wolfgang Maier, Michael T. Lynskey, Sandra A. Brown, Pamela A. F. Madden, Markus M. Nöthen, David Goldman, Andrew C. Heath, Samuli Ripatti, Brenda W. J. H. Penninx, Alison Goate, Ralph E. Tarter, Aarno Palotie, Toni-Kim Clarke, Jessica E. Salvatore, Satu Männistö, Hamdi Mbarek, Ina Giegling, Patrik K. E. Magnusson, Sarah Bertelsen, Amanda G. Wills, Caroline Hayward, Fabian Streit, Judy L. Silberg, Penelope A. Lind, Henry R. Kranzler, Michael M. Vanyukov, Laura M. Hack, Bettina Konte, Franziska Degenhardt, Pierre Fontanillas, Robbee Wedow, Amy E. Adkins, Robert Culverhouse, Jerome C. Foo, William E. Copeland, Colin A. Hodgkinson, Anthony Batzler, Kathleen K. Bucholz, Stephanie H. Witt, Matt McGue, Dana B. Hancock, Jouke-Jan Hottenga, William G. Iacono, Maureen Reynolds, Nancy L. Pedersen, Nicholas G. Martin, Mervi Alanne-Kinnunen, Marius Lahti-Pulkkinen, Abraham A. Palmer, Stefanie Heilmann-Heimbach, Tatiana Foroud, Brien P. Riley, Yi-Ling Chou, Nathaniel Thomas, Richard A. Grucza, Joanna M. Biernacka, Jen-Chyong Wang, Benjamin W. Domingue, Leah Wetherill, Emma C. Johnson, Richard J. Rose, John Whitfield, Eric O. Johnson, E. Jane Costello, Andrew M. McIntosh, Norbert Scherbaum, Laura J. Bierut, Euijung Ryu, Alison D. Murray, Johan G. Eriksson, Joseph M. Boden, Scott Gordon, Benjamin M. Neale, Christian J. Hopfer, Arpana Agrawal, Grant W. Montgomery, Nancy L. Saccone, Lannie Ligthart, Nancy Diazgranados, John K. Hewitt, Michael C. Stallings, Daniel E. Adkins, Karl Mann, Alexis C. Edwards, John Horwood, Jari Lahti, Psychiatry, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, APH - Digital Health, Institute for Molecular Medicine Finland, University of Helsinki, Department of Psychology and Logopedics, Helsinki Collegium for Advanced Studies, Medicum, Centre of Excellence in Complex Disease Genetics, Department of Public Health, Samuli Olli Ripatti / Principal Investigator, University Management, Biostatistics Helsinki, Clinicum, Aarno Palotie / Principal Investigator, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Developmental Psychology Research Group, Complex Disease Genetics, Genomics of Neurological and Neuropsychiatric Disorders, Genetic Epidemiology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Biological Psychology, and APH - Methodology

Subjects
0301 basic medicine, Netherlands Twin Register (NTR), LD SCORE REGRESSION, Medizin, Genome-wide association study, 3124 Neurology and psychiatry, 0302 clinical medicine, Medicine, PARTICIPANTS, RISK, biology, alcoholism, HERITABILITY, General Neuroscience, Mental Disorders, ADH1B, 3. Good health, Phenotype, psychiatric disorders, Schizophrenia, medicine.medical_specialty, Genotype, 515 Psychology, Genetic genealogy, NATIONAL EPIDEMIOLOGIC SURVEY, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, pleiotropy, Humans, Genetic Predisposition to Disease, Allele, GENOME-WIDE ASSOCIATION, Psychiatry, Alleles, METAANALYSIS, business.industry, Alcohol dependence, 3112 Neurosciences, CONSUMPTION, alcohol use, biology.organism_classification, medicine.disease, Comorbidity, 030104 developmental biology, Cannabis, business, COMORBIDITY, 030217 neurology & neurosurgery
Abstract

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 × 10–13) and African ancestries (rs2066702; P = 2.2 × 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.

Published
2018
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18. Psychiatric Comorbidities in Restless Legs Syndrome

Author

Mauro Manconi, Sandra Sefidan, Ulrike Ehlert, Angela Seiz, Norbert Dahmen, Esther Werth, Claudio L. Bassetti, Ulf Kallweit, University of Zurich, and Kallweit, Ulf

Subjects
Adult, Male, medicine.medical_specialty, Adolescent, Comorbidity, 2738 Psychiatry and Mental Health, Young Adult, 03 medical and health sciences, Psychiatric comorbidity, 0302 clinical medicine, Quality of life, Restless Legs Syndrome, mental disorders, medicine, Humans, In patient, 030212 general & internal medicine, Restless legs syndrome, Young adult, Psychiatry, Aged, Sleep disorder, 10093 Institute of Psychology, business.industry, Mental Disorders, Middle Aged, medicine.disease, Sleep in non-human animals, 10040 Clinic for Neurology, body regions, Psychiatry and Mental health, 2728 Neurology (clinical), Quality of Life, Physical therapy, Female, Neurology (clinical), 150 Psychology, business, 030217 neurology & neurosurgery
Abstract

Restless legs syndrome (RLS) is a neurological sleep disorder with frequent (39%) coexisting psychiatric comorbidities. Patients with any psychiatric comorbidity had fewer periodic leg movements in sleep. Psychiatric disorders should be taken into account in patients with RLS.

Published
2016
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19. Randomized controlled study of early medication change for non-improvers to antidepressant therapy in major depression – The EMC trial

Author

Stanislav Gorbulev, Stefanie Wagner, Daniel Wachtlin, Anne-Katrin Kaiser, Konrad F Schlicht, André Tadić, Kai Kronfeld, Dietrich van Calker, Dieter F. Braus, Nadine Dreimüller, Mathias Berger, Isabella Helmreich, Norbert Dahmen, Klaus Lieb, Oliver Tüscher, Christoph Hiemke, and Alice Engel

Subjects
Adult, Male, medicine.medical_specialty, Adolescent, Citalopram, Lithium, law.invention, Depressive Disorder, Treatment-Resistant, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Pharmacotherapy, Randomized controlled trial, law, Early Medical Intervention, Internal medicine, medicine, Humans, Escitalopram, Pharmacology (medical), Psychiatry, Biological Psychiatry, Aged, Pharmacology, Venlafaxine Hydrochloride, Guideline, Middle Aged, medicine.disease, Antidepressive Agents, 030227 psychiatry, Clinical trial, Psychiatry and Mental health, Treatment Outcome, Neurology, Delayed-Action Preparations, Antidepressive Agents, Second-Generation, Antidepressant, Major depressive disorder, Drug Therapy, Combination, Female, Neurology (clinical), Psychology, 030217 neurology & neurosurgery, medicine.drug
Abstract

Patients with Major Depressive Disorder (MDD) and no improvement after two weeks of antidepressant pharmacotherapy have a high risk of treatment failure. The aim of the study was to determine whether an early medication change (EMC) strategy is superior to a guideline-based treatment in MDD patients without improvement after two weeks of antidepressant pharmacotherapy. Eight-hundred-and-eighty-nine patients with MDD were enrolled, 879 patients received the SSRI escitalopram. Of those, 192 patients had no improvement, defined as a reduction of < 20% on the Hamilton Depression Rating Scale (HAMD-17) after 14 days of treatment, and were randomly assigned to open treatment with the EMC strategy (n = 97; venlafaxine XR for study days 15-56; in case of sustained non-improvement on day 28, lithium augmentation for days 29-56) or TAU (n = 95; escitalopram continuation; non-responders on day 28 were switched to venlafaxine XR for four weeks, i.e. days 29-56). The primary outcome was remission (HAMD-17 ≤ 7) after 8 weeks of treatment as assessed by blinded raters. Remission rates were 24% for EMC and 16% for TAU, which was not significantly different (p = 0.2056). Sensitivity analyses for the primary and secondary effectiveness endpoints consistently showed favorable results for patients randomized to EMC. The results confirm data from post-hoc analyses of clinical trials showing that early non-improvement identifies patients who likely need alternate interventions. However, the herein used two-step switch/augmentation strategy for this risk group was not more effective than the control intervention. Alternate strategies and other design aspects are discussed in order to support researchers addressing the same research question.

Published
2016
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20. Potential of Oral Fluid as a Clinical Specimen for Compliance Monitoring of Psychopharmacotherapy

Author

Michael Böttcher, Jasna Neumann, Olof Beck, and Norbert Dahmen

Subjects
Adult, Male, medicine.medical_specialty, Venlafaxine, Citalopram, 030226 pharmacology & pharmacy, 01 natural sciences, Gastroenterology, Specimen Handling, 03 medical and health sciences, Plasma, Young Adult, 0302 clinical medicine, Internal medicine, medicine, Escitalopram, Humans, Pharmacology (medical), Aged, Pharmacology, Mouth, medicine.diagnostic_test, business.industry, Mental Disorders, 010401 analytical chemistry, Middle Aged, 0104 chemical sciences, Promethazine, Body Fluids, Therapeutic drug monitoring, Free fraction, Aripiprazole, Female, Pipamperone, Drug Monitoring, business, medicine.drug, Antipsychotic Agents
Abstract

Background Oral fluid (OF) is being developed as a specimen for the determination of drug intake as an alternative to serum and plasma. It is generally considered as an attractive specimen due to the noninvasive nature of the sampling procedure and the relation to the free fraction of drug in the blood. These features are of particular value in drug treatment of psychiatric disorders. To establish OF for the purpose of monitoring drug therapy, the relationship between concentrations in OF and serum/plasma must be documented. This study explored one promising sampling device and comprised the following 10 drugs: aripiprazole, citalopram, duloxetine, escitalopram, mirtazapine, pipamperone, pregabalin, promethazine, quetiapine, and venlafaxine. Methods For this purpose, 100 paired serum and OF samples were collected from patients undergoing pharmacotherapy and analyzed using a liquid chromatography-tandem mass spectrometry method. A commercial method from Chromsystems for the determination of these drugs in plasma was used and was adapted for OF and ultrafiltrated (Centrifree device) serum. Results The ratio of each individual pair of samples was used to calculate a mean and SD value between OF and serum free and total concentrations. The OF concentration ratios to serum total fraction differed markedly between substances and differed from 10-fold lower to 8-fold higher. The ratios to serum free fractions were always higher. The relation between the OF and serum concentrations was also evaluated by regression analysis and determination of slopes and correlation coefficients. For all measured relations, there was a statistically significant relation between the OF and serum concentrations. The degree of drug protein binding was in agreement with literature. The aripiprazole, duloxetine, pipamperone, pregabalin, and promethazine concentrations in ultrafiltrated serum were not possible to measure because of low concentrations and nonspecific binding. Conclusions Despite a strong statistical correlation between OF and serum concentrations observed for most of the studied substances, it is still evident that OF concentrations cannot simply substitute serum/plasma as therapeutic drug monitoring specimen, but rather be considered as a unique specimen. We believe that OF is a promising matrix especially for compliance testing in psychiatry settings. The Greiner Bio-One device used in this study provides a sampling procedure that offers advantages over the available alternatives.

Published
2018

21. Modeling Linkage Disequilibrium Increases Accuracy of Polygenic Risk Scores

Author

Bjarni J. Vilhjálmsson, Jian Yang, Hilary K. Finucane, Alexander Gusev, Sara Lindström, Stephan Ripke, Giulio Genovese, Po-Ru Loh, Gaurav Bhatia, Ron Do, Tristan Hayeck, Hong-Hee Won, Sekar Kathiresan, Michele Pato, Carlos Pato, Rulla Tamimi, Eli Stahl, Noah Zaitlen, Bogdan Pasaniuc, Gillian Belbin, Eimear E. Kenny, Mikkel H. Schierup, Philip De Jager, Nikolaos A. Patsopoulos, Steve McCarroll, Mark Daly, Shaun Purcell, Daniel Chasman, Benjamin Neale, Michael Goddard, Peter M. Visscher, Peter Kraft, Nick Patterson, Alkes L. Price, Benjamin M. Neale, Aiden Corvin, James T.R. Walters, Kai-How Farh, Peter A. Holmans, Phil Lee, Brendan Bulik-Sullivan, David A. Collier, Hailiang Huang, Tune H. Pers, Ingrid Agartz, Esben Agerbo, Margot Albus, Madeline Alexander, Farooq Amin, Silviu A. Bacanu, Martin Begemann, Richard A. Belliveau, Judit Bene, Sarah E. Bergen, Elizabeth Bevilacqua, Tim B. Bigdeli, Donald W. Black, Richard Bruggeman, Nancy G. Buccola, Randy L. Buckner, William Byerley, Wiepke Cahn, Guiqing Cai, Dominique Campion, Rita M. Cantor, Vaughan J. Carr, Noa Carrera, Stanley V. Catts, Kimberly D. Chambert, Raymond C.K. Chan, Ronald Y.L. Chen, Eric Y.H. Chen, Wei Cheng, Eric F.C. Cheung, Siow Ann Chong, C. Robert Cloninger, David Cohen, Nadine Cohen, Paul Cormican, Nick Craddock, James J. Crowley, David Curtis, Michael Davidson, Kenneth L. Davis, Franziska Degenhardt, Jurgen Del Favero, Lynn E. DeLisi, Ditte Demontis, Dimitris Dikeos, Timothy Dinan, Srdjan Djurovic, Gary Donohoe, Elodie Drapeau, Jubao Duan, Frank Dudbridge, Naser Durmishi, Peter Eichhammer, Johan Eriksson, Valentina Escott-Price, Laurent Essioux, Ayman H. Fanous, Martilias S. Farrell, Josef Frank, Lude Franke, Robert Freedman, Nelson B. Freimer, Marion Friedl, Joseph I. Friedman, Menachem Fromer, Lyudmila Georgieva, Elliot S. Gershon, Ina Giegling, Paola Giusti-Rodrguez, Stephanie Godard, Jacqueline I. Goldstein, Vera Golimbet, Srihari Gopal, Jacob Gratten, Jakob Grove, Lieuwe de Haan, Christian Hammer, Marian L. Hamshere, Mark Hansen, Thomas Hansen, Vahram Haroutunian, Annette M. Hartmann, Frans A. Henskens, Stefan Herms, Joel N. Hirschhorn, Per Hoffmann, Andrea Hofman, Mads V. Hollegaard, David M. Hougaard, Masashi Ikeda, Inge Joa, Antonio Julia, Rene S. Kahn, Luba Kalaydjieva, Sena Karachanak-Yankova, Juha Karjalainen, David Kavanagh, Matthew C. Keller, Brian J. Kelly, James L. Kennedy, Andrey Khrunin, Yunjung Kim, Janis Klovins, James A. Knowles, Bettina Konte, Vaidutis Kucinskas, Zita Ausrele Kucinskiene, Hana Kuzelova-Ptackova, Anna K. Kahler, Claudine Laurent, Jimmy Lee Chee Keong, S. Hong Lee, Sophie E. Legge, Bernard Lerer, Miaoxin Li, Tao Li, Kung-Yee Liang, Jeffrey Lieberman, Svetlana Limborska, Carmel M. Loughland, Jan Lubinski, Jouko Lnnqvist, Milan Macek, Patrik K.E. Magnusson, Brion S. Maher, Wolfgang Maier, Jacques Mallet, Sara Marsal, Manuel Mattheisen, Morten Mattingsdal, Robert W. McCarley, Colm McDonald, Andrew M. McIntosh, Sandra Meier, Carin J. Meijer, Bela Melegh, Ingrid Melle, Raquelle I. Mesholam-Gately, Andres Metspalu, Patricia T. Michie, Lili Milani, Vihra Milanova, Younes Mokrab, Derek W. Morris, Ole Mors, Preben B. Mortensen, Kieran C. Murphy, Robin M. Murray, Inez Myin-Germeys, Bertram Mller-Myhsok, Mari Nelis, Igor Nenadic, Deborah A. Nertney, Gerald Nestadt, Kristin K. Nicodemus, Liene Nikitina-Zake, Laura Nisenbaum, Annelie Nordin, Eadbhard O’Callaghan, Colm O’Dushlaine, F. Anthony O’Neill, Sang-Yun Oh, Ann Olincy, Line Olsen, Jim Van Os, Christos Pantelis, George N. Papadimitriou, Sergi Papiol, Elena Parkhomenko, Michele T. Pato, Tiina Paunio, Milica Pejovic-Milovancevic, Diana O. Perkins, Olli Pietilinen, Jonathan Pimm, Andrew J. Pocklington, John Powell, Alkes Price, Ann E. Pulver, Shaun M. Purcell, Digby Quested, Henrik B. Rasmussen, Abraham Reichenberg, Mark A. Reimers, Alexander L. Richards, Joshua L. Roffman, Panos Roussos, Douglas M. Ruderfer, Veikko Salomaa, Alan R. Sanders, Ulrich Schall, Christian R. Schubert, Thomas G. Schulze, Sibylle G. Schwab, Edward M. Scolnick, Rodney J. Scott, Larry J. Seidman, Jianxin Shi, Engilbert Sigurdsson, Teimuraz Silagadze, Jeremy M. Silverman, Kang Sim, Petr Slominsky, Jordan W. Smoller, Hon-Cheong So, Chris C.A. Spencer, Eli A. Stahl, Hreinn Stefansson, Stacy Steinberg, Elisabeth Stogmann, Richard E. Straub, Eric Strengman, Jana Strohmaier, T. Scott Stroup, Mythily Subramaniam, Jaana Suvisaari, Dragan M. Svrakic, Jin P. Szatkiewicz, Erik Sderman, Srinivas Thirumalai, Draga Toncheva, Paul A. Tooney, Sarah Tosato, Juha Veijola, John Waddington, Dermot Walsh, Dai Wang, Qiang Wang, Bradley T. Webb, Mark Weiser, Dieter B. Wildenauer, Nigel M. Williams, Stephanie Williams, Stephanie H. Witt, Aaron R. Wolen, Emily H.M. Wong, Brandon K. Wormley, Jing Qin Wu, Hualin Simon Xi, Clement C. Zai, Xuebin Zheng, Fritz Zimprich, Naomi R. Wray, Kari Stefansson, Rolf Adolfsson, Ole A. Andreassen, Douglas H.R. Blackwood, Elvira Bramon, Joseph D. Buxbaum, Anders D. Børglum, Sven Cichon, Ariel Darvasi, Enrico Domenici, Hannelore Ehrenreich, Tonu Esko, Pablo V. Gejman, Michael Gill, Hugh Gurling, Christina M. Hultman, Nakao Iwata, Assen V. Jablensky, Erik G. Jonsson, Kenneth S. Kendler, George Kirov, Jo Knight, Todd Lencz, Douglas F. Levinson, Qingqin S. Li, Jianjun Liu, Anil K. Malhotra, Steven A. McCarroll, Andrew McQuillin, Jennifer L. Moran, Bryan J. Mowry, Markus M. Nthen, Roel A. Ophoff, Michael J. Owen, Aarno Palotie, Carlos N. Pato, Tracey L. Petryshen, Danielle Posthuma, Marcella Rietschel, Brien P. Riley, Dan Rujescu, Pak C. Sham, Pamela Sklar, David St. Clair, Daniel R. Weinberger, Jens R. Wendland, Thomas Werge, Mark J. Daly, Patrick F. Sullivan, Michael C. O’Donovan, David J. Hunter, Muriel Adank, Habibul Ahsan, Kristiina Aittomäki, Laura Baglietto, Sonja Berndt, Carl Blomquist, Federico Canzian, Jenny Chang-Claude, Stephen J. Chanock, Laura Crisponi, Kamila Czene, Norbert Dahmen, Isabel dos Santos Silva, Douglas Easton, A. Heather Eliassen, Jonine Figueroa, Olivia Fletcher, Montserrat Garcia-Closas, Mia M. Gaudet, Lorna Gibson, Christopher A. Haiman, Per Hall, Aditi Hazra, Rebecca Hein, Brian E. Henderson, Albert Hofman, John L. Hopper, Astrid Irwanto, Mattias Johansson, Rudolf Kaaks, Muhammad G. Kibriya, Peter Lichtner, Eiliv Lund, Enes Makalic, Alfons Meindl, Hanne Meijers-Heijboer, Bertram Müller-Myhsok, Taru A. Muranen, Heli Nevanlinna, Petra H. Peeters, Julian Peto, Ross L. Prentice, Nazneen Rahman, María José Sánchez, Daniel F. Schmidt, Rita K. Schmutzler, Melissa C. Southey, Ruth Travis, Clare Turnbull, Andre G. Uitterlinden, Rob B. van der Luijt, Quinten Waisfisz, Zhaoming Wang, Alice S. Whittemore, Rose Yang, Wei Zheng, ANS - Amsterdam Neuroscience, Adult Psychiatry, Other departments, CCA -Cancer Center Amsterdam, ARD - Amsterdam Reproduction and Development, Human Genetics, Grove, Jakob, Complex Trait Genetics, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, Vilhjalmsson, Bjarni J, Yang, Jian, Finucane, Hilary K, Gusev, Alexander, Lee, SH, Price, Alkes L, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) study, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Study, Psychosis Endophenotype International Consortium, Wellcome Trust Case Control Consortium, Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON), Human genetics, NCA - Brain mechanisms in health and disease, CCA - Oncogenesis, CCA - Quality of life, CCA - Cancer biology and immunology, Psychiatry, Department of Technology and Operations Management, Department of Organisation and Personnel Management, Child and Adolescent Psychiatry / Psychology, Clinical Genetics, Cell biology, and Internal Medicine

Subjects
Multifactorial Inheritance, Linkage disequilibrium, Complex disease, heritability, Bioinformatics, Medical and Health Sciences, Linkage Disequilibrium, 0302 clinical medicine, Theoretical, External reference, Models, Statistics, GWAS, Genetics(clinical), Genetics (clinical), Mathematics, Genetics & Heredity, Schizophrenia Working Group of the Psychiatric Genomics Consortium, 0303 health sciences, Single Nucleotide, Biological Sciences, Serious Mental Illness, Prognosis, Thresholding, Regression, Mental Health, Phenotype, polygenic risk scores, Mixed model, Multiple Sclerosis, Genotype, Quantitative Trait Loci, polygenic risk score, schizophrenia, GWAS, Discovery, Quantitative trait locus, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Genetics, Humans, p-value, Pruning (decision trees), Polymorphism, Genome-Wide Association Study, Schizophrenia, Models, Theoretical, 030304 developmental biology, genome-wide association study, and Risk of Inherited Variants in Breast Cancer (DRIVE) study, Brain Disorders, Data set, schizophrenia, Sample size determination, polygenic risk score, Polygenic risk score, 030217 neurology & neurosurgery, linkage disequilibrium
Abstract

Polygenic risk scores have shown great promise in predicting complex disease risk and will become more accurate as training sample sizes increase. The standard approach for calculating risk scores involves linkage disequilibrium (LD)-based marker pruning and applying a p value threshold to association statistics, but this discards information and can reduce predictive accuracy. We introduce LDpred, a method that infers the posterior mean effect size of each marker by using a prior on effect sizes and LD information from an external reference panel. Theory and simulations show that LDpred outperforms the approach of pruning followed by thresholding, particularly at large sample sizes. Accordingly, predicted R-2 increased from 20.1% to 25.3% in a large schizophrenia dataset and from 9.8% to 12.0% in a large multiple sclerosis dataset. A similar relative improvement in accuracy was observed for three additional large disease datasets and for non-European schizophrenia samples. The advantage of LDpred over existing methods will grow as sample sizes increase. Refereed/Peer-reviewed

Published
2015
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22. Analysis of genome-wide significant bipolar disorder genes in borderline personality disorder

Author

Norbert Dahmen, Marcella Rietschel, Bertram Krumm, Jens Treutlein, Cornelia E. Schwarze, Arian Mobascher, Josef Frank, Klaus Lieb, Björn H. Schott, Lydia Dietl, Markus M. Nöthen, Martin Jungkunz, Stephanie H. Witt, Franziska Degenhardt, Nikolaus Kleindienst, André Tadić, Sven Cichon, Christian Schmahl, Stefan Roepke, Thomas W. Mühleisen, Dan Rujescu, and Martin Bohus

Subjects
Genome-wide association study, behavioral disciplines and activities, Genome, 03 medical and health sciences, 0302 clinical medicine, Borderline Personality Disorder, mental disorders, Genetic variation, Genetics, medicine, Humans, ANK3, Bipolar disorder, Genotyping, Borderline personality disorder, Biological Psychiatry, Genetics (clinical), bipolar disorder, medicine.disease, 030227 psychiatry, comorbidity, Psychiatry and Mental health, CACNA1C, Cohort, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Brief Reports, genetic overlap, Psychology, 030217 neurology & neurosurgery, Genome-Wide Association Study, Clinical psychology
Abstract

Supplemental Digital Content is available in the text., The objective of this study was to investigate the hypothesis that borderline personality disorder (BPD) and bipolar disorder (BD) share genetic variation through analysis of known genetic risk factors for BD in a well-characterized BPD case–control cohort. Genotyping of five genome-wide significant variants identified for BD (in CACNA1C, ANK3, and ODZ4) was performed in 673 BPD cases and 748 controls. A nominally significant association with BPD was found for rs1006737 in CACNA1C (P=0.0498). Sex-specific analysis showed that this signal was present only in women. This is the first report of an association between a BD risk gene and BPD where selection was not based on a priori hypotheses about its function, but on an unbiased hypothesis-free screening of the genome. Genome-wide association data of large samples of BPD are warranted and will eventually identify new risk genes and the overlap between BPD and BD if it exists.

Published
2014
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23. Association of VMAT2 gene polymorphisms with alcohol dependence

Author

Ion Anghelescu, Daniel Sommerlad, Michael Soyka, Thomas Sander, Armin Szegedi, Ulrich W. Preuss, Christiana Mueller, Norbert Dahmen, Peter Zill, and Christoph Fehr

Subjects
Adult, Male, Candidate gene, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Gene Frequency, Humans, SNP, GABRA2, Allele, Genetic Association Studies, Biological Psychiatry, Genetics, Haplotype, Alcohol dependence, Genetic Variation, Middle Aged, Alcoholism, Psychiatry and Mental health, Phenotype, Neurology, ADH4, Vesicular Monoamine Transport Proteins, biology.protein, Female, Neurology (clinical)
Abstract

Alcohol-related diseases cause significant harm in the western world. Up to 65 % of the phenotypic variance is genetically determined. Few candidate genes have been identified, comprising ADH4, ALDH2, COMT, CRHR1, DAT (SLC6A3), GABRA2 and MAOA. While abnormalities in the dopaminergic mesolimbic reward system are considered important mediators of alcoholism, studies analyzing variants of dopamine receptors showed conflicting results. Other modulators of the reward system are synaptosomal genes. Among candidate genes, polygenic variants of the Vesicular Monamine Transporter 2 (VMAT2) gene locus associated with alterations of drinking behavior were published. These variants comprise single nucleotide polymorphisms (SNPs) within the promoter region and the open reading frame. In this study, we confirm the association of VMAT2 SNP rs363387 (allelic association: p = 0.015) with alcohol dependence. This SNP defines several haplotypes including up to four SNPs (minimal p = 0.0045). In addition, numeric effects in the subgroups of males and patients with positive family history were found. We suggest that several rs363387 T-allele containing haplotypes increase the risk of alcohol dependence (OR 1.53), whereas G-allele containing haplotypes confer protection against alcohol dependence. Taken together, there is supporting evidence for a contribution of VMAT2 gene variants to phenotypes of alcohol dependence.

Published
2013
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24. Genetic contribution to alcohol dependence: Investigation of a heterogeneous german sample of individuals with alcohol dependence, chronic alcoholic pancreatitis, and alcohol-related cirrhosis

Author

Stefan Herms, Wolfgang Gaebel, Per Hoffmann, Céline S. Reinbold, Norbert Dahmen, Jonas Rosendahl, Ulla Roggenbuck, Benedikt Brors, Norbert Wodarz, Markus M. Nöthen, Thomas Berg, Michael Soyka, Jana Strohmaier, Stephan Buch, Felix Stickel, Helene Dukal, Ulrich S. Zimmermann, Monika Ridinger, Marcella Rietschel, Susanne Lucae, Jens Treutlein, Norbert Scherbaum, Josef Frank, Dilafruz Juraeva, Stefanie Heilmann-Heimbach, Stephanie H. Witt, Karl Mann, Bertram Müller-Myhsok, Jochen Hampe, Jerome C. Foo, Karl-Heinz Jöckel, Franziska Degenhardt, Wolfgang Maier, Fabian Streit, Sven Cichon, Rainer Spanagel, Marcus Ising, Henrike Scholz, Wolfgang H. Sommer, Liz Rietschel, Falk Kiefer, and Andreas J. Forstner

Subjects
0301 basic medicine, medicine.medical_specialty, Cirrhosis, lcsh:QH426-470, alcohol dependence, Medizin, Genome-wide association study, Locus (genetics), 610 Medicine & health, Gastroenterology, Article, 03 medical and health sciences, Liver disease, Internal medicine, Genetics, Medicine, Allele frequency, Genetics (clinical), genome-wide association study, business.industry, Alcohol dependence, alcohol dehydrogenase, ADH1B, chronic alcoholic pancreatitis, alcoholic liver cirrhosis, ADH1C, medicine.disease, lcsh:Genetics, 030104 developmental biology, Pancreatitis, business
Abstract

The present study investigated the genetic contribution to alcohol dependence (AD) using genome-wide association data from three German samples. These comprised patients with: (i) AD; (ii) chronic alcoholic pancreatitis (ACP); and (iii) alcohol-related liver cirrhosis (ALC). Single marker, gene-based, and pathway analyses were conducted. A significant association was detected for the ADH1B locus in a gene-based approach (puncorrected = 1.2 × 10-6; pcorrected = 0.020). This was driven by the AD subsample. No association with ADH1B was found in the combined ACP + ALC sample. On first inspection, this seems surprising, since ADH1B is a robustly replicated risk gene for AD and may therefore be expected to be associated also with subgroups of AD patients. The negative finding in the ACP + ALC sample, however, may reflect genetic stratification as well as random fluctuation of allele frequencies in the cases and controls, demonstrating the importance of large samples in which the phenotype is well assessed. OA gold

Published
2017
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25. Contents Vol. 62, 2013

Author

Dimple Kondal, J. Franch, I. Urrutía, Nidhi Gupta, Boitumelo Stokie Motswagole, O. Izaola, J.A. Vázquez, J. Vendrell, Juergen Brinkmeyer, Arian Mobascher, R. Gomis, Tonje Holte Stea, Sunil Bansal, Paulette H. in 't Veld, Gerhard Gründer, Kashish Goel, Dirce Maria Lobo Marchioni, Anura V Kurpad, E. Menéndez, I. Mora-Peces, Seema Gulati, D.A. de Luis, Lemogang D. Kwape, Mamatha Mishra, Jürgen Gallinat, Norbert Dahmen, Amalia Diaz-Lacava, Pieter van 't Veer, R. Carmena, R. Aller, Esmée L. Doets, Motlalepula Mokotedi, A. Goday, S. Gaztambide, Georg Winterer, E. Delgado, M.T. Martínez-Larrad, Rosemary I. Kobue-Lekalake, Daiva Gorczyca, Jörn Schneede, Anoop Misra, Adam Jankowski, Christoph von der Goltz, Omer Ozcan, Andreas Reine, S. Valdés, Lena Rademacher, Klaus Wiedemann, Anna Prescha, Vaishali Madkaikar, Swati Bhardwaj, Michelle Alessandra de Castro, M. Azam Mansoor, Regina Mara Fisberg, L. Castaño, Eliseu Verly, Noel W. Solomons, Chester Luis Galvão Cesar, Christina Dinter, R. Casamitjana, Anna Brzozowska, G. Rojo-Martínez, M. Serrano-Rios, Falk Kiefer, L. Ribas-Barba, G. Pascual-Manich, Norbert Thuerauf, Tiyapo C. Mongwaketse, Lisette C. P. G. M. de Groot, Druck Reinhardt Druck Basel, Tomislav Majić, J.M. Eiros Bouza, Roberta Schein Bigio, Thomas F. Wienker, Holger Thiele, Karolina Szeremeta, Anna Szczecińska, Nadine Petrovsky, A. Calle-Pascual, Alpaslan Cosar, R. Conde, A. López-Alba, Michael Wagner, Susan L. Colles, Hans Konrad Biesalski, E. Bordiú, Adrienne E J M Cavelaars, F. Soriguer, Elvira Abbruzzese, Rosalie A. M. Dhonukshe-Rutten, Bernard T. Bulawayo, M. Catalá, Satz Mengensatzproduktion, Johannes Kornhuber, Tinku Thomas, E. Ortega, A. Bosch-Comas, C. Castell, J. Girbés, and Jochen Mutschler

Subjects
Gerontology, Nutrition and Dietetics, Anthropology, Philosophy, Medicine (miscellaneous)
Published
2013
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26. Impaired sleep quality and sleep duration in smokers-results from the German Multicenter Study on Nicotine Dependence

Author

Thomas F. Wienker, Jürgen Gallinat, Gerhard Gründer, Andreas Jaehne, Jürgen Brinkmeyer, Michael Wagner, Johannes Kornhuber, Bertram Szagun, Norbert Thuerauf, Amalia Diaz-Lacava, Ulrike Grittner, Georg Winterer, Norbert Dahmen, Arian Mobascher, Stefan Cohrs, Dieter Riemann, Andrea Rodenbeck, Falk Kiefer, and Dieter Kunz

Subjects
medicine.medical_specialty, Population, Medicine (miscellaneous), Poison control, Sleep Wake Disorders, Pittsburgh Sleep Quality Index, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, 030212 general & internal medicine, Risk factor, education, Psychiatry, Pharmacology, education.field_of_study, Sleep disorder, business.industry, medicine.disease, Sleep in non-human animals, 3. Good health, Psychiatry and Mental health, Anxiety, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract

Cigarette smoking is a severe health burden being related to a number of chronic diseases. Frequently, smokers report about sleep problems. Sleep disturbance, in turn, has been demonstrated to be involved in the pathophysiology of several disorders related to smoking and may be relevant for the pathophysiology of nicotine dependence. Therefore, determining the frequency of sleep disturbance in otherwise healthy smokers and its association with degree of nicotine dependence is highly relevant. In a population-based case-control study, 1071 smokers and 1243 non- smokers without lifetime Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Axis I disorder were investigated. Sleep quality (SQ) of participants was determined by the Pittsburgh Sleep Quality Index. As possible confounders, age, sex and level of education and income, as well as depressiveness, anxiety, attention deficit hyperac- tivity, alcohol drinking behaviour and perceived stress, were included into multiple regression analyses. Significantly more smokers than non-smokers (28.1% versus 19.1%; P < 0.0001) demonstrated a disturbed global SQ. After con- trolling for the confounders, impaired scores in the component scores of sleep latency, sleep duration and global SQ were found significantly more often in smokers than non-smokers. Consistently, higher degrees of nicotine dependence and intensity of smoking were associated with shorter sleep duration. This study demonstrates for the first time an elevated prevalence of sleep disturbance in smokers compared with non-smokers in a population without lifetime history of psychiatric disorders even after controlling for potentially relevant risk factors. It appears likely that smoking is a behaviourally modifiable risk factor for the occurrence of impaired SQ and short sleep duration.

Published
2012
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27. Schizophrenia risk polymorphisms in the TCF4 gene interact with smoking in the modulation of auditory sensory gating

Author

Marion Clepce, Norbert Dahmen, Wolfgang Maier, Leonhard Lennertz, Noah Savary, Holger Thiele, Arian Mobascher, Nadine Petrovsky, Michael Nothnagel, Thomas F. Wienker, Gerhard Gründer, Ingo Frommann, Tomislav Majić, Norbert Thuerauf, Jürgen Gallinat, Michael Wagner, Falk Kiefer, Boris B. Quednow, Amalia Diaz-Lacava, Rainald Mössner, Jürgen Brinkmeyer, Katja N. Spreckelmeyer, Francesco Musso, Georg Winterer, Peter Nürnberg, and Mohammad R. Toliat

Subjects
Male, Linkage disequilibrium, Audiology, Linkage Disequilibrium, chemistry.chemical_compound, Transcription Factor 4, 0302 clinical medicine, Gene Frequency, physiopathology [Smoking], Risk Factors, Germany, genetics [Schizophrenia], physiology [Evoked Potentials, Auditory], Cotinine, Prepulse inhibition, Genetics, education.field_of_study, Multidisciplinary, Geography, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Smoking, blood [Cotinine], blood [Smoking], Electroencephalography, Biological Sciences, genetics [Transcription Factors], Sensory Gating, 3. Good health, medicine.anatomical_structure, Schizophrenia, physiology [Sensory Gating], Evoked Potentials, Auditory, Female, ddc:500, Adult, medicine.medical_specialty, Genotype, Population, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Commentaries, medicine, Humans, genetics [Basic Helix-Loop-Helix Leucine Zipper Transcription Factors], education, Allele frequency, Analysis of Variance, Sensory gating, medicine.disease, 030227 psychiatry, chemistry, Endophenotype, physiopathology [Schizophrenia], TCF4 protein, human, 030217 neurology & neurosurgery, Transcription Factors
Abstract

Several polymorphisms of the transcription factor 4 ( TCF4 ) have been shown to increase the risk for schizophrenia, particularly TCF4 rs9960767. This polymorphism is associated with impaired sensorimotor gating measured by prepulse inhibition—an established endophenotype of schizophrenia. We therefore investigated whether TCF4 polymorphisms also affect another proposed endophenotype of schizophrenia, namely sensory gating assessed by P50 suppression of the auditory evoked potential. Although sensorimotor gating and sensory gating are not identical, recent data suggest that they share genetic fundamentals. In a multicenter study at six academic institutions throughout Germany, we applied an auditory P50 suppression paradigm to 1,821 subjects (1,023 never-smokers, 798 smokers) randomly selected from the general population. Samples were genotyped for 21 TCF4 polymorphisms. Given that smoking is highly prevalent in schizophrenia and affects sensory gating, we also assessed smoking behavior, cotinine plasma concentrations, exhaled carbon monoxide, and the Fagerström Test (FTND). P50 suppression was significantly decreased in carriers of schizophrenia risk alleles of the TCF4 polymorphisms rs9960767, rs10401120rs, rs17597926, and 17512836 ( P < 0.0002–0.00005). These gene effects were modulated by smoking behavior as indicated by significant interactions of TCF4 genotype and smoking status; heavy smokers (FTND score ≥4) showed stronger gene effects on P50 suppression than light smokers and never-smokers. Our finding suggests that sensory gating is modulated by an interaction of TCF4 genotype with smoking, and both factors may play a role in early information processing deficits also in schizophrenia. Consequently, considering smoking behavior may facilitate the search for genetic risk factors for schizophrenia.

Published
2012
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28. Neurocognitive impairments in non-deprived smokers-results from a population-based multi-center study on smoking-related behavior

Author

Gerd Gründer, Arian Mobascher, Nadine Petrovsky, Norbert Thuerauf, J. Walter de Millas, Amalia Diaz-Lacava, Jürgen Gallinat, Marion Clepce, Juergen Brinkmeyer, Katja N. Spreckelmeyer, Georg Winterer, Christoph von der Goltz, Falk Kiefer, Norbert Dahmen, Michael Wagner, Svenja Schulze-Rauschenbach, and Thomas F. Wienker

Subjects
Pharmacology, education.field_of_study, medicine.medical_specialty, medicine.diagnostic_test, Population, Medicine (miscellaneous), Cognition, Neuropsychological test, Impulsivity, Nicotine, Psychiatry and Mental health, medicine, Verbal fluency test, medicine.symptom, Psychology, education, Psychiatry, Episodic memory, Neurocognitive, Clinical psychology, medicine.drug
Abstract

The aim of the present study was to examine neurocognitive function associated with chronic nicotine use. A total of 2163 healthy participants (1002 smokers, 1161 never-smoking controls) participated in a population-based case- control design.The main outcome measures were six cognitive domain factors derived from a neuropsychological test battery. In smokers, the battery was administered after controlled smoking of one cigarette. Analyses included age, sex and education as covariates. Results demonstrated small, but significant deficits in smokers for visual attention (P < 0.001) and cognitive impulsivity (P < 0.006), while verbal episodic memory, verbal fluency, verbal working memory, and Stroop-interference did not differ between groups. These attention/impulsivity deficits were also present in smokers with only a low amount of cigarette consumption. Lifetime nicotine use (pack-years) was not correlated with cognition in smokers. In conclusion, this study confirmed subtle and specific cognitive deficits in non-deprived smokers. The independence of these deficits from consumption intensity may argue for an a priori deficit of some cognitive abilities in smokers. These specific deficits may constitute intermediate phenotypes for genetic research on nicotine use.

Published
2012
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29. Genome-wide significant association between alcohol dependence and a variant in the ADH gene cluster

Author

Jens Treutlein, Michael Soyka, Susanne Lucae, Christine Schmäl, Monika Ridinger, Bertram Müller-Myhsok, Markus M. Nöthen, Norbert Wodarz, Norbert Dahmen, Josef Frank, Rainald Mössner, Karl Mann, Wolfgang Maier, Manuel Mattheisen, Marcella Rietschel, Stefan Herms, Marcus Ising, Peter Zill, Wolfgang Gaebel, Michael Steffens, Per Hoffmann, Norbert Scherbaum, Sven Cichon, and Falk Kiefer

Subjects
Pharmacology, Genetics, Psychiatry and Mental health, Linkage disequilibrium, Polymorphism (computer science), Gene cluster, Medicine (miscellaneous), SNP, ADH1B, Single-nucleotide polymorphism, Genome-wide association study, Biology, Heritability
Abstract

Alcohol dependence (AD) is an important contributory factor to the global burden of disease. The etiology of AD involves both environmental and genetic factors, and the disorder has a heritability of around 50%. The aim of the present study was to identify susceptibility genes for AD by performing a genome-wide association study (GWAS). The sample comprised 1333 male in-patients with severe AD according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, and 2168 controls. These included 487 patients and 1358 controls from a previous GWAS study by our group. All individuals were of German descent. Single-marker tests and a polygenic score-based analysis to assess the combined contribution of multiple markers with small effects were performed. The single nucleotide polymorphism (SNP) rs1789891, which is located between the ADH1B and ADH1C genes, achieved genome-wide significance [P = 1.27E-8, odds ratio (OR) = 1.46]. Other markers from this region were also associated with AD, and conditional analyses indicated that these made a partially independent contribution. The SNP rs1789891 is in complete linkage disequilibrium with the functional Arg272Gln variant (P = 1.24E-7, OR = 1.31) of the ADH1C gene, which has been reported to modify the rate of ethanol oxidation to acetaldehyde in vitro. A polygenic score-based approach produced a significant result (P = 9.66E-9). This is the first GWAS of AD to provide genome-wide significant support for the role of the ADH gene cluster and to suggest a polygenic component to the etiology of AD. The latter result may indicate that many more AD susceptibility genes still await identification.

Published
2011
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30. Dopamine-related genes and spontaneous smoking cessation in ever-heavy smokers

Author

Dan Rujescu, Barbara Nitz, Lutz P. Breitling, Norbert Dahmen, Hermann Brenner, Dietrich Rothenbacher, Heiko Müller, Georg Winterer, Thomas Illig, and Elke Raum

Subjects
Male, medicine.medical_specialty, Genotype, Dopamine, medicine.medical_treatment, media_common.quotation_subject, Pharmacology, Polymorphism, Single Nucleotide, Linkage Disequilibrium, Cohort Studies, Germany, Dopamine receptor D2, Internal medicine, Epidemiology, Genetics, medicine, Humans, Age of Onset, Survival analysis, Aged, media_common, Dopamine transporter, Norepinephrine Plasma Membrane Transport Proteins, biology, Receptors, Dopamine D2, business.industry, Addiction, Smoking, Tobacco Use Disorder, Middle Aged, Abstinence, Survival Analysis, Dopa Decarboxylase, biology.protein, Educational Status, Molecular Medicine, Smoking cessation, Female, Smoking Cessation, business, Pharmacogenetics
Abstract

Several studies have provided evidence for associations of polymorphisms located in and near dopamine-related genes and nicotine dependence and other smoking-related phenotypes, including pharmacogenetic interactions. Aim: The purpose of the present work was to examine the association of SNPs in the DOPA decarboxylase (DDC), dopamine receptor D2 (DRD2) and dopamine transporter (SLC6A3) genes with smoking cessation in a large retrospective study featuring approximately 900 cessation events. Materials & methods: Data originated from the enrollment questionnaire of the epidemiological ESTHER study of community-dwelling adults aged 50–74 years, conducted in the German state of Saarland between July 2000 and December 2002. Restricting the analyses to subjects who reported to have regularly smoked >20 cigarettes per day at some point in their life, we used survival analysis methods to model the time from initiation of regular smoking to cessation (defined as quitting with abstinence lasting until enrollment) and its relation with eight polymorphisms in the aforementioned genes (five in DDC, two in DRD2 and one in SLC6A3) in 1446 participants. Results: Neither individual variants nor DDC haplotypes were associated with the probability of overcoming nicotine dependence in this cohort. Conclusion: The repeated suggestion of associations between the variants examined and nicotine dependence in previous reports seems to contrast the negative results in the present study. This would appear consistent with the hypothesis that the establishment of regular heavy smoking might abolish associations between genetic determinants of nicotine dependence and nicotine dependence-related phenotypes, in particular the probability of successful smoking cessation. Original submitted 15 February 2011; Revision submitted 2 May 2011

Published
2011
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31. Reliability of Three Alternate Forms of the Trail Making Tests A and B

Author

Isabella Helmreich, Stefanie Wagner, André Tadić, Norbert Dahmen, and Klaus Lieb

Subjects
Adult, Male, Aging, Psychometrics, Intelligence, Trail Making Test, Vocabulary, behavioral disciplines and activities, Developmental psychology, Executive Function, Young Adult, Cognition, Reaction Time, medicine, Humans, Learning, Reliability (statistics), Aged, Intelligence Tests, Depressive Disorder, Major, medicine.diagnostic_test, Mental Disorders, Reproducibility of Results, Repeated measures design, General Medicine, Neuropsychological test, Middle Aged, medicine.disease, Executive functions, Antidepressive Agents, Diagnostic and Statistical Manual of Mental Disorders, Psychiatry and Mental health, Clinical Psychology, Neuropsychology and Physiological Psychology, Practice, Psychological, Major depressive disorder, Female, Psychology, human activities, Psychomotor Performance, Clinical psychology
Abstract

The majority of patients with Major Depressive Disorder (MDD) suffer from significant executive dysfunctions. To investigate the time course of executive functions during antidepressant treatment, repeated measures of executive functions are necessary. In order to avoid practice effects, the assessment of alternate forms is suggested. The aim of this study was to compare the processing times of four alternate versions of the Trail Making Test (TMT) A and B in patients with MDD. Fifty-five subjects with DSM-IV MDD were included in the study. We analyzed mean processing times and retest reliability of the four versions of TMT A and B. Mean processing times did not differ between the four tested versions of TMT A and B. Retest reliability of TMT A and B was between 0.76 and 0.89 and between 0.86 and 0.94, respectively. Because of their identical difficulty and high reliability, the herein described versions of the TMT A and B are suitable for sequential testing of executive functioning.

Published
2011
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32. The German multi-centre study on smoking-related behavior-description of a population-based case-control study

Author

Michael Wagner, Jürgen Brinkmeyer, Amalia Diaz-Lacava, Daniela A. Holler, Thomas F. Wienker, Svenja Schulze-Rauschenbach, Christoph von der Goltz, Gerhard Gründer, Katja N. Spreckelmeyer, Norbert Thürauf, Annette Lindenberg, Falk Kiefer, Walter de Millas, Georg Winterer, Norbert Dahmen, Marion Clepce, Jürgen Gallinat, Arian Mobascher, and Michael Steffens

Subjects
Pharmacology, education.field_of_study, medicine.medical_specialty, business.industry, media_common.quotation_subject, Population, Case-control study, Medicine (miscellaneous), Social environment, language.human_language, German, Psychiatry and Mental health, language, Medicine, Personality, Risk factor, education, business, Risk assessment, Psychiatry, Psychosocial, media_common, Demography
Abstract

Tobacco smoking is a major risk factor for most of the diseases leading in mortality. Nicotine dependence (ND), which sustains regular smoking, is now acknowledged to be under substantial genetic control with some environmental contribution. At present, however, genetic studies on ND are mostly conducted in populations that have been poorly characterized with regard to ND-related phenotypes for the simple reason that the respective populations were not primarily collected to study ND. The German multi-centre study 'Genetics of Nicotine Dependence and Neurobiological Phenotypes', which is funded by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) as part of the Priority Program (Schwerpunktprogramm) SPP1226: 'Nicotine-Molecular and Physiological Effects in CNS', was intended to overcome some of these inherent problems of current genetic studies of ND. The multi-centre study is a population-based case-control study of smokers and never-smokers (n = 2396). The study was unique worldwide because it was the first large-scale genetic study specifically addressing ND with the collection of a wide range of environmental, psychosocial and neurobiological phenotypes. Study design and major population characteristics with emphasis on risk prediction of smoking status were presented in this paper.

Published
2011
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33. P50 sensory gating and smoking in the general population

Author

Francesco Musso, Georg Winterer, Thomas F. Wienker, Norbert Thuerauf, Gerhard Gründer, Ingo Frommann, Arian Mobascher, Jürgen Gallinat, Melanie Schmitz, Katja N. Spreckelmeyer, Norbert Dahmen, Jürgen Brinkmeyer, Daniela A. Holler, Falk Kiefer, Amalia Diaz-Lacava, Marion Clepce, Michael Wagner, and Walter de Millas

Subjects
Pharmacology, Fagerstrom Test for Nicotine Dependence, education.field_of_study, medicine.medical_specialty, Sensory gating, Population, Medicine (miscellaneous), Gating, Audiology, medicine.disease, Brain mapping, Functional imaging, Psychiatry and Mental health, medicine.anatomical_structure, Schizophrenia, Endophenotype, medicine, education, Psychology, Neuroscience
Abstract

P50 gating is a major functional biomarker in research on schizophrenia and other psychiatric conditions with high smoking prevalence. It is used as endophenotype for studying nicotinic systems genetics and as surrogate endpoint measure for drug development of nicotinic agonists. Surprisingly, little is known about P50 gating in the general population and the relationship to smoking-related characteristics. In this multicenter study at six academic institutions throughout Germany, n = 907 never-smokers (NS

Published
2011
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34. Polymorphisms in oxidative stress-related genes and postmenopausal breast cancer risk

Author

Per Hall, Petra Seibold, Peter Schmezer, Norbert Dahmen, Dieter Flesch-Janys, Jenny Chang-Claude, Jianjun Liu, Rebecca Hein, and Odilia Popanda

Subjects
Cancer Research, Candidate gene, Case-control study, Breast Neoplasms, Single-nucleotide polymorphism, Middle Aged, Biology, medicine.disease, Bioinformatics, Polymorphism, Single Nucleotide, Risk Assessment, Postmenopause, Oxidative Stress, Breast cancer, Risk Estimate, Oncology, medicine, Genetic predisposition, Humans, Female, Genetic Predisposition to Disease, Thioredoxin, Allele
Abstract

Breast cancer is the most frequent cancer type among women in western countries. In addition to established risk factors like hormone replacement therapy, oxidative stress may play a role in carcinogenesis through an unbalanced generation of reactive oxygen species that leads to genetic instability. The aim of this study is to assess the influence of common single nucleotide polymorphisms (SNPs) in candidate genes related to oxidative stress on postmenopausal breast cancer risk. We genotyped 109 polymorphisms (mainly tagging SNPs) in 22 candidate genes in 1,639 postmenopausal breast cancer cases and 1,967 controls (set 1) from the German population-based case-control study "MARIE". SNPs showing association in set 1 were tested in further 863 cases and 2,863 controls from MARIE (set 2) using a joint analysis strategy. Six polymorphisms evaluated in the combined set showed significantly modified breast cancer risk per allele in the joint analysis, including SNPs in CYBA (encoding a subunit of the NADPH oxidase: rs3794624), MT2A (metallothionein 2A: rs1580833), TXN (thioredoxin: rs2301241), and in TXN2 (thioredoxin 2: rs2267337, rs2281082, rs4821494). Associations with the CYBA rs3794624 (OR per allele: 0.93, 95% CI 0.87-0.99) and TXN rs2301241 variants (OR per allele: 1.05, 95% CI 1.00-1.10) were confirmed in the summary risk estimate analysis using up to three additional studies. We found some evidence for association of polymorphisms in genes of the thioredoxin system, CYBA, and MT2A with postmenopausal breast cancer risk. Summary evidence including independent datasets indicated moderate effects in CYBA and TXN that warrant confirmation in large independent studies.

Published
2011
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35. Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption

Author

Michiel L. Bots, Georgy Bakalkin, Claire Troakes, Gérard Waeber, Anna-Liisa Hartikainen, Danielle M. Dick, Kay-Tee Khaw, Stéphane Cauchi, Toni-Kim Clarke, Jian'an Luan, Jaakko Kaprio, Charlotte Onland-Moret, Yurii S. Aulchenko, Wolfgang H. Sommer, Ben A. Oostra, Alberto Fernández-Medarde, Jouke-Jan Hottenga, Kari Stefansson, Angela Doering, Lachlan J. M. Coin, Kijoung Song, Ida Surakk, Sylvane Desrivières, Pimphen Charoen, Nicholas G. Martin, Jacqueline C.M. Witteman, John C. Chambers, Tim D. Spector, Stéphane Lobbens, Guangju Zhai, Peter Vollenweider, David Stacey, Anbarasu Lourdusamy, Ulrike Heberlein, Victor Hesselbrock, Leena Peltonen, James Scott, Miklós Palkovits, Albert Hofman, Xin Yuan, Cornelia M. van Duijn, Gunter Schumann, Yvonne T. van der Schouw, Nicole Vogelzangs, Nicole Soranzo, Paul Elliott, Brenda W.J.H. Penninx, Nicholas J. Wareham, Eugenio Santos, Silvia Polidoro, Diederick E. Grobbee, Norbert Dahmen, Daniel F. Gudbjartsson, Dorret I. Boomsma, Rainer Spanagel, Oliver Staehlin, Anke Tönjes, Matthieu Maroteaux, Ainhoa Bilbao, Eco J. C. de Geus, Francesca Ducci, Vincent Mooser, Mark I. McCarthy, Paolo Vineis, Christine Cavalcanti-Proença, Weihua Zhang, Nelson B. Freimer, Ruth J. F. Loos, Andres Metspalu, Tatiana Foroud, Rudolf A. de Boer, Thorarinn Tyrfingsson, Anneli Pouta, Beverley Balkau, Matti Isohanni, Paul F. O'Reilly, Massimo Mangino, Stephan J. L. Bakker, Elemi J. Breetvelt, Marjo-Riitta Järvelin, Tõnu Esko, Inga Prokopenko, Delphine Beury, Erich Wichmann, Gerjan Navis, Jaana Laitinen, John Whitfield, Karen H. Berger, Thorgeir E. Thorgeirsson, Alanna C. Easton, Brigitte Kuehnel, Ulla Sovio, Cuno S.P.M. Uiterwaal, Unnur Thorsteinsdottir, Fazil Aliev, Najaf Amin, Dale R. Nyholt, Alejandro Núñez, Dawn M. Waterworth, Mattijs E. Numans, Pim van der Harst, Michael Stumvoll, Howard J. Edenberg, Johannes H. Smit, Gonneke Willemsen, Andrew C. Heath, Simonetta Guarrera, Fulvio Ricceri, Joline W.J. Beulens, Giuseppe Matullo, Anokhi Ali Khan, Jean-Antoine Girault, Christian Mueller, Jaspal S. Kooner, André G. Uitterlinden, Jing Hua Zhao, Cardiovascular Centre (CVC), Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), Epidemiology, Clinical Genetics, Internal Medicine, Psychiatry, EMGO - Mental health, NCA - Attention & Cognition, NCA - Anxiety & Depression, Biological Psychology, Neuroscience Campus Amsterdam - Anxiety & Depression, Neuroscience Campus Amsterdam - Attention & Cognition, and EMGO+ - Mental Health

Subjects
Netherlands Twin Register (NTR), alcohol consumption, Population, autism, Single-nucleotide polymorphism, Genome-wide association study, genome-wide analysis, epidemiologic, transcriptional expression analysis, Biology, Quantitative trait locus, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, ADDICTIVE BEHAVIOR, DEPENDENCE, Genotype, medicine, SNP, education, Genotyping, 030304 developmental biology, Genetics, 0303 health sciences, education.field_of_study, Multidisciplinary, MEN, Alcohol Drinking/genetics, Alcohol Drinking/metabolism, Animals, Drosophila melanogaster/genetics, Drosophila melanogaster/metabolism, European Continental Ancestry Group/genetics, Female, Gene Expression Regulation/genetics, Genome-Wide Association Study, Humans, Male, Mice, Nuclear Proteins/biosynthesis, Nuclear Proteins/genetics, Polymorphism, Single Nucleotide, Proteins/genetics, Proteins/metabolism, Quantitative Trait, Heritable, Biological Sciences, medicine.disease, GENOTYPES, 3. Good health, DROSOPHILA, Autism, 030217 neurology & neurosurgery
Abstract

Alcohol consumption is a moderately heritable trait, but the genetic basis in humans is largely unknown, despite its clinical and societal importance. We report a genome-wide association study meta-analysis of ∼2.5 million directly genotyped or imputed SNPs with alcohol consumption (gram per day per kilogram body weight) among 12 population-based samples of European ancestry, comprising 26,316 individuals, with replication genotyping in an additional 21,185 individuals. SNP rs6943555 in autism susceptibility candidate 2 gene ( AUTS2 ) was associated with alcohol consumption at genome-wide significance ( P = 4 × 10 −8 to P = 4 × 10 −9 ). We found a genotype-specific expression of AUTS2 in 96 human prefrontal cortex samples ( P = 0.026) and significant ( P < 0.017) differences in expression of AUTS2 in whole-brain extracts of mice selected for differences in voluntary alcohol consumption. Down-regulation of an AUTS2 homolog caused reduced alcohol sensitivity in Drosophila ( P < 0.001). Our finding of a regulator of alcohol consumption adds knowledge to our understanding of genetic mechanisms influencing alcohol drinking behavior.

Published
2011
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36. Risk gene variants for nicotine dependence in the CHRNA5-CHRNA3-CHRNB4 cluster are associated with cognitive performance

Author

Katharina Heim, Ina Giegling, Norbert Dahmen, Hermann Brenner, Heiko Müller, Christian Gieger, Jürgen Gallinat, H-Erich Wichmann, Annette M. Hartmann, Lutz P. Breitling, Holger Prokisch, Kirstin Mittelstrass, Andreas Gal, Thomas Meitinger, Hans-Jürgen Möller, Christoph Fehr, Thomas Illig, Claudia Lamina, Dan Rujescu, Barbara Nitz, Elke Raum, and Georg Winterer

Subjects
Adult, Male, Risk, Genotype, Gene Expression, Nerve Tissue Proteins, Single-nucleotide polymorphism, Receptors, Nicotinic, Biology, Bioinformatics, Polymorphism, Single Nucleotide, Nicotine, Cellular and Molecular Neuroscience, Cognition, Gene cluster, medicine, Humans, Genetic Predisposition to Disease, RNA, Messenger, Risk factor, Allele, Genetic Association Studies, Genetics (clinical), Aged, Genetics, Chromosomes, Human, Pair 15, Gene Expression Profiling, CHRNA5, Haplotype, Wechsler Scales, Genetic Variation, Tobacco Use Disorder, Middle Aged, Psychiatry and Mental health, Multigene Family, biology.protein, Female, medicine.drug
Abstract

Recent studies strongly support an association of the nicotinic acetylcholine receptor gene cluster CHRNA5-CHRNA3-CHRNB4 with nicotine dependence (ND). However, the precise genotype-phenotype relationship is still unknown. Clinical and epidemiological data on smoking behavior raise the possibility that the relevant gene variants may indirectly contribute to the development of ND by affecting cognitive performance in some smokers who consume nicotine for reasons of "cognition enhancement." Here, we tested seven single nucleotide polymorphisms (SNPs) rs684513, rs637137, rs16969968, rs578776, rs1051730, rs3743078, rs3813567 from the CHRNA5-CHRNA3-CHRNB4 gene cluster for association with ND, measures of cognitive performance and gene expression. As expected, we found all SNPs being associated with ND in three independent cohorts (KORA, NCOOP, ESTHER) comprising 5,561 individuals. In an overlapping sample of 2,186 subjects we found three SNPs (rs16969968, rs1051730, rs3743078) being associated with cognitive domains from the Wechsler-Adult-Intelligence Scale (WAIS-R)-most notably in the performance subtest "object assembly" and the verbal subtest "similarities." In a refined analysis of a subsample of 485 subjects, two of these three SNPs (rs16969968, rs1051730) were associated with n-back task performance/Continuous Performance Test. Furthermore, two CHRNA5 risk alleles (rs684513, rs637137) were associated with CHRNA5 mRNA expression levels in whole blood in a subgroup of 190 subjects. We here report for the first time an association of CHRNA5-CHRNA3-CHRNB4 gene variants with cognition possibly mediating in part risk for developing ND. The observed phenotype-genotype associations may depend on altered levels of gene expression. © 2010 Wiley-Liss, Inc.

Published
2010
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37. Meta-analysis and imputation refines the association of 15q25 with smoking quantity

Author

Mark J. Caulfield, Paul Scheet, Ruth J. F. Loos, Ozren Polasek, Vincent Mooser, Michael Wittig, Stephen E. Epstein, James F. Wilson, Gonçalo R. Abecasis, Jennifer E. Huffman, Augusto D. Pichard, Mary Susan Burnett, Rajesh Rawal, Federica Tozzi, Nilesh J. Samani, Hans J. Grabe, Robert L. Wilensky, Miles Parkes, Jing Hua Zhao, Jaspal S. Kooner, Daniel J. Rader, Wade H. Berrettini, Per Bakke, Robert W. Mahley, Astrid Petersmann, Alan F. Wright, Kenneth M. Kent, Lowell F. Satler, Alistair S. Hall, Xin Yuan, Hakon Hakonarson, Henry Völzke, Peter Vollenweider, Xiangjun Xiao, John B. Vincent, Joseph M. Lindsay, Scott M. Grundy, Christopher G. Mathew, Caroline Hayward, Susan Campbell, John R. Thompson, Alexander Teumer, Ins Barroso, David Schlessinger, Jack Satsangi, Benjamin J. Wright, Carl A. Anderson, Fabio Busonero, James L. Kennedy, Harry Campbell, Dan Rujescu, Anne Barton, H.-Erich Wichmann, Philip J. Barter, Veronique Vitart, Antonio Terracciano, Ruth McPherson, S. Horstmann, Anna F. Dominiczak, Martin Preisig, Susanne Lucae, David St Clair, Lina Zgaga, Jane Worthington, Joseph M. Devaney, Wendy Thomson, Anne Farmer, Antero Kesäniemi, Ulrich John, Tariq Ahmad, William H. Matthai, Jason Z. Liu, Muredach P. Reilly, Ivana Kolcic, Igor Rudan, Norbert Dahmen, Martin Farrall, Anthony J. Balmforth, Nicholas J. Wareham, Steve Eyre, T. Brueckl, Kay-Tee Khaw, Liming Qu, Christopher W. Knouff, Sarah H. Wild, Patricia B. Munroe, Claudia Lamina, Dawn M. Waterworth, John Strauss, John C. Chambers, Marcus Ising, Richard O. Day, Amund Gulsvik, Gérard Waeber, Arne Schäfer, Andre Franke, Clyde Francks, Pierandrea Muglia, Mingyao Li, Peter McGuffin, Keith Matthews, Manuela Uda, Sreekumar G. Pillai, Jonathan Marchini, Lefkos T. Middleton, Ron Waksman, and Wellcome Trust Case Control Consortium

Subjects
Genetics, 0303 health sciences, education.field_of_study, Population, Single-nucleotide polymorphism, Genome-wide association study, Locus (genetics), Biology, Article, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Genome-Wide Association, Nicotine Dependence, Lung-Cancer, Susceptibility Locus, Risk-Factors, Disease, Genes, SNPS, Colaus Study, SNP, 1000 Genomes Project, Allele, education, 030217 neurology & neurosurgery, Imputation (genetics), genome-wide association study, smoking initiation, smoking quantity, 030304 developmental biology
Abstract

Smoking is a leading global cause of disease and mortality(1). We established the Oxford-GlaxoSmithKline study (Ox-GSK) to perform a genome-wide meta-analysis of SNP association with smoking-related behavioral traits. Our final data set included 41,150 individuals drawn from 20 disease, population and control cohorts. Our analysis confirmed an effect on smoking quantity at a locus on 15q25 (P = 9.45 x 10(-19)) that includes CHRNA5, CHRNA3 and CHRNB4, three genes encoding neuronal nicotinic acetylcholine receptor subunits. We used data from the 1000 Genomes project to investigate the region using imputation, which allowed for analysis of virtually all common SNPs in the region and offered a fivefold increase in marker density over HapMap2 (ref. 2) as an imputation reference panel. Our fine-mapping approach identified a SNP showing the highest significance, rs55853698, located within the promoter region of CHRNA5. Conditional analysis also identified a secondary locus (rs6495308) in CHRNA3.

Published
2010
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38. The catechol o-methyltransferase (COMT) val158met polymorphism modulates the association of serious life events (SLE) and impulsive aggression in female patients with borderline personality disorder (BPD)

Author

Ömür Başkaya, Klaus Lieb, Stefanie Wagner, N. J. Anicker, Norbert Dahmen, and André Tadić

Subjects
Child abuse, medicine.medical_specialty, Catechol-O-methyl transferase, Aggression, Poison control, Impulsivity, medicine.disease, behavioral disciplines and activities, Genetic determinism, Psychiatry and Mental health, Sexual abuse, mental disorders, medicine, medicine.symptom, Psychiatry, Psychology, Borderline personality disorder
Abstract

Wagner S, Baskaya O, Anicker NJ, Dahmen N, Lieb K, Tadic A. The catechol o‐methyltransferase (COMT) val158met polymorphism modulates the association of serious life events (SLE) and impulsive aggression in female patients with borderline personality disorder (BPD). Objective: We analyzed i) the effects of serious life events (SLE) on impulsive aggression, and ii) modulating effects of the COMT Val158Met polymorphism on the association between SLEs and impulsive aggression in borderline personality disorder (BPD). Method: One hundred and twelve female BPD patients from Germany were included in this study. Impulsive aggression was assessed by the Buss‐Durkee‐Hostility Inventory (BDHI). Results: Childhood sexual abuse was associated with lower BDHI sum score (P = 0.003). In COMT Val158Val carriers, but not in Val/Met and Met/Met carriers, childhood sexual abuse and the cumulative number of SLEs were associated with lower BDHI sum scores (P Conclusion: This study analyzing a specific gene × environment interaction in female BPD patients suggests an association between SLEs and impulsive aggression, as well as a modulating effect of the COMT Val158Val genotype on the relation between SLEs and impulsive aggression.

Published
2009
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39. The 5-HTTLPR Polymorphism modulates the association of serious life events (SLE) and impulsivity in patients with Borderline Personality Disorder

Author

Stefanie Wagner, Klaus Lieb, Ömür Başkaya, Norbert Dahmen, and André Tadić

Subjects
Adult, Male, medicine.medical_specialty, Adolescent, Genotype, Impulsivity, Polymorphism, Single Nucleotide, Genetic determinism, Young Adult, Barratt Impulsiveness Scale, Borderline Personality Disorder, Polymorphism (computer science), mental disorders, medicine, Humans, Young adult, Child, Psychiatry, Borderline personality disorder, Crime Victims, Biological Psychiatry, Serotonin transporter, Serotonin Plasma Membrane Transport Proteins, biology, Middle Aged, medicine.disease, Psychiatry and Mental health, Sexual abuse, Child, Preschool, Impulsive Behavior, biology.protein, Regression Analysis, Female, medicine.symptom, Psychology
Abstract

Background Impulsivity belongs to the key features of Borderline Personality Disorder (BPD). It has been linked to altered serotoninergic neurotransmission and, genetically, to an over-representation of the short (S) allele of the serotonin transporter promoter-linked polymorphic region polymorphism (5-HTTLPR). On the other hand, serious life events (SLE) are of major importance in the development of BPD. However, the inter-relations between SLEs, impulsivity, and 5-HTTLPR are not understood. Method 159 BPD patients from Germany were included in this study. Impulsivity was assessed by the Barratt Impulsiveness Scale (BIS). We analysed (1) the effects of SLEs on impulsivity; and (2) modulating effects of the 5-HTTLPR polymorphism on the effects of SLEs on impulsivity. Results Regression analyses confirmed a decreasing effect of childhood sexual abuse, the cumulative SLE-related reactions and the impairment by SLEs on BIS sum score. Regarding BIS sum score, all SLEs except for rape were associated with a decrease of impulsivity in SS/SL carriers and an increase of BIS sum score in LL carriers. Conclusions This study analyzing a specific gene x environment interaction in BPD patients suggests an interaction between SLEs and the 5-HTTLPR S/L polymorphism in the development of impulsivity in BPD patients. Clinical and research implications are discussed.

Published
2009
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40. Polymorphisms in the BRCA1 and ABCB1 genes modulate menopausal hormone therapy associated breast cancer risk in postmenopausal women

Author

Rebecca Hein, Anne Spickenheuer, Silke Kropp, Thomas Dünnebier, Dieter Flesch-Janys, Roland Eils, Wilhelm Braendle, Thomas Brüning, Marc Zapatka, Margie Parthimos, Yon Ko, Christina Justenhoven, Norbert Dahmen, Benedikt Brors, Beate Pesch, Jenny Chang-Claude, Ute Hamann, Sascha Abbas, Hiltrud Brauch, Christian Baisch, and Lars Beckmann

Subjects
Oncology, Cancer Research, medicine.medical_specialty, Genotype, Hormone Replacement Therapy, medicine.medical_treatment, Genes, BRCA1, Breast Neoplasms, Polymorphism, Single Nucleotide, Breast cancer, Risk Factors, Germany, Internal medicine, Odds Ratio, Humans, Medicine, Gene, Alleles, Genetic Association Studies, Aged, Postmenopausal women, business.industry, Estrogen Replacement Therapy, Estrogens, Middle Aged, medicine.disease, Postmenopause, Haplotypes, Case-Control Studies, Female, Menopausal hormone therapy, Hormone therapy, Progestins, business
Abstract

Menopausal hormone therapy (HT) is associated with an increased breast cancer risk among postmenopausal women. In this study, we investigated genetic effect modification of HT associated breast cancer risk in 3,149 postmenopausal breast cancer patients and 5,489 controls from the two German population-based case-control studies MARIE and GENICA. Twenty-eight polymorphisms of 14 candidate genes including two drug and hormone transporter genes (ABCB1/MDR1 and SHBG), four genes involved in cell cycle regulation (BRCA1, P21/CDKN1A, STK15/AURKA and TP53), six cytokine genes (IGFBP3, IL6, TGFB1, TNF, LTA and IGF1), and two cytokine receptor genes (EGFR and ERBB2) were genotyped using validated methods. Conditional logistic regression was used to assess multiplicative statistical interaction between polymorphisms and duration of estrogen-progestagen therapy and estrogen monotherapy use with regard to breast cancer risk assuming log-additive and co-dominant modes of inheritance. Women homozygous for the major ABCB1_rs2214102_G allele were found to be at a significantly increased breast cancer risk associated with combined estrogen-progestagen therapy [odds ratio (OR) = 1.17, 95% confidence interval (CI) = 1.12-1.23, P (interaction) = 0.022]. Additionally, risk associated with estrogen monotherapy was modified by BRCA1_rs799917. We observed a trend with increasing minor T alleles leading to the highest risk in homozygous carriers of the minor allele [OR (95% CI) = 1.17 (0.98-1.39), 1.06 (0.98-1.14), and 1.02 (0.94-1.11) for homozygous minor, heterozygous, and homozygous major allele carriers, respectively; P (interaction) = 0.032]. Our results suggest that genetic variants in ABCB1 and BRCA1 may modify the effect of HT on postmenopausal breast cancer risk.

Published
2009
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41. Association of a variant in the muscarinic acetylcholine receptor 2 gene (CHRM2 ) with nicotine addiction

Author

H.-J. Möller, K. Mittelstraß, Norbert Dahmen, Heinz Erich Wichmann, Ina Giegling, Juergen Gallinat, Claudia Lamina, Heiko Müller, Hermann Brenner, Andreas Gal, Barbara Nitz, Annette M. Hartmann, Arian Mobascher, Georg Winterer, Lutz P. Breitling, Christoph Fehr, Thomas Illig, Elke Raum, Dan Rujescu, A Ruppert, Ch. Gieger, and Dietrich Rothenbacher

Subjects
Adult, Male, Nicotine, Candidate gene, Adolescent, media_common.quotation_subject, Single-nucleotide polymorphism, Biology, Bioinformatics, Cellular and Molecular Neuroscience, Muscarinic acetylcholine receptor, medicine, Humans, SNP, Genetic Predisposition to Disease, Allele, Alleles, Genetics (clinical), Aged, media_common, Aged, 80 and over, Genetics, Receptor, Muscarinic M2, Addiction, Smoking, Genetic Variation, Tobacco Use Disorder, Odds ratio, Middle Aged, Psychiatry and Mental health, Female, medicine.drug
Abstract

Genetic factors contribute to the overall risk of developing nicotine addiction, which is the major cause of preventable deaths in western countries. However, knowledge regarding specific polymorphisms influencing smoking phenotypes remains scarce. In the present study we provide evidence that a common single nucleotide polymorphism (SNP) in the 5′ untranslated region of CHRM2, the gene coding for the muscarinic acetylcholine receptor 2 is associated with nicotine addiction. CHRM2 was defined as a candidate gene for nicotine addiction based on previous evidence that linked variations in CHRM2 to alcohol and drug dependence. A total of more than 5,500 subjects representative of the German population were genotyped and assessed regarding their smoking habits. The impact of three SNPs in CHRM2 on smoking behavior/nicotine addiction was investigated using logistic regression models or a quasi-Poisson regression model, respectively. We found the T allele of SNP rs324650 to be associated with an increased risk of smoking/nicotine dependence according to three different models, the recessive models of regular or heavy smokers vs. never-smokers (odds ratio 1.17 in both analyses) and according to the Fagerstrom index of nicotine addiction. In the analysis stratified by gender this association was only found in females. Our data provide further evidence that variations in CHRM2 may be associated with the genetic risk of addiction in general or with certain personality traits that predispose to the development of addiction. Alternatively, variations in CHRM2 could modulate presynaptic auto-regulation in cholinergic systems and may thereby affect an individual's response to nicotine more specifically. © 2009 Wiley-Liss, Inc.

Published
2009
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42. Interaction between gene variants of the serotonin transporter promoter region (5-HTTLPR) and catecholO-methyltransferase (COMT) in borderline personality disorder

Author

Ömür Başkaya, Robert von Cube, Norbert Dahmen, Anja Victor, Ioanna Kouti, Julia Hoch, Klaus Lieb, André Tadić, Wolfgang Höppner, and Nina J. Anicker

Subjects
Adult, Male, medicine.medical_specialty, Single-nucleotide polymorphism, Catechol O-Methyltransferase, Polymorphism, Single Nucleotide, behavioral disciplines and activities, Cellular and Molecular Neuroscience, Gene Frequency, Gene interaction, Borderline Personality Disorder, Internal medicine, mental disorders, Genotype, medicine, Humans, Allele, Promoter Regions, Genetic, Borderline personality disorder, Alleles, Genetics (clinical), Serotonin transporter, Serotonin Plasma Membrane Transport Proteins, Genetics, Catechol-O-methyl transferase, biology, business.industry, Middle Aged, medicine.disease, Psychiatry and Mental health, Logistic Models, Endocrinology, 5-HTTLPR, biology.protein, Female, business
Abstract

Borderline personality disorder (BPD) is characterized by a heterogeneous symptomatology with instability in impulse control, interpersonal relationships and self-image. BPD patients display repeated self-injury, chronic suicidal tendencies and emotional dysregulation, mainly dysregulation of negative affect. In its etiology, genetic and environmental factors have been suggested. Recently, an investigation in male healthy volunteers found gene–gene effects of the catechol-O-methyl-transferase (COMT) low-activity (Met158) and the low-expression allele of the deletion/insertion (short/long or S/L, respectively) polymorphism in the serotonin transporter-linked promoter region (5-HTTLPR) on the central processing of aversive stimuli. The purpose of the present study was to test for association between BPD and the COMT Val158Met single nucleotide polymorphism (SNP), the 5-HTTLPR S/L variant and the interaction of these two gene variants. One hundred sixty one well-defined Caucasian BPD patients and 156 healthy controls were recruited from central Germany. In BPD patients, the genotype COMT Met158Met was over-represented compared to healthy controls (P = 0.0085; adjusted P = 0.034). We observed no differences in 5-HTTLPR genotypes between BPD and controls (P = 0.286). Additionally, the COMT Met158Met genotype was significantly over-represented in BPD patients carrying at least one 5-HTTLPR S allele (P = 0.0007; adjusted P = 0.028). Logistic regression analysis confirmed an interaction of the COMT Met158 and the 5-HTTLPR S allele (P = 0.001). These data suggest an involvement of altered dopaminergic and/or noradrenergic neurotransmission as well as an interactive effect of COMT and 5-HTTLPR gene variants in the etiology of BPD, and underline the usefulness of analyses of gene–gene effects in diseases of complex inheritance with multiple genes involved. © 2008 Wiley-Liss, Inc.

Published
2009
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43. Blood laboratory findings in patients suffering from self-perceived electromagnetic hypersensitivity (EHS)

Author

Alice Engel, David Ghezel-Ahmadi, and Norbert Dahmen

Subjects
Adult, Male, medicine.medical_specialty, Physiology, Biophysics, Thyrotropin, Aspartate transaminase, Hematocrit, Electromagnetic hypersensitivity, chemistry.chemical_compound, Electromagnetic Fields, Internal medicine, Hypersensitivity, medicine, Humans, Radiology, Nuclear Medicine and imaging, In patient, Aspartate Aminotransferases, Aged, Inflammation, Creatinine, biology, medicine.diagnostic_test, business.industry, Liver Diseases, Alanine Transaminase, Anemia, General Medicine, Middle Aged, Thyroid Diseases, Pathophysiology, C-Reactive Protein, Endocrinology, chemistry, Alanine transaminase, biology.protein, Female, Perception, medicine.symptom, business, Hormone
Abstract

Risks from electromagnetic devices are of considerable concern. Electrohypersensitive (EHS) persons attribute a variety of rather unspecific symptoms to exposure to electromagnetic fields. The pathophysiology of EHS is unknown and therapy remains a challenge. We hypothesized that some electrosensitive individuals are suffering from common somatic health problems. Toward this end we analysed clinical laboratory parameters including thyroid-stimulating hormone (TSH), alanine transaminase (ALT), aspartate transaminase (AST), creatinine, hemoglobine, hematocrit and c-reactive protein (CRP) in subjects suffering from EHS and in controls that are routinely used in clinical medicine to identify or screen for common somatic disorders. One hundred thirty-two patients (n = 42 males and n = 90 females) and 101 controls (n = 34 males and n = 67 females) were recruited. Our results identified laboratory signs of thyroid dysfunction, liver dysfunction and chronic inflammatory processes in small but remarkable fractions of EHS sufferers as potential sources of symptoms that merit further investigation in future studies. In the cases of TSH and ALT/AST there were significant differences between cases and controls. The hypotheses of anaemia or kidney dysfunction playing a major role in EHS could be unambiguously refuted. Clinically it is recommended to check for signs of treatable somatic conditions when caring for individuals suffering from self-proclaimed EHS.

Published
2009
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44. Development and Validation of a High-Throughput Screening Method for Two Polymorphisms in the Serotonin Transporter Gene

Author

Alexander Weise, Mathias Max Weber, Annette Wunsch, Norbert Dahmen, Moritz Eidens, Thomas Forst, Andreas Pfützner, and Stefan Prause

Subjects
Adult, Male, Population, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Polymorphism (computer science), Genetics, Humans, Genetic Predisposition to Disease, Allele, education, Allele frequency, Alleles, Serotonin transporter, Serotonin Plasma Membrane Transport Proteins, Pharmacology, education.field_of_study, General Medicine, Middle Aged, biology.protein, Molecular Medicine, Population study, Female, Restriction fragment length polymorphism
Abstract

Background and Aim: The human serotonin (5-hydroxytryptamine) transporter, encoded by the SLC6A4 gene on chromosome 17q11.1–q12, is the cellular reuptake site for serotonin and a site of action for several drugs with central nervous system effects, including both therapeutic agents (e.g. antidepressants) and drugs of abuse (e.g. cocaine). It is known that the serotonin transporter plays an important role in the metabolic cycle of a broad range of antidepressants, antipsychotics, anxiolytics, antiemetics, and antimigraine drugs. The identification and characterization of variations that increase the response to common medications is a hallenging and increasingly important task with regard to prediction of drug response. Therefore, the aim of this study was to establish a high-throughput single nucleotide polymorphism (SNP) screening method for two polymorphisms in the serotonin transporter gene, focusing on the SLC6A4 variations rs140701 and rs2066713. Methods: We developed a classical restriction fragment length polymorphism (RFLP) PCR protocol as a reference, followed by a new protocol established for the LightCycler® real-time PCR method. To validate the method, the allele frequencies in 169 individuals (112 women, 57 men) were determined and compared with published data. The population was divided into two groups: one group comprised 87 individuals with various mental disorders and the other consisted of 82 healthy persons. Results: No difference was found in the prevalence of the two SNPs between the two populations. Subsequently, the determined allele frequencies were compared with previously published data. We found that 68% of the whole study population (groups I and II) carried a mutated allele of the rs140701 variation. With regard to the rs2066713 polymorphism, we found an allele frequency of 61% in the population. Both results are consistent with published data. Conclusion: The developed protocol for RT-PCR analysis of both variations turned out to be reliable and economical, and thus suitable for routine laboratory use.

Published
2009
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45. Low novelty seeking and high self directedness scores in alcohol-dependent patients without comorbid psychiatric disorders homozygous for the A10 allele of the dopamine transporter gene

Author

Arnim Quante, Christoph Klawe, Francesca Regen, Peter Singer, Armin Szegedi, Ion Anghelescu, Norbert Dahmen, Christoph Hiemke, and Christoph Fehr

Subjects
Adult, Male, medicine.medical_specialty, Genotype, Minisatellite Repeats, Self-directedness, medicine, Humans, Big Five personality traits, Psychiatry, Alleles, Biological Psychiatry, Psychiatric Status Rating Scales, Dopamine Plasma Membrane Transport Proteins, Polymorphism, Genetic, Homozygote, Novelty seeking, Conscientiousness, medicine.disease, Neuroticism, Alcoholism, Psychiatry and Mental health, Reward dependence, Case-Control Studies, Personal Autonomy, Exploratory Behavior, Harm avoidance, Female, Temperament and Character Inventory, Psychology
Abstract

The gene for the human dopamine transporter DAT1 displays several polymorphisms, including a 40-bp variable number of tandem repeats (VNTR) ranging from 3 to 13 copies in the 3'-untranslated region (UTR) of the gene. Some hints for an association of certain VNTR with psychiatric disorders, behavioural problems and temperament traits have been found. This study explored possible associations between the most frequent DAT1 polymorphism, namely the A10 VNTR, and personality traits as measured by the Temperament and Character Inventory (TCI) and the NEO Five Factor Inventory (NEO-FFI) in alcohol-dependent patients (ADP). One hundred and forty-four ADP and 144 age-, educational level- and sex-matched controls (CO) were genotyped and interviewed with the TCI and NEO-FFI. ADP showed higher neuroticism, lower extraversion, lower openness, lower agreeableness and lower conscientiousness than CO on the NEO-FFI and higher scores in harm avoidance, reward dependence and self transcendence and lower scores in self directedness and cooperativeness on the TCI than controls. There were no genetic links regarding those personality traits, the diagnosis of alcohol dependence and the VNTR. Only in a subgroup of ADP, those without psychiatric co-diagnoses and homozygous for A10, significantly lower scores in novelty seeking and higher scores in self directedness than in all the other ADP and CO could be detected. Summarizing, the 40-bp VNTR did not help to differentiate between ADP and CO, but might contribute to some personality dimensions in certain ADP subgroups.

Published
2009
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46. Association analysis of SCN9A gene variants with borderline personality disorder

Author

Norbert Dahmen, Anja Victor, Ömür Başkaya, Wolfgang Höppner, Klaus Lieb, and André Tadić

Subjects
Adult, Genetic Markers, Male, Oncology, Candidate gene, medicine.medical_specialty, Population, Single-nucleotide polymorphism, Impulsivity, Polymorphism, Single Nucleotide, behavioral disciplines and activities, Borderline Personality Disorder, Internal medicine, mental disorders, medicine, Humans, Dissociative disorders, Sex Distribution, education, Borderline personality disorder, Biological Psychiatry, Genetic association, Psychiatric Status Rating Scales, Genetics, education.field_of_study, medicine.disease, Psychiatry and Mental health, Haplotypes, Case-Control Studies, Female, SCN9A Gene, medicine.symptom, Psychology
Abstract

Borderline personality disorder (BPD) is a serious psychiatric disorder affecting about 1-2% of the general population. Key features of BPD are emotional instability, strong impulsivity, repeated self-injurious behavior (SIB) and dissociation. In the etiology of BPD and its predominant symptoms, genetic factors have been suggested. The voltage-gated sodium channel Nav1.7 is expressed in sensory neurons and in the hippocampus, a key region of the limbic system probably dysfunctional in BPD and dissociative disorders. The alpha-subunit of Nav1.7 is encoded by the SCN9A gene on chromosome 2 and variations of SCN9A can lead to complete inability to sense pain. The aim of the present study was to test for associations between SCN9A gene variants and BPD as well as BPD-related phenotypes. We genotyped ten tagging single nucleotide polymorphisms (SNPs) within the SCN9A gene in 161 well-defined Caucasian BPD patients and 156 healthy controls. We found no globally significant association of SCN9A markers with BPD at level 5%. However, in the female and in the male subsample, different SCN9A markers and individual haplotypes showed uncorrected p-values

Published
2008
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47. Psychiatrische Patienten in der Notaufnahme

Author

S. Reuter, Norbert Dahmen, N. Gerlach, Peter Tonn, and F.-G. Pajonk

Subjects
Gynecology, medicine.medical_specialty, business.industry, Psychiatric emergencies, Emergency Medicine, medicine, business
Abstract

Psychiatrische Storungen in einer zentralen Notaufnahme (ZNA) sind keine Seltenheit. Bisherige Untersuchungen legen nahe, dass der uberwiegende Anteil dieser Storungen nicht erkannt und nicht behandelt wird. Zur Verbesserung der diagnostischen Qualitat konnen die meist psychiatrisch unerfahrenen Arzte auf kurze, aussagekraftige und valide Screeninginstrumente zuruckgreifen. Die Therapie psychiatrischer Storungsbilder in der ZNA sollte sich als syndromorientierte Krisenintervention verstehen, die bei gegebener Notwendigkeit auch eine langerfristige Behandlung bahnen oder initiieren kann. Dabei spielt neben psychotherapeutischen Strategien die Pharmakotherapie eine wichtige Rolle. Wir machen Vorschlage fur den differenzierten Einsatz von Psychopharmaka in der ZNA. Aufgrund der vorliegenden Daten erscheint eine enge Anbindung eines Psychiaters an eine ZNA sinnvoll.

Published
2008
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48. Prevalence of eating disorders and eating attacks in narcolepsy

Author

Alice Engel, Julia Becht, Peter Tonn, Norbert Dahmen, and Monika Thommes

Subjects
medicine.medical_specialty, Neuropsychiatric Disease and Treatment, narcolepsy, Neurosciences. Biological psychiatry. Neuropsychiatry, Anorexia, Anorexia nervosa, eating attack, Binge-eating disorder, mental disorders, Medicine, Psychiatry, RC346-429, Biological Psychiatry, Original Research, business.industry, Bulimia nervosa, digestive, oral, and skin physiology, medicine.disease, Obesity, Psychiatry and Mental health, Eating disorders, bulimia, anorexia, eating disorder, Anorectic, SIAB, Neurology. Diseases of the nervous system, medicine.symptom, business, Narcolepsy, RC321-571
Abstract

Norbert Dahmen, Julia Becht, Alice Engel, Monika Thommes, Peter TonnPsychiatry Department, University of Mainz, GermanyAbstract: Narcoleptic patients suffer frequently from obesity and type II diabetes. Most patients show a deficit in the energy balance regulating orexinergic system. Nevertheless, it is not known, why narcoleptic patients tend to be obese. We examined 116 narcoleptic patients and 80 controls with the structured interview for anorectic and bulimic eating disorders (SIAB) to test the hypothesis that typical or atypical eating attacks or eating disorders may be more frequent in narcoleptic patients. No difference in the current prevalence of eating disorders bulimia nervosa, binge eating disorder, or anorexia nervosa was found, nor was the frequency of eating attacks higher in the narcolepsy group. We conclude that present eating disorders and eating attacks as defined in DSM IV are not the reason for the observed differences in body composition. Additional factors, such as basal metabolic rates and lifestyle factors need to be considered.Keywords: narcolepsy, eating disorder, SIAB, bulimia, anorexia, eating attack

Published
2008

49. Association of Common Polymorphisms in the Nicotinic Acetylcholine Receptor Alpha4 Subunit Gene with an Electrophysiological Endophenotype in a Large Population-Based Sample

Author

Gerd Gründer, Michael Wagner, Norbert Dahmen, Falk Kiefer, Peter Nürnberg, Johannes Kornhuber, Amalia Diaz-Lacava, Arian Mobascher, Holger Thiele, Michael Steffens, Juergen Gallinat, Mohammad R. Toliat, Georg Winterer, Norbert Thürauf, Thomas Becker, Dmitriy Drichel, Thomas F. Wienker, and Ortrud K. Steinlein

Subjects
Male, 0301 basic medicine, Nicotinic Acetylcholine Receptors, Physiology, Event-Related Potentials, lcsh:Medicine, Receptors, Nicotinic, Electroencephalography, 600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit, Biochemistry, Exon, Cognition, Mathematical and Statistical Techniques, 0302 clinical medicine, Medizinische Fakultät, Germany, Medicine and Health Sciences, lcsh:Science, Cerebral Cortex, Clinical Neurophysiology, Genetics, Brain Mapping, N100, education.field_of_study, Multidisciplinary, medicine.diagnostic_test, Smoking, Brain, Tobacco Use Disorder, Temporal Lobe, Frontal Lobe, Electrophysiology, Nicotinic acetylcholine receptor, Bioassays and Physiological Analysis, Brain Electrophysiology, Physical Sciences, Regression Analysis, Female, Anatomy, Function and Dysfunction of the Nervous System, Statistics (Mathematics), Research Article, Signal Transduction, Adult, Transmembrane Receptors, Imaging Techniques, Endophenotypes, Cognitive Neuroscience, Population, Neurophysiology, Neuroimaging, Single-nucleotide polymorphism, Linear Regression Analysis, Biology, Research and Analysis Methods, Polymorphism, Single Nucleotide, 03 medical and health sciences, Diagnostic Medicine, Event-related potential, Reaction Time, medicine, Humans, ddc:610, Statistical Methods, education, Electrophysiological Techniques, lcsh:R, Biology and Life Sciences, Proteins, Cell Biology, Electrophysiological Phenomena, 030104 developmental biology, Acetylcholine Receptors, Endophenotype, Cognitive Science, lcsh:Q, Mathematics, 030217 neurology & neurosurgery, Neuroscience
Abstract

PLoS one 11(4), e0152984 (2016). doi:10.1371/journal.pone.0152984, Published by PLoS, Lawrence, Kan.

Published
2016
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50. Glutathione-S-transferase polymorphism, metallothionein expression, and mercury levels among students in Austria

Author

Claudia Gundacker, Martin Gencik, Peter Jagiello, Karl J. Wittmann, Günter Komarnicki, Norbert Dahmen, and Alexandra Gencikova

Subjects
Male, Food Chain, Environmental Engineering, Gene Expression, chemistry.chemical_element, Food Contamination, Biology, Gene expression, Genotype, Animals, Humans, Environmental Chemistry, Metallothionein, Waste Management and Disposal, Gene, Genotyping, Glutathione Transferase, Whole blood, Genetics, Polymorphism, Genetic, Fishes, Epistasis, Genetic, Feeding Behavior, Mercury, Pollution, Molecular biology, Mercury (element), Cross-Sectional Studies, Glutathione S-transferase, chemistry, Austria, Inactivation, Metabolic, biology.protein, Female, Gene Deletion, Hair
Abstract

Background: Detoxification is an essential process in all living organisms. Humans accumulate heavy metals primarily as a result of lifestyle and environmental contamination. However, not all humans experience the estimated individual exposure. This suggests the presence of genetic regulatory mechanisms. Objective: In order to identify genetic factors underlying the inter-individual variance in detoxification capacity for the heavy metal mercury, 192 students were investigated. Wefocused on the relationshipbetween polymorphisms inglutathione-S-transferase(GST) genes and mercury concentrations in blood, urine, and hair. The correlation between blood mercury levels, GSTT1 and GSTM1 polymorphism, and gene expression of certain metallothionein subgroups (MT1, MT3) was evaluated in a further group of students (N=30). Methods: Mercury levels in acid digested samples were measured by cold vapor AAS. Genotyping of the GSTT1 and GSTM1-gene deletion polymorphism was performed by means of PCR. Gene expression of several MT genes was analyzed in lymphocytes from fresh peripheral blood by semiquantitative RT-PCR. Results: The following was noted: a) hair mercury concentrations are significantly increased in persons with the double deleted genotype (GSTT1−/− and GSTM1−/−) as compared to persons with the intact genotype, and b) MT1X expression is higher in persons with the intact genotype (GSTT1+/+ and GSTM1+/+). Conclusions: We conclude that the epistatic effect of the GSTT1 and the GSTM1 deletion polymorphism is a risk factor for increased susceptibility to mercury exposure. The relationship between MT gene expression and GST gene polymorphisms needs further investigation. If MT expression depends on GST polymorphisms it would have important implications on the overall metal detoxification capability of the human organism. © 2007 Elsevier B.V. All rights reserved.

Published
2007
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