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Identification and characterization of novel associations in the CASP8/ALS2CR12 region on chromosome 2 with breast cancer risk.
Wei-Yu Lin, Nicola J Camp, Maya Ghoussaini, Jonathan Beesley, Kyriaki Michailidou, John L Hopper, Carmel Apicella, Melissa C Southey, Jennifer Stone, Marjanka K Schmidt, Annegien Broeks, Laura J Van't Veer, Emiel J Th Rutgers, Kenneth Muir, Artitaya Lophatananon, Sarah Stewart-Brown, Pornthep Siriwanarangsan, Peter A Fasching, Lothar Haeberle, Arif B Ekici, Matthias W Beckmann, Julian Peto, Isabel Dos-Santos-Silva, Olivia Fletcher, Nichola Johnson, Manjeet K Bolla, Qin Wang, Joe Dennis, Elinor J Sawyer, Timothy Cheng, Ian Tomlinson, Michael J Kerin, Nicola Miller, Frederik Marme, Harald M Surowy, Barbara Burwinkel, Pascal Guénel, Thérèse Truong, Florence Menegaux, Claire Mulot, Stig E Bojesen, Børge G Nordestgaard, Sune F Nielsen, Henrik Flyger, Javier Benitez, M Pilar Zamora, José Ignacio Arias Perez, Primitiva Menéndez, Anna González-Neira, Guillermo Pita, M Rosario Alonso, Nuria Alvarez, Daniel Herrero, Hoda Anton-Culver, Hermann Brenner, Aida Karina Dieffenbach, Volker Arndt, Christa Stegmaier, Alfons Meindl, Peter Lichtner, Rita K Schmutzler, Bertram Müller-Myhsok, Hiltrud Brauch, Thomas Brüning, Yon-Dschun Ko, , Daniel C Tessier, Daniel Vincent, Francois Bacot, Heli Nevanlinna, Kristiina Aittomäki, Carl Blomqvist, Sofia Khan, Keitaro Matsuo, Hidemi Ito, Hiroji Iwata, Akiyo Horio, Natalia V Bogdanova, Natalia N Antonenkova, Thilo Dörk, Annika Lindblom, Sara Margolin, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Jaana M Hartikainen, Anna H Wu, Chiu-Chen Tseng, David Van Den Berg, Daniel O Stram, Patrick Neven, Els Wauters, Hans Wildiers, Diether Lambrechts, Jenny Chang-Claude, Anja Rudolph, Petra Seibold, Dieter Flesch-Janys, Paolo Radice, Paolo Peterlongo, Siranoush Manoukian, Bernardo Bonanni, Fergus J Couch, Xianshu Wang, Celine Vachon, Kristen Purrington, Graham G Giles, Roger L Milne, Catriona McLean, Christopher A Haiman, Brian E Henderson, Fredrick Schumacher, Loic Le Marchand, Jacques Simard, Mark S Goldberg, France Labrèche, Martine Dumont, Soo Hwang Teo, Cheng Har Yip, Norhashimah Hassan, Eranga Nishanthie Vithana, Vessela Kristensen, Wei Zheng, Sandra Deming-Halverson, Martha J Shrubsole, Jirong Long, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Saila Kauppila, Irene L Andrulis, Julia A Knight, Gord Glendon, Sandrine Tchatchou, Peter Devilee, Robert A E M Tollenaar, Caroline Seynaeve, Christi J van Asperen, Montserrat Garcia-Closas, Jonine Figueroa, Jolanta Lissowska, Louise Brinton, Kamila Czene, Hatef Darabi, Mikael Eriksson, Judith S Brand, Maartje J Hooning, Antoinette Hollestelle, Ans M W van den Ouweland, Agnes Jager, Jingmei Li, Jianjun Liu, Keith Humphreys, Xiao-Ou Shu, Wei Lu, Yu-Tang Gao, Hui Cai, Simon S Cross, Malcolm W R Reed, William Blot, Lisa B Signorello, Qiuyin Cai, Paul D P Pharoah, Barbara Perkins, Mitul Shah, Fiona M Blows, Daehee Kang, Keun-Young Yoo, Dong-Young Noh, Mikael Hartman, Hui Miao, Kee Seng Chia, Thomas Choudary Putti, Ute Hamann, Craig Luccarini, Caroline Baynes, Shahana Ahmed, Mel Maranian, Catherine S Healey, Anna Jakubowska, Jan Lubiński, Katarzyna Jaworska-Bieniek, Katarzyna Durda, Suleeporn Sangrajrang, Valerie Gaborieau, Paul Brennan, James McKay, Susan Slager, Amanda E Toland, Drakoulis Yannoukakos, Chen-Yang Shen, Chia-Ni Hsiung, Pei-Ei Wu, Shian-Ling Ding, Alan Ashworth, Michael Jones, Nick Orr, Anthony J Swerdlow, Helen Tsimiklis, Enes Makalic, Daniel F Schmidt, Quang M Bui, Stephen J Chanock, David J Hunter, Rebecca Hein, Norbert Dahmen, Lars Beckmann, Kirsimari Aaltonen, Taru A Muranen, Tuomas Heikkinen, Astrid Irwanto, Nazneen Rahman, Clare A Turnbull, Quinten Waisfisz, Hanne E J Meijers-Heijboer, Muriel A Adank, Rob B van der Luijt, Per Hall, Georgia Chenevix-Trench, Alison Dunning, Douglas F Easton, Angela Cox.
Hum. Mol. Genet.
PUBLISHED: 08-28-2014
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Previous studies have suggested that polymorphisms in CASP8 on chromosome 2 are associated with breast cancer risk. To clarify the role of CASP8 in breast cancer susceptibility, we carried out dense genotyping of this region in the Breast Cancer Association Consortium (BCAC). Single-nucleotide polymorphisms (SNPs) spanning a 1 Mb region around CASP8 were genotyped in 46 450 breast cancer cases and 42 600 controls of European origin from 41 studies participating in the BCAC as part of a custom genotyping array experiment (iCOGS). Missing genotypes and SNPs were imputed and, after quality exclusions, 501 typed and 1232 imputed SNPs were included in logistic regression models adjusting for study and ancestry principal components. The SNPs retained in the final model were investigated further in data from nine genome-wide association studies (GWAS) comprising in total 10 052 case and 12 575 control subjects. The most significant association signal observed in European subjects was for the imputed intronic SNP rs1830298 in ALS2CR12 (telomeric to CASP8), with per allele odds ratio and 95% confidence interval [OR (95% confidence interval, CI)] for the minor allele of 1.05 (1.03-1.07), P = 1 × 10(-5). Three additional independent signals from intronic SNPs were identified, in CASP8 (rs36043647), ALS2CR11 (rs59278883) and CFLAR (rs7558475). The association with rs1830298 was replicated in the imputed results from the combined GWAS (P = 3 × 10(-6)), yielding a combined OR (95% CI) of 1.06 (1.04-1.08), P = 1 × 10(-9). Analyses of gene expression associations in peripheral blood and normal breast tissue indicate that CASP8 might be the target gene, suggesting a mechanism involving apoptosis.
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Association between dopa decarboxylase gene variants and borderline personality disorder.
Psychiatry Res
PUBLISHED: 04-08-2014
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Despite heritability estimates of 37-69%, research has identified few genetic risk variants for borderline personality disorder (BPD). The present collaborative candidate gene study of 987 BPD cases and 1110 healthy controls found an association between BPD and single nucleotide polymorphism rs12718541 in the dopa decarboxylase gene.
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XRCC5 as a Risk Gene for Alcohol Dependence: Evidence from a Genome-Wide Gene-Set-Based Analysis and Follow-up Studies in Drosophila and Humans.
Neuropsychopharmacology
PUBLISHED: 02-05-2014
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Genetic factors have as large role as environmental factors in the etiology of alcohol dependence (AD). Although genome-wide association studies (GWAS) enable systematic searches for loci not hitherto implicated in the etiology of AD, many true findings may be missed owing to correction for multiple testing. The aim of the present study was to circumvent this limitation by searching for biological system-level differences, and then following up these findings in humans and animals. Gene-set-based analysis of GWAS data from 1333 cases and 2168 controls identified 19 significantly associated gene-sets, of which 5 could be replicated in an independent sample. Clustered in these gene-sets were novel and previously identified susceptibility genes. The most frequently present gene, ie in 6 out of 19 gene-sets, was X-ray repair complementing defective repair in Chinese hamster cells 5 (XRCC5). Previous human and animal studies have implicated XRCC5 in alcohol sensitivity. This phenotype is inversely correlated with the development of AD, presumably as more alcohol is required to achieve the desired effects. In the present study, the functional role of XRCC5 in AD was further validated in animals and humans. Drosophila mutants with reduced function of Ku80-the homolog of mammalian XRCC5-due to RNAi silencing showed reduced sensitivity to ethanol. In humans with free access to intravenous ethanol self-administration in the laboratory, the maximum achieved blood alcohol concentration was influenced in an allele-dose-dependent manner by genetic variation in XRCC5. In conclusion, our convergent approach identified new candidates and generated independent evidence for the involvement of XRCC5 in alcohol dependence.Neuropsychopharmacology advance online publication, 13 August 2014; doi:10.1038/npp.2014.178.
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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.
Cancer Epidemiol. Biomarkers Prev.
PUBLISHED: 02-03-2014
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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.
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Functional polymorphism in the neuropeptide Y gene promoter (rs16147) is associated with serum leptin levels and waist-hip ratio in women.
Ann. Nutr. Metab.
PUBLISHED: 05-04-2013
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The neuropeptide-Y (NP-Y) gene is a strong candidate gene in the pathophysiology of obesity-linked behavior, and several single-nucleotide polymorphisms of NP-Y have already been linked to body weight and appetite. However, the results from current studies remain inconclusive. The aim of the present study was to test whether a certain functional genetic variant (SNP rs16147) in the NP-Y promoter gene is associated with serum leptin levels and body fat distribution.
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A genomewide association study of smoking relapse in four European population-based samples.
Psychiatr. Genet.
PUBLISHED: 04-02-2013
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Genomewide association studies (GWAS) have identified clear evidence of genetic markers for nicotine dependence. Other smoking phenotypes have been tested, but the results are less consistent. The tendency to relapse versus the ability to maintain long-term abstinence has received little attention in genetic studies; thus, our aim was to provide a better biological understanding of this phenotype through the identification of genetic loci associated with smoking relapse.
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The effect of nicotine on sensorimotor gating is modulated by a CHRNA3 polymorphism.
Psychopharmacology (Berl.)
PUBLISHED: 03-20-2013
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Prepulse inhibition (PPI) of the acoustic startle response, a measure of sensorimotor gating, can be enhanced by nicotine. Moreover, the TT genotype of the nicotinic acetylcholine receptor (nAChR) ?3-subunit (CHRNA3) rs1051730 polymorphism has previously been associated with diminished PPI and nicotine dependence.
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Nicotine enhances antisaccade performance in schizophrenia patients and healthy controls.
Int. J. Neuropsychopharmacol.
PUBLISHED: 02-11-2013
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Nicotine has been proposed to be a cognitive enhancer, particularly in schizophrenia patients. So far, the published studies of nicotine effects on antisaccade performance in schizophrenia patients only tested participants who were deprived smokers. Thus, we aimed to test both smoking and non-smoking patients as well as healthy controls in order to extend previous findings. Moreover, we employed a paradigm using standard and delayed trials. We hypothesized that, if nicotine is a genuine cognitive enhancer, its administration would improve antisaccade performance both in smoking and non-smoking participants. A total of 22 patients with schizophrenia (12 smokers and 10 non-smokers) and 26 controls (14 smokers and 12 non-smokers) completed the study. The effects of a nicotine patch (14 mg for smokers, 7 mg for non-smokers) on antisaccade performance were tested in a randomized, double-blind, placebo-controlled, cross-over trial. Schizophrenia patients made significantly more antisaccade errors than controls (p = 0.03). Both patients and controls made fewer antisaccade errors in the delayed trials than in the standard trials (p < 0.0001). Nicotine significantly reduced antisaccade error rate in the standard trials, but not in the delayed trials (p = 0.02). Smoking status did not influence the nicotine effect on antisaccade error rate (p = 0.10) indicating an equal procognitive effect of nicotine in smokers and non-smokers. Overall the present findings indicate that beneficial effects of nicotine on antisaccade performance are not confined to smoking schizophrenia patients. Instead, the findings likely represent genuine nicotine-induced enhancement of cognitive performance.
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Association of VMAT2 gene polymorphisms with alcohol dependence.
J Neural Transm
PUBLISHED: 02-09-2013
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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.
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A genome-wide association study to identify genetic susceptibility loci that modify ductal and lobular postmenopausal breast cancer risk associated with menopausal hormone therapy use: a two-stage design with replication.
Breast Cancer Res. Treat.
PUBLISHED: 01-31-2013
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Menopausal hormone therapy (MHT) is associated with an elevated risk of breast cancer in postmenopausal women. To identify genetic loci that modify breast cancer risk related to MHT use in postmenopausal women, we conducted a two-stage genome-wide association study (GWAS) with replication. In stage I, we performed a case-only GWAS in 731 invasive breast cancer cases from the German case-control study Mammary Carcinoma Risk Factor Investigation (MARIE). The 1,200 single nucleotide polymorphisms (SNPs) showing the lowest P values for interaction with current MHT use (within 6 months prior to breast cancer diagnosis), were carried forward to stage II, involving pooled case-control analyses including additional MARIE subjects (1,375 cases, 1,974 controls) as well as 795 cases and 764 controls of a Swedish case-control study. A joint P value was calculated for a combined analysis of stages I and II. Replication of the most significant interaction of the combined stage I and II was performed using 5,795 cases and 5,390 controls from nine studies of the Breast Cancer Association Consortium (BCAC). The combined stage I and II yielded five SNPs on chromosomes 2, 7, and 18 with joint P values <6 × 10(-6) for effect modification of current MHT use. The most significant interaction was observed for rs6707272 (P = 3 × 10(-7)) on chromosome 2 but was not replicated in the BCAC studies (P = 0.21). The potentially modifying SNPs are in strong linkage disequilibrium with SNPs in TRIP12 and DNER on chromosome 2 and SETBP1 on chromosome 18, previously linked to carcinogenesis. However, none of the interaction effects reached genome-wide significance. The inability to replicate the top SNP × MHT interaction may be due to limited power of the replication phase. Our study, however, suggests that there are unlikely to be SNPs that interact strongly enough with MHT use to be clinically significant in European women.
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Large-scale genotyping identifies 41 new loci associated with breast cancer risk.
Kyriaki Michailidou, Per Hall, Anna González-Neira, Maya Ghoussaini, Joe Dennis, Roger L Milne, Marjanka K Schmidt, Jenny Chang-Claude, Stig E Bojesen, Manjeet K Bolla, Qin Wang, Ed Dicks, Andrew Lee, Clare Turnbull, Nazneen Rahman, , Olivia Fletcher, Julian Peto, Lorna Gibson, Isabel Dos Santos Silva, Heli Nevanlinna, Taru A Muranen, Kristiina Aittomäki, Carl Blomqvist, Kamila Czene, Astrid Irwanto, Jianjun Liu, Quinten Waisfisz, Hanne Meijers-Heijboer, Muriel Adank, Rob B van der Luijt, Rebecca Hein, Norbert Dahmen, Lars Beckman, Alfons Meindl, Rita K Schmutzler, Bertram Müller-Myhsok, Peter Lichtner, John L Hopper, Melissa C Southey, Enes Makalic, Daniel F Schmidt, André G Uitterlinden, Albert Hofman, David J Hunter, Stephen J Chanock, Daniel Vincent, Francois Bacot, Daniel C Tessier, Sander Canisius, Lodewyk F A Wessels, Christopher A Haiman, Mitul Shah, Robert Luben, Judith Brown, Craig Luccarini, Nils Schoof, Keith Humphreys, Jingmei Li, Børge G Nordestgaard, Sune F Nielsen, Henrik Flyger, Fergus J Couch, Xianshu Wang, Celine Vachon, Kristen N Stevens, Diether Lambrechts, Matthieu Moisse, Robert Paridaens, Marie-Rose Christiaens, Anja Rudolph, Stefan Nickels, Dieter Flesch-Janys, Nichola Johnson, Zoe Aitken, Kirsimari Aaltonen, Tuomas Heikkinen, Annegien Broeks, Laura J Van't Veer, C Ellen van der Schoot, Pascal Guénel, Thérèse Truong, Pierre Laurent-Puig, Florence Menegaux, Frederik Marme, Andreas Schneeweiss, Christof Sohn, Barbara Burwinkel, M Pilar Zamora, Jose Ignacio Arias Perez, Guillermo Pita, M Rosario Alonso, Angela Cox, Ian W Brock, Simon S Cross, Malcolm W R Reed, Elinor J Sawyer, Ian Tomlinson, Michael J Kerin, Nicola Miller, Brian E Henderson, Fredrick Schumacher, Loic Le Marchand, Irene L Andrulis, Julia A Knight, Gord Glendon, Anna Marie Mulligan, Annika Lindblom, Sara Margolin, Maartje J Hooning, Antoinette Hollestelle, Ans M W van den Ouweland, Agnes Jager, Quang M Bui, Jennifer Stone, Gillian S Dite, Carmel Apicella, Helen Tsimiklis, Graham G Giles, Gianluca Severi, Laura Baglietto, Peter A Fasching, Lothar Haeberle, Arif B Ekici, Matthias W Beckmann, Hermann Brenner, Heiko Muller, Volker Arndt, Christa Stegmaier, Anthony Swerdlow, Alan Ashworth, Nick Orr, Michael Jones, Jonine Figueroa, Jolanta Lissowska, Louise Brinton, Mark S Goldberg, France Labrèche, Martine Dumont, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Mervi Grip, Hiltrud Brauch, Ute Hamann, Thomas Brüning, Paolo Radice, Paolo Peterlongo, Siranoush Manoukian, Bernardo Bonanni, Peter Devilee, Rob A E M Tollenaar, Caroline Seynaeve, Christi J van Asperen, Anna Jakubowska, Jan Lubiński, Katarzyna Jaworska, Katarzyna Durda, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Jaana M Hartikainen, Natalia V Bogdanova, Natalia N Antonenkova, Thilo Dörk, Vessela N Kristensen, Hoda Anton-Culver, Susan Slager, Amanda E Toland, Stephen Edge, Florentia Fostira, Daehee Kang, Keun-Young Yoo, Dong-Young Noh, Keitaro Matsuo, Hidemi Ito, Hiroji Iwata, Aiko Sueta, Anna H Wu, Chiu-Chen Tseng, David Van Den Berg, Daniel O Stram, Xiao-Ou Shu, Wei Lu, Yu-Tang Gao, Hui Cai, Soo Hwang Teo, Cheng Har Yip, Sze Yee Phuah, Belinda K Cornes, Mikael Hartman, Hui Miao, Wei Yen Lim, Jen-Hwei Sng, Kenneth Muir, Artitaya Lophatananon, Sarah Stewart-Brown, Pornthep Siriwanarangsan, Chen-Yang Shen, Chia-Ni Hsiung, Pei-Ei Wu, Shian-Ling Ding, Suleeporn Sangrajrang, Valerie Gaborieau, Paul Brennan, James McKay, William J Blot, Lisa B Signorello, Qiuyin Cai, Wei Zheng, Sandra Deming-Halverson, Martha Shrubsole, Jirong Long, Jacques Simard, Montse Garcia-Closas, Paul D P Pharoah, Georgia Chenevix-Trench, Alison M Dunning, Javier Benitez, Douglas F Easton.
Nat. Genet.
PUBLISHED: 01-30-2013
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Breast cancer is the most common cancer among women. Common variants at 27 loci have been identified as associated with susceptibility to breast cancer, and these account for ?9% of the familial risk of the disease. We report here a meta-analysis of 9 genome-wide association studies, including 10,052 breast cancer cases and 12,575 controls of European ancestry, from which we selected 29,807 SNPs for further genotyping. These SNPs were genotyped in 45,290 cases and 41,880 controls of European ancestry from 41 studies in the Breast Cancer Association Consortium (BCAC). The SNPs were genotyped as part of a collaborative genotyping experiment involving four consortia (Collaborative Oncological Gene-environment Study, COGS) and used a custom Illumina iSelect genotyping array, iCOGS, comprising more than 200,000 SNPs. We identified SNPs at 41 new breast cancer susceptibility loci at genome-wide significance (P < 5 × 10(-8)). Further analyses suggest that more than 1,000 additional loci are involved in breast cancer susceptibility.
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Genome-wide association studies identify four ER negative-specific breast cancer risk loci.
Montserrat Garcia-Closas, Fergus J Couch, Sara Lindstrom, Kyriaki Michailidou, Marjanka K Schmidt, Mark N Brook, Nick Orr, Suhn Kyong Rhie, Elio Riboli, Heather S Feigelson, Loic Le Marchand, Julie E Buring, Diana Eccles, Penelope Miron, Peter A Fasching, Hiltrud Brauch, Jenny Chang-Claude, Jane Carpenter, Andrew K Godwin, Heli Nevanlinna, Graham G Giles, Angela Cox, John L Hopper, Manjeet K Bolla, Qin Wang, Joe Dennis, Ed Dicks, Will J Howat, Nils Schoof, Stig E Bojesen, Diether Lambrechts, Annegien Broeks, Irene L Andrulis, Pascal Guénel, Barbara Burwinkel, Elinor J Sawyer, Antoinette Hollestelle, Olivia Fletcher, Robert Winqvist, Hermann Brenner, Arto Mannermaa, Ute Hamann, Alfons Meindl, Annika Lindblom, Wei Zheng, Peter Devillee, Mark S Goldberg, Jan Lubiński, Vessela Kristensen, Anthony Swerdlow, Hoda Anton-Culver, Thilo Dörk, Kenneth Muir, Keitaro Matsuo, Anna H Wu, Paolo Radice, Soo Hwang Teo, Xiao-Ou Shu, William Blot, Daehee Kang, Mikael Hartman, Suleeporn Sangrajrang, Chen-Yang Shen, Melissa C Southey, Daniel J Park, Fleur Hammet, Jennifer Stone, Laura J Van't Veer, Emiel J Rutgers, Artitaya Lophatananon, Sarah Stewart-Brown, Pornthep Siriwanarangsan, Julian Peto, Michael G Schrauder, Arif B Ekici, Matthias W Beckmann, Isabel Dos Santos Silva, Nichola Johnson, Helen Warren, Ian Tomlinson, Michael J Kerin, Nicola Miller, Federick Marme, Andreas Schneeweiss, Christof Sohn, Thérèse Truong, Pierre Laurent-Puig, Pierre Kerbrat, Børge G Nordestgaard, Sune F Nielsen, Henrik Flyger, Roger L Milne, Jose Ignacio Arias Perez, Primitiva Menéndez, Heiko Muller, Volker Arndt, Christa Stegmaier, Peter Lichtner, Magdalena Lochmann, Christina Justenhoven, Yon-Dschun Ko, , Taru A Muranen, Kristiina Aittomäki, Carl Blomqvist, Dario Greco, Tuomas Heikkinen, Hidemi Ito, Hiroji Iwata, Yasushi Yatabe, Natalia N Antonenkova, Sara Margolin, Vesa Kataja, Veli-Matti Kosma, Jaana M Hartikainen, Rosemary Balleine, Chiu-Chen Tseng, David Van Den Berg, Daniel O Stram, Patrick Neven, Anne-Sophie Dieudonné, Karin Leunen, Anja Rudolph, Stefan Nickels, Dieter Flesch-Janys, Paolo Peterlongo, Bernard Peissel, Loris Bernard, Janet E Olson, Xianshu Wang, Kristen Stevens, Gianluca Severi, Laura Baglietto, Catriona McLean, Gerhard A Coetzee, Ye Feng, Brian E Henderson, Fredrick Schumacher, Natalia V Bogdanova, France Labrèche, Martine Dumont, Cheng Har Yip, Nur Aishah Mohd Taib, Ching-Yu Cheng, Martha Shrubsole, Jirong Long, Katri Pylkäs, Arja Jukkola-Vuorinen, Saila Kauppila, Julia A Knight, Gord Glendon, Anna Marie Mulligan, Robertus A E M Tollenaar, Caroline M Seynaeve, Mieke Kriege, Maartje J Hooning, Ans M W van den Ouweland, Carolien H M van Deurzen, Wei Lu, Yu-Tang Gao, Hui Cai, Sabapathy P Balasubramanian, Simon S Cross, Malcolm W R Reed, Lisa Signorello, Qiuyin Cai, Mitul Shah, Hui Miao, Ching Wan Chan, Kee Seng Chia, Anna Jakubowska, Katarzyna Jaworska, Katarzyna Durda, Chia-Ni Hsiung, Pei-Ei Wu, Jyh-Cherng Yu, Alan Ashworth, Michael Jones, Daniel C Tessier, Anna González-Neira, Guillermo Pita, M Rosario Alonso, Daniel Vincent, Francois Bacot, Christine B Ambrosone, Elisa V Bandera, Esther M John, Gary K Chen, Jennifer J Hu, Jorge L Rodriguez-Gil, Leslie Bernstein, Michael F Press, Regina G Ziegler, Robert M Millikan, Sandra L Deming-Halverson, Sarah Nyante, Sue A Ingles, Quinten Waisfisz, Helen Tsimiklis, Enes Makalic, Daniel Schmidt, Minh Bui, Lorna Gibson, Bertram Müller-Myhsok, Rita K Schmutzler, Rebecca Hein, Norbert Dahmen, Lars Beckmann, Kirsimari Aaltonen, Kamila Czene, Astrid Irwanto, Jianjun Liu, Clare Turnbull, Nazneen Rahman, Hanne Meijers-Heijboer, André G Uitterlinden, Fernando Rivadeneira, Curtis Olswold, Susan Slager, Robert Pilarski, Foluso Ademuyiwa, Irene Konstantopoulou, Nicholas G Martin, Grant W Montgomery, Dennis J Slamon, Claudia Rauh, Michael P Lux, Sebastian M Jud, Thomas Brüning, Joellen Weaver, Priyanka Sharma, Harsh Pathak, Will Tapper, Sue Gerty, Lorraine Durcan, Dimitrios Trichopoulos, Rosario Tumino, Petra H Peeters, Rudolf Kaaks, Daniele Campa, Federico Canzian, Elisabete Weiderpass, Mattias Johansson, Kay-Tee Khaw, Ruth Travis, Francoise Clavel-Chapelon, Laurence N Kolonel, Constance Chen, Andy Beck, Susan E Hankinson, Christine D Berg, Robert N Hoover, Jolanta Lissowska, Jonine D Figueroa, Daniel I Chasman, Mia M Gaudet, W Ryan Diver, Walter C Willett, David J Hunter, Jacques Simard, Javier Benitez, Alison M Dunning, Mark E Sherman, Georgia Chenevix-Trench, Stephen J Chanock, Per Hall, Paul D P Pharoah, Celine Vachon, Douglas F Easton, Christopher A Haiman, Peter Kraft.
Nat. Genet.
PUBLISHED: 01-29-2013
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Estrogen receptor (ER)-negative tumors represent 20-30% of all breast cancers, with a higher proportion occurring in younger women and women of African ancestry. The etiology and clinical behavior of ER-negative tumors are different from those of tumors expressing ER (ER positive), including differences in genetic predisposition. To identify susceptibility loci specific to ER-negative disease, we combined in a meta-analysis 3 genome-wide association studies of 4,193 ER-negative breast cancer cases and 35,194 controls with a series of 40 follow-up studies (6,514 cases and 41,455 controls), genotyped using a custom Illumina array, iCOGS, developed by the Collaborative Oncological Gene-environment Study (COGS). SNPs at four loci, 1q32.1 (MDM4, P = 2.1 × 10(-12) and LGR6, P = 1.4 × 10(-8)), 2p24.1 (P = 4.6 × 10(-8)) and 16q12.2 (FTO, P = 4.0 × 10(-8)), were associated with ER-negative but not ER-positive breast cancer (P > 0.05). These findings provide further evidence for distinct etiological pathways associated with invasive ER-positive and ER-negative breast cancers.
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?CaMKII autophosphorylation controls the establishment of alcohol drinking behavior.
Neuropsychopharmacology
PUBLISHED: 01-22-2013
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The ?-Ca(2+)/calmodulin-dependent protein kinase II (?CaMKII) is a crucial enzyme controlling plasticity in the brain. The autophosphorylation of ?CaMKII works as a molecular memory for a transient calcium activation, thereby accelerating learning. We investigated the role of ?CaMKII autophosphorylation in the establishment of alcohol drinking as an addiction-related behavior in mice. We found that alcohol drinking was initially diminished in ?CaMKII autophosphorylation-deficient ?CaMKII(T286A) mice, but could be established at wild-type level after repeated withdrawals. The locomotor activating effects of a low-dose alcohol (2 g/kg) were absent in ?CaMKII(T286A) mice, whereas the sedating effects of high-dose (3.5 g/kg) were preserved after acute and subchronic administration. The in vivo microdialysis revealed that ?CaMKII(T286A) mice showed no dopamine (DA) response in the nucleus accumbens to acute or subchronic alcohol administration, but enhanced serotonin (5-HT) responses in the prefrontal cortex. The attenuated DA response in ?CaMKII(T286A) mice was in line with altered c-Fos activation in the ventral tegmental area after acute and subchronic alcohol administration. In order to compare findings in mice with the human condition, we tested 23 single-nucleotide polymorphisms (SNPs) in the CAMK2A gene for their association with alcohol dependence in a population of 1333 male patients with severe alcohol dependence and 939 controls. We found seven significant associations between CAMK2A SNPs and alcohol dependence, one of which in an autophosphorylation-related area of the gene. Together, our data suggest ?CaMKII autophosphorylation as a facilitating mechanism in the establishment of alcohol drinking behavior with changing the DA-5-HT balance as a putative mechanism.
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Lack of association of a functional catechol-O-methyltransferase gene polymorphism with risk of tobacco smoking: results from a multicenter case-control study.
Nicotine Tob. Res.
PUBLISHED: 01-03-2013
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The catechol-O-methyltransferase (COMT) modulates dopaminergic neurotransmission in the prefrontal cortex as well as in the mesolimbic reward system. Since the reward system mediates addictive behavior, the COMT gene is a strong candidate gene regarding the pathophysiology of tobacco dependence and smoking behavior. Because of rather conflicting results in previous studies, the purpose of the present study was to test for association between a functional genetic variant in the COMT gene (single nucleotide polymorphism [SNP] rs4680) and tobacco smoking behavior.
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Genome-wide significant association between alcohol dependence and a variant in the ADH gene cluster.
Addict Biol
PUBLISHED: 10-18-2011
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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.
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Dopamine-related genes and spontaneous smoking cessation in ever-heavy smokers.
Pharmacogenomics
PUBLISHED: 08-01-2011
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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.
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Investigation of insulin resistance in narcoleptic patients: dependent or independent of body mass index?
Neuropsychiatr Dis Treat
PUBLISHED: 06-08-2011
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Narcolepsy is a severe sleep-wake cycle disorder resulting in most cases from a lack of orexin, the energy balance-regulating hormone. Narcoleptic patients have been reported to suffer from an excess morbidity of Type 2 diabetes, even after correction for their often elevated body mass index.
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Differences between human plasma and serum metabolite profiles.
PLoS ONE
PUBLISHED: 05-24-2011
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Human 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.
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Reliability of three alternate forms of the trail making tests a and B.
Arch Clin Neuropsychol
PUBLISHED: 05-15-2011
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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.
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The German multi-centre study on smoking-related behavior-description of a population-based case-control study.
Addict Biol
PUBLISHED: 04-26-2011
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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.
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Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption.
Gunter Schumann, Lachlan J Coin, Anbarasu Lourdusamy, Pimphen Charoen, Karen H Berger, David Stacey, Sylvane Desrivières, Fazil A Aliev, Anokhi A Khan, Najaf Amin, Yurii S Aulchenko, Georgy Bakalkin, Stephan J Bakker, Beverley Balkau, Joline W Beulens, Ainhoa Bilbao, Rudolf A de Boer, Delphine Beury, Michiel L Bots, Elemi J Breetvelt, Stéphane Cauchi, Christine Cavalcanti-Proença, John C Chambers, Toni-Kim Clarke, Norbert Dahmen, Eco J De Geus, Danielle Dick, Francesca Ducci, Alanna Easton, Howard J Edenberg, Tonu Esko, Tõnu Esk, Alberto Fernandez-Medarde, Tatiana Foroud, Nelson B Freimer, Jean-Antoine Girault, Diederick E Grobbee, Simonetta Guarrera, Daniel F Gudbjartsson, Anna-Liisa Hartikainen, Andrew C Heath, Victor Hesselbrock, Albert Hofman, Jouke-Jan Hottenga, Matti K Isohanni, Jaakko Kaprio, Kay-Tee Khaw, Brigitte Kuehnel, Jaana Laitinen, Stéphane Lobbens, Jian'an Luan, Massimo Mangino, Matthieu Maroteaux, Giuseppe Matullo, Mark I McCarthy, Christian Mueller, Gerjan Navis, Mattijs E Numans, Alejandro Núñez, Dale R Nyholt, Charlotte N Onland-Moret, Ben A Oostra, Paul F O'Reilly, Miklós Palkovits, Brenda W Penninx, Silvia Polidoro, Anneli Pouta, Inga Prokopenko, Fulvio Ricceri, Eugenio Santos, Johannes H Smit, Nicole Soranzo, Kijoung Song, Ulla Sovio, Michael Stumvoll, Ida Surakk, Thorgeir E Thorgeirsson, Unnur Thorsteinsdottir, Claire Troakes, Thorarinn Tyrfingsson, Anke Tönjes, Cuno S Uiterwaal, André G Uitterlinden, Pim van der Harst, Yvonne T van der Schouw, Oliver Staehlin, Nicole Vogelzangs, Peter Vollenweider, Gérard Waeber, Nicholas J Wareham, Dawn M Waterworth, John B Whitfield, Erich H Wichmann, Gonneke Willemsen, Jacqueline C Witteman, Xin Yuan, Guangju Zhai, Jing H Zhao, Weihua Zhang, Nicholas G Martin, Andres Metspalu, Angela Doering, James Scott, Tim D Spector, Ruth J Loos, Dorret I Boomsma, Vincent Mooser, Leena Peltonen, Kari Stefansson, Cornelia M van Duijn, Paolo Vineis, Wolfgang H Sommer, Jaspal S Kooner, Rainer Spanagel, Ulrike A Heberlein, Marjo-Riitta Järvelin, Paul Elliott.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 04-06-2011
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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.
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P50 sensory gating and smoking in the general population.
Addict Biol
PUBLISHED: 03-11-2011
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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<20 cigarettes/lifetime), n=463 light smokers (LS) with Fagerström Test for Nicotine Dependence (FTND)?4 and n=353 heavy smokers (HS, FTND<4) were randomly selected from the general population. As part of a standardized protocol for investigating the genetics of nicotine dependence (ND), an auditory P50 paradigm was applied. The main outcome measure was P50-amplitude difference followed by time-frequency analyses and functional imaging (sLORETA). Reduced P50 gating was found in HS compared to NS with LS taking an intermediate position-correlating with the degree of ND. sLORETA and time-frequency analyses indicate that high-frequency oscillations in frontal brain regions are particularly affected. With growing age, P50 gating increased in (heavy) smokers. This is the first large-scale study (normative sample data) on P50 sensory gating and smoking in the general population. Diminished gating of P50 and associated high-frequency oscillations in the frontal brain region are indications of a deficient inhibitory cortical function in nicotine-dependent smokers. The suitability and application of sensory P50 gating as functional biomarker with regard to genetic and pharmacological studies is discussed.
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Peripheral blood and neuropsychological markers for the onset of action of antidepressant drugs in patients with Major Depressive Disorder.
BMC Psychiatry
PUBLISHED: 01-26-2011
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In Major Depressive Disorder (MDD), treatment outcomes with currently available strategies are often disappointing. Therefore, it is sensible to develop new strategies to increase remission rates in acutely depressed patients. Many studies reported that true drug response can be observed within 14 days (early improvement) of antidepressant treatment. The identical time course of symptom amelioration after early improvement in patients treated with antidepressants of all classes or with placebo strongly suggests a common biological mechanism, which is not specific for a particular antidepressant medication. However, the biology underlying early improvement and final treatment response is not understood and there is no established biological marker as yet, which can predict treatment response for the individual patient before initiation or during the course of antidepressant treatment. Peripheral blood markers and executive functions are particularly promising candidates as markers for the onset of action and thus the prediction of final treatment outcome in MDD.
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Psychological and hormonal features of smokers at risk to gain weight after smoking cessation--results of a multicenter study.
Horm Behav
PUBLISHED: 01-10-2011
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Preclinical and clinical data suggest modulating effects of appetite-regulating hormones and stress perception on food intake. Nicotine intake also interferes with regulation of body weight. Especially following smoking cessation gaining weight is a common but only partially understood consequence. The aim of this study was to examine the interaction between smoking habits, the appetite regulating hormone leptin, negative affectivity, and stress vulnerability on eating behavior in a clinical case-control study under standardized conditions. In a large population-based study sample, we compared leptin and cortisol plasma concentrations (radioimmunoassay) between current tobacco smokers with high cognitive restraint and disinhibition in eating behavior and smokers scoring low in both categories as assessed with the Three Factor Eating Questionnaire (TFEQ; Stunkard & Messick, 1985). As a measure for smoking effects on the stress axis, the saliva cortisol concentrations were compared before and after nicotine smoking. Additionally, stress perception was assessed with the Perceived Stress Scale (PSS), symptoms of depression and anxiety with the Beck Depression Inventory (BDI) and the State Trait Anxiety Inventory (STAI). In smokers showing high cognitive restraint and disinhibition we found significantly higher leptin concentrations than in the group of smokers scoring low in both categories. Furthermore there was a significant group difference in saliva cortisol concentrations after nicotine intake. Smokers showing high cognitive restraint and disinhibition were also characterized by significantly higher scores in the STAI, the PSS and the BDI. Our results suggest that smokers with a pathological eating behavior show an impaired neuroendocrine regulation of appetite and are prone to experience higher levels of stress and negative affectivity. This interaction of behavioral and neuroendocrinological factors may constitute a high risk condition for gaining weight following smoking cessation.
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Polymorphisms in oxidative stress-related genes and postmenopausal breast cancer risk.
Int. J. Cancer
PUBLISHED: 01-06-2011
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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.
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Development of a high throughput single nucleotide polymorphism screening method for the cytochrome P450 1A2 polymorphisms CYP1A2*1C and CYP1A2*1F: are they useful as predictive markers in mental disorders?
Clin. Lab.
PUBLISHED: 11-20-2010
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The cytochrome P450 1A2 (CYP1A2) gene encodes one of the most important enzymes of the Phase I drug metabolism, which is involved in the metabolism of many lipophilic xenobiotics, such as haloperidol, theophylline, phenacetine, and others. The recently discovered single nucleotide polymorphisms CYP1A2*1C (-3860G-->A) in the 5 flanking region of the gene and CYP1A2*1F (-163C-->A) in intron 1 seem to interfere with the expression rate or catalytic function of the enzyme. Polymorphism carriers may either have a risk of reduced drug degradation and side effects, or may present with an increased induction of enzymatic activity resulting in clinical non-response to the prescribed therapy. We investigated two populations, a mental disease group and a healthy control group, to identify whether these two genetic variants are correlated with the general development of a mental disorder and if they could potentially be used as predictive markers for manifestation of the same.
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An integrated genome research network for studying the genetics of alcohol addiction.
Addict Biol
PUBLISHED: 11-03-2010
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Alcohol drinking is highly prevalent in many cultures and contributes to the global burden of disease. In fact, it was shown that alcohol constitutes 3.2% of all worldwide deaths in the year 2006 and is linked to more than 60 diseases, including cancers, cardiovascular diseases, liver cirrhosis, neuropsychiatric disorders, injuries and foetal alcohol syndrome. Alcoholism, which has been proven to have a high genetic load, is one potentially fatal consequence of chronic heavy alcohol consumption, and may be regarded as one of the most prevalent neuropsychiatric diseases afflicting our society today. The aim of the integrated genome research network Genetics of Alcohol Addiction--which is a German inter-/trans-disciplinary life science consortium consisting of molecular biologists, behavioural pharmacologists, system biologists with mathematicians, human geneticists and clinicians--is to better understand the genetics of alcohol addiction by identifying and validating candidate genes and molecular networks involved in the aetiology of this pathology. For comparison, addictive behaviour to other drugs of abuse (e.g. cocaine) is studied as well. Here, we present an overview of our research consortium, the current state of the art on genetic research in the alcohol field, and list finally several of our recently published research highlights. As a result of our scientific efforts, better insights into the molecular and physiological processes underlying addictive behaviour will be obtained, new targets and target networks in the addicted brain will be defined, and subsequently, novel and individualized treatment strategies for our patients will be delivered.
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Risk gene variants for nicotine dependence in the CHRNA5-CHRNA3-CHRNB4 cluster are associated with cognitive performance.
Am. J. Med. Genet. B Neuropsychiatr. Genet.
PUBLISHED: 04-12-2010
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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.
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Meta-analysis and imputation refines the association of 15q25 with smoking quantity.
Jason Z Liu, Federica Tozzi, Dawn M Waterworth, Sreekumar G Pillai, Pierandrea Muglia, Lefkos Middleton, Wade Berrettini, Christopher W Knouff, Xin Yuan, Gérard Waeber, Peter Vollenweider, Martin Preisig, Nicholas J Wareham, Jing Hua Zhao, Ruth J F Loos, Inês Barroso, Kay-Tee Khaw, Scott Grundy, Philip Barter, Robert Mahley, Antero Kesäniemi, Ruth McPherson, John B Vincent, John Strauss, James L Kennedy, Anne Farmer, Peter McGuffin, Richard Day, Keith Matthews, Per Bakke, Amund Gulsvik, Susanne Lucae, Marcus Ising, Tanja Brueckl, Sonja Horstmann, H-Erich Wichmann, Rajesh Rawal, Norbert Dahmen, Claudia Lamina, Ozren Polašek, Lina Zgaga, Jennifer Huffman, Susan Campbell, Jaspal Kooner, John C Chambers, Mary Susan Burnett, Joseph M Devaney, Augusto D Pichard, Kenneth M Kent, Lowell Satler, Joseph M Lindsay, Ron Waksman, Stephen Epstein, James F Wilson, Sarah H Wild, Harry Campbell, Veronique Vitart, Muredach P Reilly, Mingyao Li, Liming Qu, Robert Wilensky, William Matthai, Hakon H Hakonarson, Daniel J Rader, Andre Franke, Michael Wittig, Arne Schäfer, Manuela Uda, Antonio Terracciano, Xiangjun Xiao, Fabio Busonero, Paul Scheet, David Schlessinger, David St Clair, Dan Rujescu, Gonçalo R Abecasis, Hans Jörgen Grabe, Alexander Teumer, Henry Völzke, Astrid Petersmann, Ulrich John, Igor Rudan, Caroline Hayward, Alan F Wright, Ivana Kolčić, Benjamin J Wright, John R Thompson, Anthony J Balmforth, Alistair S Hall, Nilesh J Samani, Carl A Anderson, Tariq Ahmad, Christopher G Mathew, Miles Parkes, Jack Satsangi, Mark Caulfield, Patricia B Munroe, Martin Farrall, Anna Dominiczak, Jane Worthington, Wendy Thomson, Steve Eyre, Anne Barton, , Vincent Mooser, Clyde Francks, Jonathan Marchini.
Nat. Genet.
PUBLISHED: 03-18-2010
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Smoking is a leading global cause of disease and mortality. 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.
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Sequence variants at CHRNB3-CHRNA6 and CYP2A6 affect smoking behavior.
Thorgeir E Thorgeirsson, Daniel F Gudbjartsson, Ida Surakka, Jacqueline M Vink, Najaf Amin, Frank Geller, Patrick Sulem, Thorunn Rafnar, Tonu Esko, Stefan Walter, Christian Gieger, Rajesh Rawal, Massimo Mangino, Inga Prokopenko, Reedik Mägi, Kaisu Keskitalo, Iris H Gudjonsdottir, Solveig Gretarsdottir, Hreinn Stefansson, John R Thompson, Yurii S Aulchenko, Mari Nelis, Katja K Aben, Martin den Heijer, Asger Dirksen, Haseem Ashraf, Nicole Soranzo, Ana M Valdes, Claire Steves, André G Uitterlinden, Albert Hofman, Anke Tönjes, Peter Kovacs, Jouke Jan Hottenga, Gonneke Willemsen, Nicole Vogelzangs, Angela Döring, Norbert Dahmen, Barbara Nitz, Michele L Pergadia, Berta Saez, Verónica De Diego, Victoria Lezcano, Maria D Garcia-Prats, Samuli Ripatti, Markus Perola, Johannes Kettunen, Anna-Liisa Hartikainen, Anneli Pouta, Jaana Laitinen, Matti Isohanni, Shen Huei-Yi, Maxine Allen, Maria Krestyaninova, Alistair S Hall, Gregory T Jones, Andre M van Rij, Thomas Mueller, Benjamin Dieplinger, Meinhard Haltmayer, Steinn Jonsson, Stefan E Matthiasson, Högni Oskarsson, Thorarinn Tyrfingsson, Lambertus A Kiemeney, Jose I Mayordomo, Jes S Lindholt, Jesper Holst Pedersen, Wilbur A Franklin, Holly Wolf, Grant W Montgomery, Andrew C Heath, Nicholas G Martin, Pamela A F Madden, Ina Giegling, Dan Rujescu, Marjo-Riitta Järvelin, Veikko Salomaa, Michael Stumvoll, Tim D Spector, H-Erich Wichmann, Andres Metspalu, Nilesh J Samani, Brenda W Penninx, Ben A Oostra, Dorret I Boomsma, Henning Tiemeier, Cornelia M van Duijn, Jaakko Kaprio, Jeffrey R Gulcher, , Mark I McCarthy, Leena Peltonen, Unnur Thorsteinsdottir, Kari Stefansson.
Nat. Genet.
PUBLISHED: 03-18-2010
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Smoking is a common risk factor for many diseases. We conducted genome-wide association meta-analyses for the number of cigarettes smoked per day (CPD) in smokers (n = 31,266) and smoking initiation (n = 46,481) using samples from the ENGAGE Consortium. In a second stage, we tested selected SNPs with in silico replication in the Tobacco and Genetics (TAG) and Glaxo Smith Kline (Ox-GSK) consortia cohorts (n = 45,691 smokers) and assessed some of those in a third sample of European ancestry (n = 9,040). Variants in three genomic regions associated with CPD (P < 5 x 10(-8)), including previously identified SNPs at 15q25 represented by rs1051730[A] (effect size = 0.80 CPD, P = 2.4 x 10(-69)), and SNPs at 19q13 and 8p11, represented by rs4105144[C] (effect size = 0.39 CPD, P = 2.2 x 10(-12)) and rs6474412-T (effect size = 0.29 CPD, P = 1.4 x 10(-8)), respectively. Among the genes at the two newly associated loci are genes encoding nicotine-metabolizing enzymes (CYP2A6 and CYP2B6) and nicotinic acetylcholine receptor subunits (CHRNB3 and CHRNA6), all of which have been highlighted in previous studies of smoking and nicotine dependence. Nominal associations with lung cancer were observed at both 8p11 (rs6474412[T], odds ratio (OR) = 1.09, P = 0.04) and 19q13 (rs4105144[C], OR = 1.12, P = 0.0006).
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Rationale and design of the randomised clinical trial comparing early medication change (EMC) strategy with treatment as usual (TAU) in patients with major depressive disorder--the EMC trial.
Trials
PUBLISHED: 02-26-2010
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In major depressive disorder (MDD), the traditional belief of a delayed onset of antidepressants effects has lead to the concept of current guidelines that treatment durations should be between 3-8 weeks before medication change in case of insufficient outcome. Post hoc analyses of clinical trials, however, have shown that improvement usually occurs within the first 10-14 days of treatment and that such early improvement (Hamilton Depression Rating Scale [HAMD] decrease >or=20%) has a substantial predictive value for final treatment outcome. Even more important, non-improvement (HAMD decrease <20%) after 14 days of treatment was found to be highly predictive for a poor final treatment outcome.
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Association analysis between gene variants of the tyrosine hydroxylase and the serotonin transporter in borderline personality disorder.
World J. Biol. Psychiatry
PUBLISHED: 02-12-2010
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For patients with borderline personality disorder (BPD), we previously reported an independent effect of the catechol-o-methyl-transferase (COMT) low-activity (Met(158)) allele and an interaction with the low-expression allele of the deletion/insertion (short/long or S/L, resp.) polymorphism in the serotonin transporter-linked promoter region (5-HTTLPR). The purpose of the present study was to extend these findings to the tyrosine hydroxylase (TH) Val(81)Met single nucleotide polymorphism (SNP), the 5-HTTLPR S/L polymorphism incorporating the recently described functional A/G SNP within the long allele of the 5-HTTLPR (rs25531) as well as the variable number of tandem repeat (VNTR) polymorphism within intron 2 of the serotonin transporter gene (STin2).
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Development of a high-throughput method for screening the dopamine D2 (DRD2) receptor gene polymorphisms based on the LightCycler system.
Clin. Lab.
PUBLISHED: 11-06-2009
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The human dopamine receptor D2 (DRD2) is known to be involved in several mental disorders. A series of studies revealed that the polymorphisms *TaqIA and *C957T are linked to these disorders and might influence drug response.
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Basal metabolic rate in narcoleptic patients.
Sleep
PUBLISHED: 07-31-2009
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We investigated basal metabolic rate (BMR) and energy expenditure (EE) in narcoleptic patients and in BMI- and age-matched controls in order to explore the hypothesis that a reduced BMR or EE plays a role in narcolepsy-associated obesity.
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Interaction between gene variants of the serotonin transporter promoter region (5-HTTLPR) and catechol O-methyltransferase (COMT) in borderline personality disorder.
Am. J. Med. Genet. B Neuropsychiatr. Genet.
PUBLISHED: 07-31-2009
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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 (Met(158)) 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 Val(158)Met 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 Met(158)Met 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 Met(158)Met 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 Met(158) 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.
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Variants in COMT and spontaneous smoking cessation: retrospective cohort analysis of 925 cessation events.
Pharmacogenet. Genomics
PUBLISHED: 07-09-2009
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Genome-wide studies have identified single nucleotide polymorphisms associated with smoking behaviour and nicotine dependence. Less is known about genetic determinants of smoking cessation, but rs4680 in COMT has recently been shown to explain a substantial proportion of the variation in cessation in the general population. We attempted to replicate the reported, clinically relevant effect in a population-based retrospective cohort analysis of 1443 ever-heavy smokers, of whom 925 had reached abstinence. In Cox regression models, neither rs4680 nor two polymorphisms nearby were associated with smoking cessation. The adjusted relative cessation rate (95% confidence interval) in rs4680 methionine carriers in reference to valine homozygotes was 0.97 (0.83-1.12). The absence of a significant effect of rs4680 in this statistically well-powered study - the 95% confidence interval even excluding the previously reported effect - highlights the need for rigorous replication efforts and suggests that rs4680 genotype should not yet be considered informative for smoking patient care.
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Genome-wide association study of alcohol dependence.
Arch. Gen. Psychiatry
PUBLISHED: 07-08-2009
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Alcohol dependence is a serious and common public health problem. It is well established that genetic factors play a major role in the development of this disorder. Identification of genes that contribute to alcohol dependence will improve our understanding of the mechanisms that underlie this disorder.
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Association analysis of serotonin receptor 1B (HTR1B) and brain-derived neurotrophic factor gene polymorphisms in Borderline personality disorder.
J Neural Transm
PUBLISHED: 07-03-2009
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The purpose of this study was to test for association between Borderline personality disorder (BPD) and variants of the HTR1B and the brain-derived neurotrophic factor (BDNF) gene. We genotyped four HTR1B and the functional BDNF G196A marker in 161 Caucasian BPD patients and 156 healthy controls. There were no significant differences between groups in genotype or haplotype distribution of HTR1B markers or in genotype distribution of the BDNF marker. Logistic regression analyses revealed an over-representation of the BDNF 196A allele in HTR1B A-161 allele carrying BPD patients.
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Gender differences in axis I and axis II comorbidity in patients with borderline personality disorder.
Psychopathology
PUBLISHED: 06-12-2009
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Differences in the clinical presentation of men and women with borderline personality disorder (BPD) are of potential interest for investigations into the neurobiology, genetics, natural history, and treatment response of BPD. The purpose of this study was to investigate gender differences in axis I and axis II comorbidity and in diagnostic criteria in BPD patients.
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Smoking cessation and variations in nicotinic acetylcholine receptor subunits alpha-5, alpha-3, and beta-4 genes.
Biol. Psychiatry
PUBLISHED: 05-20-2009
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Evidence has recently accumulated that single nucleotide polymorphisms in the genetic region encoding the nicotinic acetylcholine receptor subunits alpha-5, alpha-3, and beta-4 are associated with smoking and nicotine dependence. We aimed to determine whether these genetic variations are also predictive of smoking cessation.
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Heavy metal exposure in patients suffering from electromagnetic hypersensitivity.
Sci. Total Environ.
PUBLISHED: 04-26-2009
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Risks from electromagnetic devices are of considerable concern. Electrohypersensitive (EHS) persons attribute a variety of rather unspecific symptoms to the exposure to electromagnetic fields. The pathophysiology of EHS is unknown and therapy remains a challenge.
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Development and validation of a high-throughput screening method for two polymorphisms in the serotonin transporter gene.
Mol Diagn Ther
PUBLISHED: 04-09-2009
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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 challenging 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.
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ErbB4 genotype predicts left frontotemporal structural connectivity in human brain.
Neuropsychopharmacology
PUBLISHED: 03-31-2009
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Diminished left frontotemporal connectivity is among the most frequently reported findings in schizophrenia and there is evidence that altered neuronal myelination may in part account for this deficit. Several investigations have suggested that variations of the genes that encode the Neuregulin 1 (NRG1)-ErbB4 receptor complex are associated with schizophrenia illness. As NRG1--ErbB4 has been implicated in neuronal myelination, we investigated with diffusion tensor imaging (DTI) whether fractional anisotropy (FA)--a putative measure of neuronal myelination--is predicted by a risk haplotype of the ErbB4 gene. The effects of the ErbB4 genotype were investigated in healthy subjects (N=59; mean age: 22.6+/-1.8 years). We also measured reaction time (RT) during a selective attention/working memory paradigm (visual oddball). In the schizophrenia risk genotype group, we found lower FA in the temporal lobe white matter (WM) including frontotemporal fiber tracts, predominantly in the left hemisphere. RT was increased in the risk genotype group and correlated with FA in the affected brain region. As FA is considered to index structural integrity of WM, to which neuronal fiber myelination is contributing, our results suggest that variations of the ErbB4 genotype may confer risk for schizophrenia illness via its impact on left frontotemporal connectivity in human brain. Reliability and validity of the result is suggested by our observation that (1) the FA-genotype association was not only obtained in the entire sample but also in both the split halves and (2) a statistical relationship was found among RT, genotype and FA.
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Blood laboratory findings in patients suffering from self-perceived electromagnetic hypersensitivity (EHS).
Bioelectromagnetics
PUBLISHED: 03-05-2009
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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.
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Detection times for urinary ethyl glucuronide and ethyl sulfate in heavy drinkers during alcohol detoxification.
Alcohol Alcohol.
PUBLISHED: 03-04-2009
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Ethyl glucuronide (EtG) and ethyl sulfate (EtS) are conjugated ethanol metabolites formed in low amounts after alcohol consumption. Compared with ethanol, EtG and EtS are excreted in urine for a prolonged time, making them useful as sensitive alcohol biomarkers. This study determined the detection times for EtG and EtS in alcoholic patients undergoing alcohol detoxification.
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The 5-HTTLPR polymorphism modulates the association of serious life events (SLE) and impulsivity in patients with Borderline Personality Disorder.
J Psychiatr Res
PUBLISHED: 02-26-2009
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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.
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Impaired sleep quality and sleep duration in smokers-results from the German Multicenter Study on Nicotine Dependence.
Addict Biol
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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 hyperactivity, alcohol drinking behaviour and perceived stress, were included into multiple regression analyses. Significantly more smokers than non-smokers (28.1% versus 19.1%; P?
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An investigation of a genomewide supported psychosis variant in ZNF804A and white matter integrity in the human brain.
Magn Reson Imaging
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ZNF804A, a genomewide supported susceptibility gene for schizophrenia and bipolar disorder, has been associated with task-independent functional connectivity between the left and right dorsolateral prefrontal cortices. Several lines of evidence have converged on the hypothesis that this effect may be mediated by structural connectivity. We tested this hypothesis using diffusion tensor magnetic resonance imaging in three samples: one German sample of 50 healthy individuals, one Scottish sample of 83 healthy individuals and one Scottish sample of 84 unaffected relatives of bipolar patients. Voxel-based analysis and tract-based spatial statistics did not detect any fractional anisotropy (FA) differences between minor allele carriers and individuals homozygous for the major allele at rs1344706. Similarly, region-of-interest analyses and quantitative tractography of the genu of the corpus callosum revealed no significant FA differences between the genotype groups. Examination of effect sizes and confidence intervals indicated that this negative finding is very unlikely to be due to a lack of statistical power. In summary, despite using various analysis techniques in three different samples, our results were strikingly and consistently negative. These data therefore suggest that it is unlikely that the effects of genetic variation at rs1344706 on functional connectivity are mediated by structural integrity differences in large, long-range white matter fiber connections.
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Genetic variation in the neuropeptide Y gene promoter is associated with increased risk of tobacco smoking.
Eur Addict Res
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Neuropeptide Y (NPY) is a strong candidate gene regarding the pathophysiology of tobacco dependence. It has been associated with various addictive and psychiatric disorders, and closely interacts with the brain reward system. The aim of the present study was to test for association between a functional genetic variant in the NP-Y promoter gene (SNP rs16147) and tobacco smoking.
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Schizophrenia risk polymorphisms in the TCF4 gene interact with smoking in the modulation of auditory sensory gating.
Proc. Natl. Acad. Sci. U.S.A.
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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.
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Neurocognitive impairments in non-deprived smokers--results from a population-based multi-center study on smoking-related behavior.
Addict Biol
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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.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.