PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-13 (13)
 

Clipboard (0)
None

Select a Filter Below

Journals
more »
Year of Publication
Document Types
2.  Genome-wide association study of alcohol dependence 
Archives of general psychiatry  2009;66(7):773-784.
Context
Identification of genes contributing to alcohol dependence will improve our understanding of the mechanisms underlying this disorder.
Objective
To identify susceptibility genes for alcohol dependence through a genome-wide association study (GWAS) and follow-up study in a population of German male inpatients with an early age at onset.
Design
The GWAS included 487 male inpatients with DSM-IV alcohol dependence with an age at onset below 28 years and 1,358 population based control individuals. The follow-up study included 1,024 male inpatients and 996 age-matched male controls. All subjects were of German descent. The GWAS tested 524,396 single nucleotide polymorphisms (SNPs). All SNPs with p<10-4 were subjected to the follow-up study. In addition, nominally significant SNPs from those genes that had also shown expression changes in rat brains after chronic alcohol consumption were selected for the follow-up step.
Results
The GWAS produced 121 SNPs with nominal p<10-4. These, together with 19 additional SNPs from homologs of rat genes showing differential expression, were genotyped in the follow-up sample. Fifteen SNPs showed significant association with the same allele as in the GWAS. In the combined analysis, two closely linked intergenic SNPs met genome-wide significance (rs7590720 p=9.72×10-9; rs1344694 p=1.69×10-8). They are located on chromosome 2q35, a region which has been implicated in linkage studies for alcohol phenotypes. Nine SNPs were located in genes, including CDH13 and ADH1C genes which have been reported to be associated with alcohol dependence.
Conclusion
This is the first GWAS and follow-up study to identify a genome-wide significant association in alcohol dependence. Further independent studies are required to confirm these findings.
doi:10.1001/archgenpsychiatry.2009.83
PMCID: PMC4229246  PMID: 19581569
3.  αCaMKII Autophosphorylation Controls the Establishment of Alcohol Drinking Behavior 
Neuropsychopharmacology  2013;38(9):1636-1647.
The α-Ca2+/calmodulin-dependent protein kinase II (αCaMKII) is a crucial enzyme controlling plasticity in the brain. The autophosphorylation of αCaMKII works as a ‘molecular memory' for a transient calcium activation, thereby accelerating learning. We investigated the role of αCaMKII autophosphorylation in the establishment of alcohol drinking as an addiction-related behavior in mice. We found that alcohol drinking was initially diminished in αCaMKII autophosphorylation-deficient αCaMKIIT286A 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 αCaMKIIT286A 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 αCaMKIIT286A 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 αCaMKIIT286A 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 αCaMKII autophosphorylation as a facilitating mechanism in the establishment of alcohol drinking behavior with changing the DA–5-HT balance as a putative mechanism.
doi:10.1038/npp.2013.60
PMCID: PMC3717547  PMID: 23459588
Alcohol & Alcoholism; alphaCaMKII; Animal models; autophosphorylation; c-Fos; Dopamine; microdialysis; Serotonin; αCaMKII; autophosphorylation; alcohol; reinforcement; dopamine; serotonin
4.  Dissecting DNA repair in adult high grade gliomas for patient stratification in the post-genomic era 
Oncotarget  2014;5(14):5764-5781.
Deregulation of multiple DNA repair pathways may contribute to aggressive biology and therapy resistance in gliomas. We evaluated transcript levels of 157 genes involved in DNA repair in an adult glioblastoma Test set (n=191) and validated in ‘The Cancer Genome Atlas’ (TCGA) cohort (n=508). A DNA repair prognostic index model was generated. Artificial neural network analysis (ANN) was conducted to investigate global gene interactions. Protein expression by immunohistochemistry was conducted in 61 tumours. A fourteen DNA repair gene expression panel was associated with poor survival in Test and TCGA cohorts. A Cox multivariate model revealed APE1, NBN, PMS2, MGMT and PTEN as independently associated with poor prognosis. A DNA repair prognostic index incorporating APE1, NBN, PMS2, MGMT and PTEN stratified patients in to three prognostic sub-groups with worsening survival. APE1, NBN, PMS2, MGMT and PTEN also have predictive significance in patients who received chemotherapy and/or radiotherapy. ANN analysis of APE1, NBN, PMS2, MGMT and PTEN revealed interactions with genes involved in transcription, hypoxia and metabolic regulation. At the protein level, low APE1 and low PTEN remain associated with poor prognosis. In conclusion, multiple DNA repair pathways operate to influence biology and clinical outcomes in adult high grade gliomas.
PMCID: PMC4170616  PMID: 25026297
DNA repair; high grade glioma; glioblastoma; prognostic factor; biomarker
5.  The endogenous and reactive depression subtypes revisited: integrative animal and human studies implicate multiple distinct molecular mechanisms underlying major depressive disorder 
BMC Medicine  2014;12:73.
Background
Traditional diagnoses of major depressive disorder (MDD) suggested that the presence or absence of stress prior to onset results in either ‘reactive’ or ‘endogenous’ subtypes of the disorder, respectively. Several lines of research suggest that the biological underpinnings of ‘reactive’ or ‘endogenous’ subtypes may also differ, resulting in differential response to treatment. We investigated this hypothesis by comparing the gene-expression profiles of three animal models of ‘reactive’ and ‘endogenous’ depression. We then translated these findings to clinical samples using a human post-mortem mRNA study.
Methods
Affymetrix mouse whole-genome oligonucleotide arrays were used to measure gene expression from hippocampal tissues of 144 mice from the Genome-based Therapeutic Drugs for Depression (GENDEP) project. The study used four inbred mouse strains and two depressogenic ‘stress’ protocols (maternal separation and Unpredictable Chronic Mild Stress) to model ‘reactive’ depression. Stress-related mRNA differences in mouse were compared with a parallel mRNA study using Flinders Sensitive and Resistant rat lines as a model of ‘endogenous’ depression. Convergent genes differentially expressed across the animal studies were used to inform candidate gene selection in a human mRNA post-mortem case control study from the Stanley Brain Consortium.
Results
In the mouse ‘reactive’ model, the expression of 350 genes changed in response to early stresses and 370 in response to late stresses. A minimal genetic overlap (less than 8.8%) was detected in response to both stress protocols, but 30% of these genes (21) were also differentially regulated in the ‘endogenous’ rat study. This overlap is significantly greater than expected by chance. The VAMP-2 gene, differentially expressed across the rodent studies, was also significantly altered in the human study after correcting for multiple testing.
Conclusions
Our results suggest that ‘endogenous’ and ‘reactive’ subtypes of depression are associated with largely distinct changes in gene-expression. However, they also suggest that the molecular signature of ‘reactive’ depression caused by early stressors differs considerably from that of ‘reactive’ depression caused by late stressors. A small set of genes was consistently dysregulated across each paradigm and in post-mortem brain tissue of depressed patients suggesting a final common pathway to the disorder. These genes included the VAMP-2 gene, which has previously been associated with Axis-I disorders including MDD, bipolar depression, schizophrenia and with antidepressant treatment response. We also discuss the implications of our findings for disease classification, personalized medicine and case-control studies of MDD.
doi:10.1186/1741-7015-12-73
PMCID: PMC4046519  PMID: 24886127
Endogenous Depression; Reactive Depression; GENDEP; VAMP-2; DSM-IV; Stanley Brain Consortium; mRNA; Stress
6.  FTO, obesity and the adolescent brain 
Human Molecular Genetics  2012;22(5):1050-1058.
Genetic variations in fat mass- and obesity (FTO)-associated gene, a well-replicated gene locus of obesity, appear to be associated also with reduced regional brain volumes in elderly. Here, we examined whether FTO is associated with total brain volume in adolescence, thus exploring possible developmental effects of FTO. We studied a population-based sample of 598 adolescents recruited from the French Canadian founder population in whom we measured brain volume by magnetic resonance imaging. Total fat mass was assessed with bioimpedance and body mass index was determined with anthropometry. Genotype–phenotype associations were tested with Merlin under an additive model. We found that the G allele of FTO (rs9930333) was associated with higher total body fat [TBF (P = 0.002) and lower brain volume (P = 0.005)]. The same allele was also associated with higher lean body mass (P = 0.03) and no difference in height (P = 0.99). Principal component analysis identified a shared inverse variance between the brain volume and TBF, which was associated with FTO at P = 5.5 × 10−6. These results were replicated in two independent samples of 413 and 718 adolescents, and in a meta-analysis of all three samples (n = 1729 adolescents), FTO was associated with this shared inverse variance at P = 1.3 × 10−9. Co-expression networks analysis supported the possibility that the underlying FTO effects may occur during embryogenesis. In conclusion, FTO is associated with shared inverse variance between body adiposity and brain volume, suggesting that this gene may exert inverse effects on adipose and brain tissues. Given the completion of the overall brain growth in early childhood, these effects may have their origins during early development.
doi:10.1093/hmg/dds504
PMCID: PMC3606009  PMID: 23201753
7.  The ENIGMA Consortium: large-scale collaborative analyses of neuroimaging and genetic data 
Thompson, Paul M. | Stein, Jason L. | Medland, Sarah E. | Hibar, Derrek P. | Vasquez, Alejandro Arias | Renteria, Miguel E. | Toro, Roberto | Jahanshad, Neda | Schumann, Gunter | Franke, Barbara | Wright, Margaret J. | Martin, Nicholas G. | Agartz, Ingrid | Alda, Martin | Alhusaini, Saud | Almasy, Laura | Almeida, Jorge | Alpert, Kathryn | Andreasen, Nancy C. | Andreassen, Ole A. | Apostolova, Liana G. | Appel, Katja | Armstrong, Nicola J. | Aribisala, Benjamin | Bastin, Mark E. | Bauer, Michael | Bearden, Carrie E. | Bergmann, Ørjan | Binder, Elisabeth B. | Blangero, John | Bockholt, Henry J. | Bøen, Erlend | Bois, Catherine | Boomsma, Dorret I. | Booth, Tom | Bowman, Ian J. | Bralten, Janita | Brouwer, Rachel M. | Brunner, Han G. | Brohawn, David G. | Buckner, Randy L. | Buitelaar, Jan | Bulayeva, Kazima | Bustillo, Juan R. | Calhoun, Vince D. | Cannon, Dara M. | Cantor, Rita M. | Carless, Melanie A. | Caseras, Xavier | Cavalleri, Gianpiero L. | Chakravarty, M. Mallar | Chang, Kiki D. | Ching, Christopher R. K. | Christoforou, Andrea | Cichon, Sven | Clark, Vincent P. | Conrod, Patricia | Coppola, Giovanni | Crespo-Facorro, Benedicto | Curran, Joanne E. | Czisch, Michael | Deary, Ian J. | de Geus, Eco J. C. | den Braber, Anouk | Delvecchio, Giuseppe | Depondt, Chantal | de Haan, Lieuwe | de Zubicaray, Greig I. | Dima, Danai | Dimitrova, Rali | Djurovic, Srdjan | Dong, Hongwei | Donohoe, Gary | Duggirala, Ravindranath | Dyer, Thomas D. | Ehrlich, Stefan | Ekman, Carl Johan | Elvsåshagen, Torbjørn | Emsell, Louise | Erk, Susanne | Espeseth, Thomas | Fagerness, Jesen | Fears, Scott | Fedko, Iryna | Fernández, Guillén | Fisher, Simon E. | Foroud, Tatiana | Fox, Peter T. | Francks, Clyde | Frangou, Sophia | Frey, Eva Maria | Frodl, Thomas | Frouin, Vincent | Garavan, Hugh | Giddaluru, Sudheer | Glahn, David C. | Godlewska, Beata | Goldstein, Rita Z. | Gollub, Randy L. | Grabe, Hans J. | Grimm, Oliver | Gruber, Oliver | Guadalupe, Tulio | Gur, Raquel E. | Gur, Ruben C. | Göring, Harald H. H. | Hagenaars, Saskia | Hajek, Tomas | Hall, Geoffrey B. | Hall, Jeremy | Hardy, John | Hartman, Catharina A. | Hass, Johanna | Hatton, Sean N. | Haukvik, Unn K. | Hegenscheid, Katrin | Heinz, Andreas | Hickie, Ian B. | Ho, Beng-Choon | Hoehn, David | Hoekstra, Pieter J. | Hollinshead, Marisa | Holmes, Avram J. | Homuth, Georg | Hoogman, Martine | Hong, L. Elliot | Hosten, Norbert | Hottenga, Jouke-Jan | Hulshoff Pol, Hilleke E. | Hwang, Kristy S. | Jack, Clifford R. | Jenkinson, Mark | Johnston, Caroline | Jönsson, Erik G. | Kahn, René S. | Kasperaviciute, Dalia | Kelly, Sinead | Kim, Sungeun | Kochunov, Peter | Koenders, Laura | Krämer, Bernd | Kwok, John B. J. | Lagopoulos, Jim | Laje, Gonzalo | Landen, Mikael | Landman, Bennett A. | Lauriello, John | Lawrie, Stephen M. | Lee, Phil H. | Le Hellard, Stephanie | Lemaître, Herve | Leonardo, Cassandra D. | Li, Chiang-shan | Liberg, Benny | Liewald, David C. | Liu, Xinmin | Lopez, Lorna M. | Loth, Eva | Lourdusamy, Anbarasu | Luciano, Michelle | Macciardi, Fabio | Machielsen, Marise W. J. | MacQueen, Glenda M. | Malt, Ulrik F. | Mandl, René | Manoach, Dara S. | Martinot, Jean-Luc | Matarin, Mar | Mather, Karen A. | Mattheisen, Manuel | Mattingsdal, Morten | Meyer-Lindenberg, Andreas | McDonald, Colm | McIntosh, Andrew M. | McMahon, Francis J. | McMahon, Katie L. | Meisenzahl, Eva | Melle, Ingrid | Milaneschi, Yuri | Mohnke, Sebastian | Montgomery, Grant W. | Morris, Derek W. | Moses, Eric K. | Mueller, Bryon A. | Muñoz Maniega, Susana | Mühleisen, Thomas W. | Müller-Myhsok, Bertram | Mwangi, Benson | Nauck, Matthias | Nho, Kwangsik | Nichols, Thomas E. | Nilsson, Lars-Göran | Nugent, Allison C. | Nyberg, Lars | Olvera, Rene L. | Oosterlaan, Jaap | Ophoff, Roel A. | Pandolfo, Massimo | Papalampropoulou-Tsiridou, Melina | Papmeyer, Martina | Paus, Tomas | Pausova, Zdenka | Pearlson, Godfrey D. | Penninx, Brenda W. | Peterson, Charles P. | Pfennig, Andrea | Phillips, Mary | Pike, G. Bruce | Poline, Jean-Baptiste | Potkin, Steven G. | Pütz, Benno | Ramasamy, Adaikalavan | Rasmussen, Jerod | Rietschel, Marcella | Rijpkema, Mark | Risacher, Shannon L. | Roffman, Joshua L. | Roiz-Santiañez, Roberto | Romanczuk-Seiferth, Nina | Rose, Emma J. | Royle, Natalie A. | Rujescu, Dan | Ryten, Mina | Sachdev, Perminder S. | Salami, Alireza | Satterthwaite, Theodore D. | Savitz, Jonathan | Saykin, Andrew J. | Scanlon, Cathy | Schmaal, Lianne | Schnack, Hugo G. | Schork, Andrew J. | Schulz, S. Charles | Schür, Remmelt | Seidman, Larry | Shen, Li | Shoemaker, Jody M. | Simmons, Andrew | Sisodiya, Sanjay M. | Smith, Colin | Smoller, Jordan W. | Soares, Jair C. | Sponheim, Scott R. | Sprooten, Emma | Starr, John M. | Steen, Vidar M. | Strakowski, Stephen | Strike, Lachlan | Sussmann, Jessika | Sämann, Philipp G. | Teumer, Alexander | Toga, Arthur W. | Tordesillas-Gutierrez, Diana | Trabzuni, Daniah | Trost, Sarah | Turner, Jessica | Van den Heuvel, Martijn | van der Wee, Nic J. | van Eijk, Kristel | van Erp, Theo G. M. | van Haren, Neeltje E. M. | van ‘t Ent, Dennis | van Tol, Marie-Jose | Valdés Hernández, Maria C. | Veltman, Dick J. | Versace, Amelia | Völzke, Henry | Walker, Robert | Walter, Henrik | Wang, Lei | Wardlaw, Joanna M. | Weale, Michael E. | Weiner, Michael W. | Wen, Wei | Westlye, Lars T. | Whalley, Heather C. | Whelan, Christopher D. | White, Tonya | Winkler, Anderson M. | Wittfeld, Katharina | Woldehawariat, Girma | Wolf, Christiane | Zilles, David | Zwiers, Marcel P. | Thalamuthu, Anbupalam | Schofield, Peter R. | Freimer, Nelson B. | Lawrence, Natalia S. | Drevets, Wayne
Brain Imaging and Behavior  2014;8(2):153-182.
The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium is a collaborative network of researchers working together on a range of large-scale studies that integrate data from 70 institutions worldwide. Organized into Working Groups that tackle questions in neuroscience, genetics, and medicine, ENIGMA studies have analyzed neuroimaging data from over 12,826 subjects. In addition, data from 12,171 individuals were provided by the CHARGE consortium for replication of findings, in a total of 24,997 subjects. By meta-analyzing results from many sites, ENIGMA has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected. ENIGMA’s first project was a genome-wide association study identifying common variants in the genome associated with hippocampal volume or intracranial volume. Continuing work is exploring genetic associations with subcortical volumes (ENIGMA2) and white matter microstructure (ENIGMA-DTI). Working groups also focus on understanding how schizophrenia, bipolar illness, major depression and attention deficit/hyperactivity disorder (ADHD) affect the brain. We review the current progress of the ENIGMA Consortium, along with challenges and unexpected discoveries made on the way.
doi:10.1007/s11682-013-9269-5
PMCID: PMC4008818  PMID: 24399358
Genetics; MRI; GWAS; Consortium; Meta-analysis; Multi-site
8.  KCTD8 Gene and Brain Growth in Adverse Intrauterine Environment: A Genome-wide Association Study 
Cerebral Cortex (New York, NY)  2011;22(11):2634-2642.
The most dramatic growth of the human brain occurs in utero and during the first 2 years of postnatal life. Genesis of the cerebral cortex involves cell proliferation, migration, and apoptosis, all of which may be influenced by prenatal environment. Here, we show that variation in KCTD8 (potassium channel tetramerization domain 8) is associated with brain size in female adolescents (rs716890, P = 5.40 × 10−09). Furthermore, we found that the KCTD8 locus interacts with prenatal exposure to maternal cigarette smoking vis-à-vis cortical area and cortical folding: In exposed girls only, the KCTD8 locus explains up to 21% of variance. Using head circumference as a proxy of brain size at 7 years of age, we have replicated this gene–environment interaction in an independent sample. We speculate that KCTD8 might modulate adverse effects of smoking during pregnancy on brain development via apoptosis triggered by low intracellular levels of potassium, possibly reducing the number of progenitor cells.
doi:10.1093/cercor/bhr350
PMCID: PMC3464418  PMID: 22156575
adolescence; brain; GWAS; pregnancy
9.  Identification of common variants associated with human hippocampal and intracranial volumes 
Stein, Jason L | Medland, Sarah E | Vasquez, Alejandro Arias | Hibar, Derrek P | Senstad, Rudy E | Winkler, Anderson M | Toro, Roberto | Appel, Katja | Bartecek, Richard | Bergmann, Ørjan | Bernard, Manon | Brown, Andrew A | Cannon, Dara M | Chakravarty, M Mallar | Christoforou, Andrea | Domin, Martin | Grimm, Oliver | Hollinshead, Marisa | Holmes, Avram J | Homuth, Georg | Hottenga, Jouke-Jan | Langan, Camilla | Lopez, Lorna M | Hansell, Narelle K | Hwang, Kristy S | Kim, Sungeun | Laje, Gonzalo | Lee, Phil H | Liu, Xinmin | Loth, Eva | Lourdusamy, Anbarasu | Mattingsdal, Morten | Mohnke, Sebastian | Maniega, Susana Muñoz | Nho, Kwangsik | Nugent, Allison C | O’Brien, Carol | Papmeyer, Martina | Pütz, Benno | Ramasamy, Adaikalavan | Rasmussen, Jerod | Rijpkema, Mark | Risacher, Shannon L | Roddey, J Cooper | Rose, Emma J | Ryten, Mina | Shen, Li | Sprooten, Emma | Strengman, Eric | Teumer, Alexander | Trabzuni, Daniah | Turner, Jessica | van Eijk, Kristel | van Erp, Theo G M | van Tol, Marie-Jose | Wittfeld, Katharina | Wolf, Christiane | Woudstra, Saskia | Aleman, Andre | Alhusaini, Saud | Almasy, Laura | Binder, Elisabeth B | Brohawn, David G | Cantor, Rita M | Carless, Melanie A | Corvin, Aiden | Czisch, Michael | Curran, Joanne E | Davies, Gail | de Almeida, Marcio A A | Delanty, Norman | Depondt, Chantal | Duggirala, Ravi | Dyer, Thomas D | Erk, Susanne | Fagerness, Jesen | Fox, Peter T | Freimer, Nelson B | Gill, Michael | Göring, Harald H H | Hagler, Donald J | Hoehn, David | Holsboer, Florian | Hoogman, Martine | Hosten, Norbert | Jahanshad, Neda | Johnson, Matthew P | Kasperaviciute, Dalia | Kent, Jack W | Kochunov, Peter | Lancaster, Jack L | Lawrie, Stephen M | Liewald, David C | Mandl, René | Matarin, Mar | Mattheisen, Manuel | Meisenzahl, Eva | Melle, Ingrid | Moses, Eric K | Mühleisen, Thomas W | Nauck, Matthias | Nöthen, Markus M | Olvera, Rene L | Pandolfo, Massimo | Pike, G Bruce | Puls, Ralf | Reinvang, Ivar | Rentería, Miguel E | Rietschel, Marcella | Roffman, Joshua L | Royle, Natalie A | Rujescu, Dan | Savitz, Jonathan | Schnack, Hugo G | Schnell, Knut | Seiferth, Nina | Smith, Colin | Steen, Vidar M | Valdés Hernández, Maria C | Van den Heuvel, Martijn | van der Wee, Nic J | Van Haren, Neeltje E M | Veltman, Joris A | Völzke, Henry | Walker, Robert | Westlye, Lars T | Whelan, Christopher D | Agartz, Ingrid | Boomsma, Dorret I | Cavalleri, Gianpiero L | Dale, Anders M | Djurovic, Srdjan | Drevets, Wayne C | Hagoort, Peter | Hall, Jeremy | Heinz, Andreas | Jack, Clifford R | Foroud, Tatiana M | Le Hellard, Stephanie | Macciardi, Fabio | Montgomery, Grant W | Poline, Jean Baptiste | Porteous, David J | Sisodiya, Sanjay M | Starr, John M | Sussmann, Jessika | Toga, Arthur W | Veltman, Dick J | Walter, Henrik | Weiner, Michael W | Bis, Joshua C | Ikram, M Arfan | Smith, Albert V | Gudnason, Vilmundur | Tzourio, Christophe | Vernooij, Meike W | Launer, Lenore J | DeCarli, Charles | Seshadri, Sudha | Andreassen, Ole A | Apostolova, Liana G | Bastin, Mark E | Blangero, John | Brunner, Han G | Buckner, Randy L | Cichon, Sven | Coppola, Giovanni | de Zubicaray, Greig I | Deary, Ian J | Donohoe, Gary | de Geus, Eco J C | Espeseth, Thomas | Fernández, Guillén | Glahn, David C | Grabe, Hans J | Hardy, John | Hulshoff Pol, Hilleke E | Jenkinson, Mark | Kahn, René S | McDonald, Colm | McIntosh, Andrew M | McMahon, Francis J | McMahon, Katie L | Meyer-Lindenberg, Andreas | Morris, Derek W | Müller-Myhsok, Bertram | Nichols, Thomas E | Ophoff, Roel A | Paus, Tomas | Pausova, Zdenka | Penninx, Brenda W | Potkin, Steven G | Sämann, Philipp G | Saykin, Andrew J | Schumann, Gunter | Smoller, Jordan W | Wardlaw, Joanna M | Weale, Michael E | Martin, Nicholas G | Franke, Barbara | Wright, Margaret J | Thompson, Paul M
Nature genetics  2012;44(5):552-561.
Identifying genetic variants influencing human brain structures may reveal new biological mechanisms underlying cognition and neuropsychiatric illness. The volume of the hippocampus is a biomarker of incipient Alzheimer’s disease1,2 and is reduced in schizophrenia3, major depression4 and mesial temporal lobe epilepsy5. Whereas many brain imaging phenotypes are highly heritable6,7, identifying and replicating genetic influences has been difficult, as small effects and the high costs of magnetic resonance imaging (MRI) have led to underpowered studies. Here we report genome-wide association meta-analyses and replication for mean bilateral hippocampal, total brain and intracranial volumes from a large multinational consortium. The intergenic variant rs7294919 was associated with hippocampal volume (12q24.22; N = 21,151; P = 6.70 × 10−16) and the expression levels of the positional candidate gene TESC in brain tissue. Additionally, rs10784502, located within HMGA2, was associated with intracranial volume (12q14.3; N = 15,782; P = 1.12 × 10−12). We also identified a suggestive association with total brain volume at rs10494373 within DDR2 (1q23.3; N = 6,500; P = 5.81 × 10−7).
doi:10.1038/ng.2250
PMCID: PMC3635491  PMID: 22504417
10.  Glucocorticoid receptor (NR3C1) gene polymorphisms and onset of alcohol abuse in adolescents 
Addiction biology  2010;16(3):510-513.
Onset of alcohol use at an early age increases the risk for later alcohol dependence. We investigated the role of the glucocorticoid receptor (GR) gene (NR3C1) in onset of alcohol use and abuse in 14-year-old adolescents (n = 4534). Several NR3C1 polymorphisms were associated with onset of alcohol drinking or drunkenness at this age. Strongest associations were observed in females, with one marker (rs244465) remaining significant after correction for multiple testing (Padj = 0.0067; odds ratio = 1.7, for drunkenness). Our data provide the first evidence that GR modulates initiation of alcohol abuse and reveal a polymorphism that might contribute to susceptibility to addiction.
doi:10.1111/j.1369-1600.2010.00239.x
PMCID: PMC3428936  PMID: 20731635
Addiction; adolescent; alcohol; glucocorticoid receptor; NR3C1; polymorphism
11.  KCNJ6 is Associated with Adult Alcohol Dependence and Involved in Gene × Early Life Stress Interactions in Adolescent Alcohol Drinking 
Neuropsychopharmacology  2011;36(6):1142-1148.
Alcohol abuse and dependence have proven to be complex genetic traits that are influenced by environmental factors. Primate and human studies have shown that early life stress increases the propensity for alcohol abuse in later life. The reinforcing properties of alcohol are mediated by dopaminergic signaling; however, there is little evidence to indicate how stress alters alcohol reinforcement. KCNJ6 (the gene encoding G-protein-coupled inwardly rectifying potassium channel 2 (GIRK2)) is a brain expressed potassium channel with inhibitory effects on dopaminergic tone. The properties of GIRK2 have been shown to be enhanced by the stress peptide corticotrophin-releasing hormone. Therefore, we sought to examine the role of KCNJ6 polymorphisms in adult alcohol dependence and stress-related alcohol abuse in adolescents. We selected 11 SNPs in the promoter region of KCNJ6, which were genotyped in 1152 adult alcohol dependents and 1203 controls. One SNP, rs2836016, was found to be associated with alcohol dependence (p=0.01, false discovery rate). We then assessed rs2836016 in an adolescent sample of 261 subjects, which were characterized for early life stress and adolescent hazardous drinking, defined using the Alcohol Use Disorders Identification Test (AUDIT), to examine gene–environment interactions. In the adolescent sample, the risk genotype of rs2836016 was significantly associated with increased AUDIT scores, but only in those individuals exposed to high levels of psychosocial stress in early life (p=0.01). Our findings show that KCNJ6 is associated with alcohol dependence and may moderate the effect of early psychosocial stress on risky alcohol drinking in adolescents. We have identified a candidate gene for future studies investigating a possible functional link between the response to stress and alcohol reinforcement.
doi:10.1038/npp.2010.247
PMCID: PMC3079832  PMID: 21307845
alcoholism; genetics; GIRK2; stress; gene × environment; KCNJ6; addiction and substance abuse; biological psychiatry; neurogenetics; dopamine; alcoholism; genetics; stress
12.  Sex-Specific Role for Adenylyl Cyclase Type 7 in Alcohol Dependence 
Biological Psychiatry  2011;69(11):1100-1108.
Background
Alcohol has been shown to critically modulate cyclic adenosine-3′,5′ monophosphate (cAMP) signaling. A number of downstream effectors that respond to the cAMP signals (e.g., protein kinase A, cAMP response element binding protein) have, in turn, been examined in relation to alcohol consumption. These studies did not, however, delineate the point at which the actions of alcohol on the cAMP cascade might translate into differences in drinking behavior. To further understand the role of cAMP synthesis in alcohol drinking and dependence, we investigated a specific adenylyl cyclase isoform, adenylyl cyclase (AC) Type 7, whose activity is selectively enhanced by ethanol.
Methods
We measured alcohol consumption and preference in mice in which one copy of the Adcy7 gene was disrupted (Adcy7+/−). To demonstrate relevance of this gene for alcohol dependence in humans, we tested the association of polymorphisms in the ADCY7 gene with alcohol dependence in a sample of 1703 alcohol-dependent individuals and 1347 control subjects.
Results
We show that Adcy7+/− female mice have higher preference for alcohol than wild-type mice, whereas there is little difference in alcohol consumption or preference between Adcy7+/− male mice and wild-type control subjects. In the human sample, we found that single nucleotide polymorphisms in ADCY7 associate with alcohol dependence in women, and these markers are also associated with ADCY7 expression (messenger RNA) levels.
Conclusions
These findings implicate adenylyl cyclase Type 7 as a critical component of the molecular pathways contributing to alcohol drinking and the development of alcohol dependence.
doi:10.1016/j.biopsych.2011.01.037
PMCID: PMC3094753  PMID: 21481845
ADCY7; adenylyl cyclase; alcohol dependence; gender; genetics; sex
13.  Increased mRNA Levels of TCF7L2 and MYC of the Wnt Pathway in Tg-ArcSwe Mice and Alzheimer's Disease Brain 
Several components in the Wnt pathway, including β-catenin and glycogen synthase kinase 3 beta, have been implied in AD pathogenesis. Here, mRNA brain levels from five-month-old tg-ArcSwe and nontransgenic mice were compared using Affymetrix microarray analysis. With surprisingly small overall changes, Wnt signaling was the most affected pathway with altered expression of nine genes in tg-ArcSwe mice. When analyzing mRNA levels of these genes in human brain, transcription factor 7-like 2 (TCF7L2) and v-myc myelocytomatosis viral oncogene homolog (MYC), were increased in Alzheimer's disease (AD) (P < .05). Furthermore, no clear differences in TCF7L2 and MYC mRNA were found in brains with frontotemporal lobar degeneration, suggesting that altered regulation of these Wnt-related genes could be specific to AD. Finally, mRNA levels of three neurogenesis markers were analyzed. Increased mRNA levels of dihydropyrimidinase-like 3 were observed in AD brain, suggesting that altered Wnt pathway regulation may signify synaptic rearrangement or neurogenesis.
doi:10.4061/2011/936580
PMCID: PMC3014771  PMID: 21234373

Results 1-13 (13)