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1.  Dimensional Anxiety Mediates Linkage of GABRA2 Haplotypes With Alcoholism 
The GABAAα2 receptor gene (GABRA2) modulates anxiety and stress response. Three recent association studies implicate GABRA2 in alcoholism, however in these papers both common, opposite-configuration haplotypes in the region distal to intron3 predict risk. We have now replicated the GABRA2 association with alcoholism in 331 Plains Indian men and women and 461 Finnish Caucasian men. Using a dimensional measure of anxiety, harm avoidance (HA), we also found that the association with alcoholism is mediated, or moderated, by anxiety. Nine SNPs were genotyped revealing two haplotype blocks. Within the previously implicated block 2 region, we identified the two common, opposite-configuration risk haplotypes, A and B. Their frequencies differed markedly in Finns and Plains Indians. In both populations, most block 2 SNPs were significantly associated with alcoholism. The associations were due to increased frequencies of both homozygotes in alcoholics, indicating the possibility of alcoholic subtypes with opposite genotypes. Congruently, there was no significant haplotype association. Using HA as an indicator variable for anxiety, we found haplotype linkage to alcoholism with high and low dimensional anxiety, and to HA itself, in both populations. High HA alcoholics had the highest frequency of the more abundant haplotype (A in Finns, B in Plains Indians); low HA alcoholics had the highest frequency of the less abundant haplotype (B in Finns, A in Plains Indians) (Finns: P α0.007, OR α2.1, Plains Indians: P α0.040, OR α1.9). Non-alcoholics had intermediate frequencies. Our results suggest that within the distal GABRA2 region is a functional locus or loci that may differ between populations but that alters risk for alcoholism via the mediating action of anxiety.
doi:10.1002/ajmg.b.30336
PMCID: PMC4516162  PMID: 16874763
SNPs; polymorphisms; GABAA; American Indian; harm avoidance
2.  FKBP5 Moderates Alcohol Withdrawal Severity: Human Genetic Association and Functional Validation in Knockout Mice 
Neuropsychopharmacology  2014;39(8):2029-2038.
Alcohol withdrawal is associated with hypothalamic–pituitary–adrenal (HPA) axis dysfunction. The FKBP5 gene codes for a co-chaperone, FK506-binding protein 5, that exerts negative feedback on HPA axis function. This study aimed to examine the effects of single-nucleotide polymorphisms (SNPs) of the FKBP5 gene in humans and the effect of Fkbp5 gene deletion in mice on alcohol withdrawal severity. We genotyped six FKBP5 SNPs (rs3800373, rs9296158, rs3777747, rs9380524, rs1360780, and rs9470080) in 399 alcohol-dependent inpatients with alcohol consumption 48 h before admission and recorded scores from the Clinical Institute Withdrawal Assessment-Alcohol revised (CIWA-Ar). Fkbp5 gene knockout (KO) and wild-type (WT) mice were assessed for alcohol withdrawal using handling-induced convulsions (HICs) following both acute and chronic alcohol exposure. We found the minor alleles of rs3800373 (G), rs9296158 (A), rs1360780 (T), and rs9470080 (T) were significantly associated with lower CIWA-Ar scores whereas the minor alleles of rs3777747 (G) and rs9380524 (A) were associated with higher scores. The haplotype-based analyses also showed an association with alcohol withdrawal severity. Fkbp5 KO mice showed significantly greater HICs during withdrawal from chronic alcohol exposure compared with WT controls. This study is the first to show a genetic effect of FKBP5 on the severity of alcohol withdrawal syndrome. In mice, the absence of the Fkbp5 gene enhances sensitivity to alcohol withdrawal. We suggest that FKBP5 variants may trigger different adaptive changes in HPA axis regulation during alcohol withdrawal with concomitant effects on withdrawal severity.
doi:10.1038/npp.2014.55
PMCID: PMC4059914  PMID: 24603855
3.  The interactive effect of MAOA-LPR genotype and childhood physical neglect on aggressive behaviors in Italian male prisoners 
Genes, brain, and behavior  2014;13(6):543-549.
Aggressive disorders are moderately heritable; therefore, identification of genetic influences is important. The X-linked MAOA gene, encoding the MAOA enzyme, has a functional 30bp repeat polymorphism in the promoter region (MAOA-LPR) that has been shown to influence aggression. Childhood trauma is a known risk factor for numerous psychopathologies in adulthood including aggressive behaviors. We investigated the interactive effect of MAOA-LPR genotype and a history of childhood trauma in predicting aggressive behaviors in a prisoner population. A total of 692 male prisoners were genotyped for MAOA-LPR with genotypes grouped into high and low transcriptional activity. Participant evaluations included measures of aggression (BGHA), hostility (Buss Durkee Hostility Inventory), impulsivity (Barratt Impulsiveness Scale), violence directed towards self and others, and childhood trauma (Childhood Trauma Questionnaire (CTQ)). MAOA-LPR interacted with CTQ physical neglect (PN), the most common (47%) form of childhood trauma in this sample, to predict BGHA aggression (P=0.002). Within the group not exposed to PN, carriers of the MAOA-LPR high activity variant were more aggressive: (t(R) =2.47, p<0.014). We observed a crossover effect in that the increase in aggression scores with PN was greater in low activity individuals (t(R) =5.55, p <0.0001) than in high activity individuals (t(R) =4.18, p <0.0001). These findings suggest that childhood trauma and the functional MAOA-LPR polymorphism may interact to specifically increase risk for over aggressive behavior but not impulsivity or hostility. The MAOA-LPR low activity variant may be protective against the development of aggressive behavior under low stress conditions, at least in this prisoner population.
doi:10.1111/gbb.12140
PMCID: PMC4130458  PMID: 24805005
MAOA-LPR genotype; aggressive behavior; BGHA; childhood trauma; CTQ; physical neglect; prisoners; MAOA-LPR low activity variant; MAOA-LPR high activity variant; interactive effect
4.  Attention to Threats and Combat-Related Posttraumatic Stress Symptoms 
JAMA psychiatry  2013;70(4):401-408.
Importance
Combat places soldiers at risk for post-traumatic stress disorder (PTSD). The excessive rates of PTSD and other adjustment disorders in soldiers returning home make it imperative to identify risk and resilience factors that could be targeted by novel therapeutic treatments.
Objective
To investigate the interplay among attention to threat, combat exposure, and other risk factors for PTSD symptoms in soldiers deployed to combat.
Design and Setting
Longitudinal prospective study of Israeli Defense Force infantry soldiers carried out in 2008 through 2010. Repeated measurements during a 1-year period included baseline and predeployment data collected in training camps and deployment data collected in the combat theater.
Participants
Infantry soldiers (1085 men; mean age,18.8 years).
Main Outcome Measures
Postcombat PTSD symptoms.
Results
Soldiers developed threat vigilance during combat deployment, particularly when they were exposed to high-intensity combat, as indicated by faster response times to targets appearing at the location of threat relative to neutral stimuli (P < .001). Threat-related attention bias also interacted with combat exposure to predict risk for PTSD (P <.05). Bias toward threat at recruitment (P <.001) and bias away from threat just before deployment (P < .05) predicted postcombat PTSD symptoms. Moreover, these threat-related attention associations with PTSD were moderated by genetic and environmental factors, including serotonin transporter (5-HTTLPR) genotype.
Conclusions and Relevance
Combat exposure interacts with threat-related attention to place soldiers at risk for PTSD, and interactions with other risk factors account for considerable variance in PTSD vulnerability. Understanding these associations informs research on novel attention bias modification techniques and prevention of PTSD.
doi:10.1001/2013.jamapsychiatry.188
PMCID: PMC4469781  PMID: 23407816
5.  Differential impact of serotonin transporter activity on temperament and behavior in persons with a family history of alcoholism in the Oklahoma Family Health Patterns project 
Background
Central serotonergic (5-HT) function is implicated in pathways to alcohol dependence, including dysphoria manifested by symptoms of anxiety and depression. However, little is known about genetic variation in central 5-HT function and its potential impact on temperament and behavior in persons with a family history of alcoholism (FH+).
Methods
We tested 314 healthy young adults (23.5 yr of age, 57% female; 193 FH− and 121 FH+) enrolled in the Oklahoma Family Health Patterns project, a study of alcoholism risk in relation to temperament and behavioral dyscontrol. Dysphoria was assessed using the Eysenck neuroticism and Beck depression scales, and Cloninger’s Tridimensional Personality Questionnaire. Risk taking was assessed with the Iowa Gambling Task (IGT) and Balloon Analogue Response Task (BART). All subjects were genotyped for a functional polymorphism (5-HTTLPR) in the promoter region of the serotonin transporter gene (SCL6A4).
Results
FH+ subjects with the gain-of-function 5-HTTLPR genotype scored higher in neuroticism, harm avoidance, and symptoms of Depression (p values ≤ .03). No effect of 5-HTTLPR genotype was seen in FH−. FH+ carriers of the gain-of-function 5-HTTLPR genotype played to minimize their frequency of losses in the IGT whereas FH− carriers played a balanced strategy (p < .003). No 5-HTTLPR effects were seen in the BART. Results were unaffected by sex, education, drug use, and antisocial characteristics.
Conclusions
The functional 5-HTTLPR polymorphism predicted significant variation in negative moods and poorer affect regulation in FH+ persons, with possible consequences for behavior, as seen in a simulated gambling task. This pattern may contribute to a drinking pattern that is compensatory for such affective tendencies.
doi:10.1111/acer.12412
PMCID: PMC4047646  PMID: 24796636
serotonin transporter; family history of alcoholism; anxiety; depression
6.  A Genome-Wide Copy Number Variant Study of Suicidal Behavior 
PLoS ONE  2015;10(5):e0128369.
Suicide and suicide attempts are complex behaviors that result from the interaction of different factors, including genetic variants that increase the predisposition to suicidal behaviors. Copy number variations (CNVs) are deletions or duplications of a segment of DNA usually larger than one kilobase. These structural genetic changes, although quite rare, have been associated with genetic liability to mental disorders, such as autism, schizophrenia, and bipolar disorder. No genome-wide level studies have been published investigating the potential role of CNVs in suicidal behaviors. Based on single-nucleotide polymorphism array data, we followed the Penn-CNV standards to detect CNVs in 1,608 subjects, comprising 475 suicide and suicide attempt cases and 1,133 controls. Although the initial algorithms determined the presence of CNVs on chromosomes 6 and 12 in seven and eight cases, respectively, compared with none of the controls, visual inspection of the raw data did not support this finding. Furthermore we were unable to validate these findings by CNV-specific real-time polymerase chain reaction. Additionally, rare CNV burden analysis did not find an association between the frequency or length of rare CNVs and suicidal behavior in our sample population. Although our findings suggest CNVs do not play an important role in the etiology of suicidal behaviors, they are not inconsistent with the strong evidence from the literature suggesting that other genetic variants account for a portion of the total phenotypic variability in suicidal behavior.
doi:10.1371/journal.pone.0128369
PMCID: PMC4444178  PMID: 26010658
7.  The missing heritability of behavior: The search continues 
Psychophysiology  2014;51(12):1327-1328.
Genetic variation altering behavior is elusive. This commentary discusses implications for the search for “missing heritability” posed by a unified series of studies from the Minnesota Center for Twin and Family Research. Endophenotypes are measured in a longitudinal cohort including twins, analyzed for heritability and genetically mapped via genome-wide association and genome sequencing. The genes identified account for a fraction of the heritability, but the manner in which the studies were conducted points to explanations other than methodology. The MCTFR data are an unprecedented addition to the research information commons. Other gene discoveries will follow when they are analyzed in new ways and in combination with other studies. Even larger samples may be needed. Alternatively or in addition, locus identification, especially rare alleles, may require the study of families and population isolates with founder characteristics.
doi:10.1111/psyp.12362
PMCID: PMC4427030  PMID: 25387714
Genome-wide association; Heritability; Endophenotype; Intermediate phenotype; Founder population; Rare allele; Polygenicity; Minnesota Center for Twin and Family Research
8.  Gene Expression in the Addicted Brain 
Addiction is due to changes in the structure and function of the brain, including neuronal networks and the cells that comprise them. Within cells, gene expression changes can track and help explain their altered function. Transcriptional changes induced by addictive agents are dynamic and divergent and range from signal pathway-specific perturbations to widespread molecular and cellular dysregulation that can be measured by “omic” methods and that can be used to identify new pathways. The molecular effects of addiction depend on timing of exposure or withdrawal, the stage of adaptation, the brain region, and the behavioral model, there being many models of addiction. However, the molecular neural adaptations across different drug exposures, conditions, and regions are to some extent shared and can reflect common actions on pathways relevant to addiction. Epigenetic studies of DNA methylation and histone modifications and studies of regulatory RNA networks have been informative for elucidating the mechanisms of transcriptional change in the addicted brain.
doi:10.1016/B978-0-12-801105-8.00010-2
PMCID: PMC4427035  PMID: 25172478
9.  The serotonin transporter gene is a substrate for age and stress dependent epigenetic regulation in rhesus macaque brain: Potential roles in genetic selection and Gene × Environment interactions 
Development and psychopathology  2012;24(4):1391-1400.
In humans, it has been demonstrated that the serotonin transporter linked polymorphic region (5-HTTLPR) genotype moderates risk in the face of adversity. One mechanism by which stress could interact with genotype is via epigenetic modifications. We wanted to examine whether stress interacted with genotype to predict binding of a histone 3 protein trimethylated at lysine 3 (H3K4me3) that marks active promoters. The brains (N = 61) of male rhesus macaques that had been reared in the presence or absence of stress were archived and the hippocampusi dissected. Chromatin immunoprecipitation was performed with an antibody against H3K4me3 followed by sequencing on a SolexaG2A. The effects of age, genotype (5-HTTLPR long/long vs. short), and stress exposure (peer-reared vs. mother-reared) on levels of H3K4me3 binding were determined. We found effects of age and stress exposure. There was a decline in H3K4me3 from preadolescence to postadolescence and lower levels in peer-reared monkeys and no effects of genotype. When we controlled for age, however, we found that there were effects of 5-HTTLPR genotype and rearing condition on H3K4me3 binding. In a larger sample, we observed that cerebrospinal fluid 5-hydroxyindoleacetic acid levels were subject to interactive effects among age, rearing history, and genotype. Genes containing both genetic selection and epigenetic regulation may be particularly important in stress adaptation and development. We find evidence for selection at the solute carrier family C6 member 4 gene and observe epigenetic reorganization according to genotype, stress, and age. These data suggest that developmental stage may moderate effects of stress and serotonin transporter genotype in the emergence of alternative adaptation strategies and in the vulnerability to developmental or psychiatric disorders.
doi:10.1017/S0954579412000788
PMCID: PMC4427037  PMID: 23062305
10.  Effects of Stressful Life Events, Maternal Depression and 5-HTTLPR Genotype on Emotional Symptoms in Pre-Adolescent Children† 
There has been a large but inconsistent literature on interactions between the 5-HTTLPR polymorphism of the serotonin transporter gene and adversity on emotional disorders. We investigated these interactions in 4,334 children from a birth longitudinal cohort: the Avon Longitudinal Study of Parents and Children (ALSPAC). We measured emotional symptoms at 7 years with the Strengths and Difficulties Questionnaire. Mothers rated stressful life events between ages 5 and 7 years. Maternal depression was defined as a score ≥12 on the Edinburgh Postnatal Depression Scale at 2 or 8 months postnatally. Triallelic genoptyping of the 5-HTTLPR polymorphism was performed. We found strong associations between stressful life events (OR 1.19; 1.12–1.26; P <0.01) and maternal postnatal depression (OR 1.91; 1.63–2.24; P <0.01) with emotional symptoms in the children. There were no main 5-HTTLPR genotype effects or significant interactions between genotype and life events or maternal postnatal depression on emotional symptoms. There was marginal evidence (P =0.08) for an interaction between stressful life events and genotype in boys only, with those in the low and high 5-HTTLPR expression groups showing stronger associations. In these 7-year-old children, we did not replicate previously reported G ×E interactions between 5-HTTLPR and life events for emotional symptoms. Gene by environment interactions may be developmentally dependent and show variation depending on the type and levels of exposure and sex. Young cohorts are essential to improve our understanding of the impact of development on gene and environment interactions.
doi:10.1002/ajmg.b.30888
PMCID: PMC4392724  PMID: 19016475
genotype; environment; interactions; depression; ALSPAC
11.  Loss aversion and 5HTT gene variants in adolescent anxiety 
Loss aversion, a well-documented behavioural phenomenon, characterizes decisions under risk in adult populations. As such, loss aversion may provide a reliable measure of risky behaviour. Surprisingly, little is known about loss aversion in adolescents, a group who manifests risk-taking behaviour, or in anxiety disorders, which is associated with risk-avoidance. Finally, loss aversion is expected to be modulated by genotype, particularly the serotonin transporter (SERT) gene variant, based on its role in anxiety and impulsivity. This genetic modulation may also differ between anxious and healthy adolescents, given their distinct propensities for risk taking. The present work examines the modulation of loss aversion, an index of risk-taking, and reaction-time to decision, an index of impulsivity, by the serotonin- transporter-gene-linked polymorphisms (5HTTLPR) in healthy and clinically anxious adolescents. Findings show that loss aversion (1) does manifest in adolescents, (2) does not differ between healthy and clinically anxious participants, and (3), when stratified by SERT genotype, identifies a subset of anxious adolescents who are high SERT-expressers, and show excessively low loss-aversion and high impulsivity. This last finding may serve as preliminary evidence for 5HTTLPR as a risk factor for the development of comorbid disorders associated with risk-taking and impulsivity in clinically anxious adolescents.
doi:10.1016/j.dcn.2013.10.002
PMCID: PMC3960326  PMID: 24280015
Risk-taking; microeconomics; lambda; impulsivity; development; risk-avoidance
12.  DRD4 and striatal modulation of the link between childhood behavioral inhibition and adolescent anxiety 
Behavioral inhibition (BI), a temperament characterized by vigilance to novelty, sensitivity to approach–withdrawal cues and social reticence in childhood, is associated with risk for anxiety in adolescence. Independent studies link reward hyper-responsivity to BI, adolescent anxiety and dopamine gene variants. This exploratory study extends these observations by examining the impact of DRD4 genotype and reward hyper-responsivity on the BI–anxiety link. Adolescents (N = 78) completed a monetary incentive delay task in the fMRI environment. Participants were characterized based on a continuous score of BI and the 7-repeat allele (7R+) of the DRD4 functional polymorphism. Parent-report and self-report measures of anxiety were also collected. Across the entire sample, striatal activation increased systematically with increases in the magnitude of anticipated monetary gains and losses. DRD4 status moderated the relation between BI and activation in the caudate nucleus. Childhood BI was associated with parent report of adolescent anxiety among 7R+ participants with elevated levels of striatal response to incentive cues. DRD4 genotype influenced the relations among neural response to incentives, early childhood BI and anxiety. The findings help refine our understanding of the role reward-related brain systems play in the emergence of anxiety in temperamentally at-risk individuals, building a foundation for future larger scale studies.
doi:10.1093/scan/nst001
PMCID: PMC3989122  PMID: 23314010
fMRI; caudate; reward; genetics; temperament
13.  Temporally sequenced anticancer drugs overcome adaptive resistance by targeting a vulnerable chemotherapy-induced phenotypic transition 
Nature Communications  2015;6:6139.
Understanding the emerging models of adaptive resistance is key to overcoming cancer chemotherapy failure. Using human breast cancer explants, in vitro cell lines, mouse in vivo studies and mathematical modelling, here we show that exposure to a taxane induces phenotypic cell state transition towards a favoured transient CD44HiCD24Hi chemotherapy-tolerant state. This state is associated with a clustering of CD44 and CD24 in membrane lipid rafts, leading to the activation of Src Family Kinase (SFK)/hemopoietic cell kinase (Hck) and suppression of apoptosis. The use of pharmacological inhibitors of SFK/Hck in combination with taxanes in a temporally constrained manner, where the kinase inhibitor is administered post taxane treatment, but not when co-administered, markedly sensitizes the chemotolerant cells to the chemotherapy. This approach of harnessing chemotherapy-induced phenotypic cell state transition for improving antitumour outcome could emerge as a translational strategy for the management of cancer.
Adaptive resistance is an emerging cause of chemotherapy failure in cancer. Here the authors show that adaptive resistance to taxanes is mediated by the upregulation of SFK/Hck survival signalling, and that sequential administration of taxanes and SFK/Hck inhibition restores tumor cell chemosensitivity.
doi:10.1038/ncomms7139
PMCID: PMC4339891  PMID: 25669750
14.  A GCH1 haplotype confers sex-specific susceptibility to pain crises and altered endothelial function in adults with sickle cell anemia 
American journal of hematology  2014;89(2):187-193.
GTP cyclohydrolase (GCH1) is rate limiting for tetrahydrobiopterin (BH4) synthesis, where BH4 is a cofactor for nitric oxide (NO) synthases and aromatic hydroxylases. GCH1 polymorphisms are implicated in the pathophysiology of pain, but have not been investigated in African populations. We examined GCH1 and pain in sickle cell anemia where GCH1 rs8007267 was a risk factor for pain crises in discovery (n = 228; odds ratio [OR] 2.26; P = 0.009) and replication (n = 513; OR 2.23; P = 0.004) cohorts. In vitro, cells from sickle cell anemia subjects homozygous for the risk allele produced higher BH4. In vivo physiological studies of traits likely to be modulated by GCH1 showed rs8007267 is associated with altered endothelial dependent blood flow in females with SCA (8.42% of variation; P = 0.002). The GCH1 pain association is attributable to an African haplotype with where its sickle cell anemia pain association is limited to females (OR 2.69; 95% CI 1.21–5.94; P = 0.01) and has the opposite directional association described in Europeans independent of global admixture. The presence of a GCH1 haplotype with high BH4 in populations of African ancestry could explain the association of rs8007267 with sickle cell anemia pain crises. The vascular effects of GCH1 and BH4 may also have broader implications for cardiovascular disease in populations of African ancestry.
doi:10.1002/ajh.23613
PMCID: PMC4281092  PMID: 24136375
15.  Functional genetic variants in the vesicular monoamine transporter 1 (VMAT1) modulate emotion processing 
Molecular psychiatry  2013;19(1):129-139.
SUMMARY
Emotional behavior is in part heritable and often disrupted in psychopathology. Identification of specific genetic variants that drive this heritability may provide important new insight into molecular and neurobiological mechanisms involved in emotionality. Our results demonstrate that the presynaptic vesicular monoamine transporter 1 (VMAT1) Thr136Ile (rs1390938) polymorphism is functional in vitro, with the Ile allele leading to increased monoamine transport into presynaptic vesicles. Moreover, we show that the Thr136Ile variant predicts differential responses in emotional brain circuits consistent with its effects in vitro. Lastly, deep sequencing of bipolar disorder (BPD) patients and controls identified several rare novel VMAT1 variants. The variant Phe84Ser was only present in individuals with BPD and leads to marked increase monoamine transport in vitro. Taken together, our data show that VMAT1 polymorphisms influence monoamine signaling, the functional response of emotional brain circuits, and risk for psychopathology.
doi:10.1038/mp.2012.193
PMCID: PMC4311877  PMID: 23337945
16.  Roles of COMT, NPY and GCH1 in acute and chronic pain/stress response 
Molecular Pain  2014;10(Suppl 1):O5.
doi:10.1186/1744-8069-10-S1-O5
PMCID: PMC4304376
17.  Valence-Specific Effects of BDNF Val66Met Polymorphism on Dopaminergic Stress and Reward Processing in Humans 
The Journal of Neuroscience  2014;34(17):5874-5881.
Brain-derived neurotrophic factor (BDNF) levels in dopaminergic (DA) cells within the ventral tegmental area (VTA)/nucleus accumbens (NAc) circuitry appear to be a candidate mechanism for the neuroadaptive changes that follow stress and reward responses in animal models. However, the role of the BDNF gene variants in responses to salient cues through DA neurotransmission in humans remains unexplored. Here, we studied the effect of the common functional BDNF Val66Met (rs6265) polymorphism on rewarding experiences in the striatum and DA-mediated responses to stress. Seventy-two healthy controls were genotyped for the BDNF Val66Met polymorphism and underwent the monetary incentive delay task during an functional magnetic resonance imaging (fMRI) session. Forty-nine of them also underwent a sustained pain challenge with and without placebo administration with potential analgesic properties during PET measures of DA D2/3-receptor-mediated neurotransmission. Neuroimaging results revealed a significant effect of BDNF (Met66 carriers > Val/Val) on brain responses during the anticipation of monetary losses, baseline D2/3 receptor availability, and pain-stress-induced DA release in the NAc. Conversely, BDNF Met66 carriers showed no activation in response to monetary gains and a blunted DA response to the analgesic placebo in the NAc. These results provide initial human evidence regarding the effect of the BDNF Val66Met polymorphism on DA-mediated responses to stress, its cognitive regulation by positive expectations, and the anticipatory responses to monetary gains and losses in the VTA-NAc pathway. Our results are of relevance to the neurobiology of stress and reward interactions and the pathophysiology of stress-related disorders.
doi:10.1523/JNEUROSCI.2152-13.2014
PMCID: PMC3996214  PMID: 24760847
BDNF Val66Met; dopamine; nucleus accumbens; pain; reward; stress
18.  Brief Report: Autistic Symptoms, Developmental Regression, Mental Retardation, Epilepsy, and Dyskinesias in CNS Folate Deficiency 
We studied seven children with CNS folate deficiency (CFD). All cases exhibited psychomotor retardation, regression, cognitive delay, and dyskinesia; six had seizures; four demonstrated neurological abnormalities in the neonatal period. Two subjects had profound neurological abnormalities that precluded formal behavioral testing. Five subjects received ADOS and ADI-R testing and met diagnostic criteria for autism or autism spectrum disorders. They exhibited difficulties with transitions, insistence on sameness, unusual sensory interests, and repetitive behaviors. Those with the best language skills largely used repetitive phrases. No mutations were found in folate transporter or folate enzyme genes. These findings demonstrate that autistic features are salient in CFD and suggest that a subset of children with developmental regression, mental retardation, seizures, dyskinesia, and autism may have CNS folate abnormalities.
doi:10.1007/s10803-007-0492-z
PMCID: PMC4131536  PMID: 18027081
Folic Acid; 5-methyltetrahydrofolate; 5-MTHF; Cerebral folate deficiency; Folate transporters; Autism
19.  Annotated features of domestic cat – Felis catus genome 
GigaScience  2014;3:13.
Background
Domestic cats enjoy an extensive veterinary medical surveillance which has described nearly 250 genetic diseases analogous to human disorders. Feline infectious agents offer powerful natural models of deadly human diseases, which include feline immunodeficiency virus, feline sarcoma virus and feline leukemia virus. A rich veterinary literature of feline disease pathogenesis and the demonstration of a highly conserved ancestral mammal genome organization make the cat genome annotation a highly informative resource that facilitates multifaceted research endeavors.
Findings
Here we report a preliminary annotation of the whole genome sequence of Cinnamon, a domestic cat living in Columbia (MO, USA), bisulfite sequencing of Boris, a male cat from St. Petersburg (Russia), and light 30× sequencing of Sylvester, a European wildcat progenitor of cat domestication. The annotation includes 21,865 protein-coding genes identified by a comparative approach, 217 loci of endogenous retrovirus-like elements, repetitive elements which comprise about 55.7% of the whole genome, 99,494 new SNVs, 8,355 new indels, 743,326 evolutionary constrained elements, and 3,182 microRNA homologues. The methylation sites study shows that 10.5% of cat genome cytosines are methylated. An assisted assembly of a European wildcat, Felis silvestris silvestris, was performed; variants between F. silvestris and F. catus genomes were derived and compared to F. catus.
Conclusions
The presented genome annotation extends beyond earlier ones by closing gaps of sequence that were unavoidable with previous low-coverage shotgun genome sequencing. The assembly and its annotation offer an important resource for connecting the rich veterinary and natural history of cats to genome discovery.
doi:10.1186/2047-217X-3-13
PMCID: PMC4138527  PMID: 25143822
Felis catus; Domestic cat; Felis silvestris silvestris; European wildcat; Genome sequence; Annotation; Assembly
20.  Antibody Responses to Cryptococcus neoformans in Indian Patients with Cryptococcosis 
Medical mycology  2008;46(5):457-463.
SUMMARY
An important element of the host response to cryptococcosis is humoral immunity. Specific antibody responses in patients with cryptococcosis however, have not been extensively studied. We analyzed the antibody responses of 22 Indian patients with cryptococcosis, including both HIV+ and HIV- individuals. Sera from 10 Indian patients with AIDS and without cryptococcosis were studied as controls. Antibody responses to cryptococcal proteins were detected by immunoblot, while antibodies to glucuronoxylomannan (GXM), the main component of the cryptococcal capsular polysaccharide were measured by ELISA. Our results indicate that cryptococcosis elicits antibodies to a specific pattern of cytoplasmic proteins. Further, we find that antibody responses to both cytoplasmic proteins and GXM are less robust in HIV+ patients when compared with HIV- patients.
doi:10.1080/13693780801961345
PMCID: PMC4100580  PMID: 18608912
Cryptococcus neoformans; cryptococcosis; serology; AIDS
21.  Taking Humor Seriously: Talking about Drinking in Native American Focus Groups 
Medical anthropology  2011;30(3):295-318.
Focus groups provide a source of data that highlight community ideas on a topic of interest. How interview data will be utilized varies by project. With this in mind, we identify ways that focus group data from a particular population (Native American) articulate a health issue of individual tribal concern (alcohol consumption). Taking our analytic framework from linguistics, one of the four fields of inquiry in anthropology, we examine format ties and the performance of humor as stylistic features of tribal focus groups and illustrate how linguistic devices can be used in analyzing aspects of adolescent and adult drinking. Focus group data require systematic review and analysis to identify useful findings that can lead to inquiry points to initiate collaborative work with local experts before the data can be developed and configured into effective program initiatives.
doi:10.1080/01459740.2011.560584
PMCID: PMC4086914  PMID: 21590583
adults and adolescents; drinking; humor; linguistic analysis; Native Americans
22.  Independent Effects of 5' and 3' Functional Variants in the Serotonin Transporter Gene on Suicidal Behavior in the Context of Childhood Trauma 
Journal of psychiatric research  2013;47(7):900-907.
The serotonin transporter, encoded by the SLC6A4 gene, influences the synaptic actions of serotonin and is responsive to stress hormones. We hypothesized that 5-HTTLPR, a functional SLC6A4 promoter polymorphism, and two tightly-linked, putatively functional 3' UTR SNPs (rs3813034, rs1042173) might have independent effects on suicidal behavior in the context of childhood trauma (CT).
DNA and Childhood Trauma Questionnaire scores were available for a total of 474 African Americans, including 112 suicide attempters and 362 non-suicide attempters. Genotyping was performed for the triallelic 5-HTTLPR polymorphism, 14 SLC6A4 haplotype-tagging SNPs, and 186 ancestry informative markers.
There were independent G × E interactive effects of 5-HTTLPR (p=0.017) and the rs3813034-rs1042173 diplotype (p=0.011) on suicidal behavior. In individuals exposed to high CT the risk of suicide attempt was 0.52 in carriers of the low activity 5-HTTLPR variant and 0.32 in medium/high activity variant carriers. Likewise, CT exposed carriers of the major rs3813034-rs1042173 ATAT diplotype had an increased risk of suicidal behavior relative to the ATCG/CGCG diplotype carriers (0.40 vs 0.31). Neither the 5' nor the 3' functional variants had an effect in individuals without CT: suicide attempt risk = 0.12 – 0.22. In individuals exposed to high CT the prevalence of suicide attempt was 0.56 in carriers of both 5' and 3' risk variants, 0.39 in carriers of one risk variant and 0.25 in individuals without either risk variant.
Our findings suggest that the 5' and 3' SLC6A4 functional variants have independent effects on the risk for suicidal behavior in CT exposed individuals.
doi:10.1016/j.jpsychires.2013.03.007
PMCID: PMC3646970  PMID: 23558235
SLC6A4; 5-HTTLPR; substance dependence; rs3813034; rs1042173; suicide attempt
23.  Management of Fever in Postpneumococcal Vaccine Era: Comparison of Management Practices by Pediatric Emergency Medicine and General Emergency Medicine Physicians 
Background. The primary objective of this study was to compare management practices of general emergency physicians (GEMPs) and pediatric emergency medicine physicians (PEMPs) for well-appearing young febrile children. Methods. We retrospectively reviewed the charts of well-appearing febrile children aged 3–36 months who presented to a large urban children's hospital (PED), staffed by PEMPs, or a large urban general emergency department (GED), staffed by GEMPs. Demographics, immunization status, laboratory tests ordered, antibiotic usage, and final diagnoses were collected. Results. 224 cases from the PED and 237 cases from the GED were reviewed. Children seen by PEMPs had significantly less CXRs (23 (10.3%) versus 51 (21.5%), P = 0.001) and more rapid viral testing done (102 (45%) versus 40 (17%), P < 0.0001). A diagnosis of a viral infection was more common in the PED, while a diagnosis of bacterial infection (including otitis media) was more common in the GED. More GED patients were prescribed antibiotics (41% versus 27%, P = 0.002), while more PED patients were treated with oseltamivir (6.7% versus 0.4%, P < 0.001). Conclusions. Our findings identify important differences in the care of the young, well-appearing febrile child by PEMPs and GEMPs and highlight the need for standardization of care.
doi:10.1155/2014/702053
PMCID: PMC4058597  PMID: 24982807
24.  Associations between prefrontal γ-aminobutyric acid concentration and the tryptophan hydroxylase isoform 2 gene, a panic disorder risk allele in women 
Interactions between the central serotonergic and γ-aminobutyric acid (GABA) systems play key roles in the prefrontal cortical regulation of emotion and cognition and in the pathophysiology and pharmacotherapy of highly prevalent psychiatric disorders. The goal of this study was to test the effects of common variants of the tryptophan hydroxylase isoform 2 (TPH2) gene on GABA concentration in the prefrontal cortex (PFC) using magnetic resonance spectroscopy. In this study involving 64 individuals, we examined the associations between prefrontal cortical GABA concentration and 12 single nucleotide polymorphisms (SNPs) spanning the TPH2 gene, including rs4570625 (–703 G/T SNP), a potentially functional TPH2 polymorphism that has been associated with decreased TPH2 mRNA expression and panic disorder. Our results revealed a significant association between increased GABA concentration in the PFC and the T-allele frequencies of 2 TPH2 SNPs, namely, rs4570625 (of –703 G/T) and rs2129575 (p ≤ 0.0004) and the C-allele frequency of 1 TPH2 SNP, namely, rs1386491 (p = 0.0003) in female subjects. We concluded that rs4570625 (–703 G/T), rs2129575, and rs1386491 play a significant role in GABAergic neurotransmission and may contribute to the sex-specific dysfunction of the GABAergic system in the PFC.
doi:10.1017/S1461145713000254
PMCID: PMC4025920  PMID: 23552096
GABA; tryptophan hydroxylase 2; magnetic resonance spectroscopy; single nucleotide polymorphisms; genetics
25.  Age-modulated association between prefrontal NAA and the BDNF gene 
Brain-derived neurotrophic factor (BDNF) has been implicated in the pathophysiology of psychiatric and neurological disorders and in the mechanisms of antidepressant pharmacotherapy. Psychiatric and neurological conditions have also been associated with reduced brain levels of N-acetyl-aspartate (NAA), which has been used as a putative marker of neural integrity. However, few studies have explored the relationship between BDNF polymorphisms and NAA levels directly. Here, we present data from a single-voxel proton magnetic resonance spectroscopy study of 64 individuals and explore the relationship between BDNF polymorphisms and prefrontal NAA level. Our results indicate an association between a single nucleotide polymorphism (SNP) within BDNF, known as rs1519480, and reduced NAA level (p=0.023). NAA levels were further predicted by age and Asian ancestry. There was a significant interaction between rs1519480 and age on NAA level (p=0.031) Specifically, the effect of rs1519480 on NAA level became significant at age ≥ 34.17. NAA level decreased with advancing age for genotype TT (p=0.001) but not for genotype CT (p=0.82) or CC (p=0.34). Additional in silico analysis of 142 postmortem brain samples revealed an association between the same SNP and reduced BDNF mRNA expression in the prefrontal cortex. The rs1519480 SNP influences BDNF mRNA expression and has an impact on prefrontal NAA level over time. This genetic mechanism may contribute to interindividual variation in cognitive performance seen during normal aging, as well as contributing to the risk for developing psychiatric and neurological conditions.
doi:10.1017/S1461145712001204
PMCID: PMC4025926  PMID: 23253771
BDNF; N-acetyl-aspartate; proton magnetic resonance spectroscopy; SNP; genetic variation

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