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1.  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.
PMCID: PMC4281092  PMID: 24136375
2.  Functional genetic variants in the vesicular monoamine transporter 1 (VMAT1) modulate emotion processing 
Molecular psychiatry  2013;19(1):129-139.
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.
PMCID: PMC4311877  PMID: 23337945
3.  Roles of COMT, NPY and GCH1 in acute and chronic pain/stress response 
Molecular Pain  2014;10(Suppl 1):O5.
PMCID: PMC4304376
4.  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.
PMCID: PMC3996214  PMID: 24760847
BDNF Val66Met; dopamine; nucleus accumbens; pain; reward; stress
5.  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.
PMCID: PMC4131536  PMID: 18027081
Folic Acid; 5-methyltetrahydrofolate; 5-MTHF; Cerebral folate deficiency; Folate transporters; Autism
6.  Annotated features of domestic cat – Felis catus genome 
GigaScience  2014;3:13.
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.
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.
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.
PMCID: PMC4138527  PMID: 25143822
Felis catus; Domestic cat; Felis silvestris silvestris; European wildcat; Genome sequence; Annotation; Assembly
7.  Antibody Responses to Cryptococcus neoformans in Indian Patients with Cryptococcosis 
Medical mycology  2008;46(5):457-463.
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.
PMCID: PMC4100580  PMID: 18608912
Cryptococcus neoformans; cryptococcosis; serology; AIDS
8.  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.
PMCID: PMC4086914  PMID: 21590583
adults and adolescents; drinking; humor; linguistic analysis; Native Americans
9.  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.
PMCID: PMC3646970  PMID: 23558235
SLC6A4; 5-HTTLPR; substance dependence; rs3813034; rs1042173; suicide attempt
10.  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.
PMCID: PMC4058597  PMID: 24982807
11.  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.
PMCID: PMC4025920  PMID: 23552096
GABA; tryptophan hydroxylase 2; magnetic resonance spectroscopy; single nucleotide polymorphisms; genetics
12.  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.
PMCID: PMC4025926  PMID: 23253771
BDNF; N-acetyl-aspartate; proton magnetic resonance spectroscopy; SNP; genetic variation
13.  Genetics of impulsive behaviour 
Impulsivity, defined as the tendency to act without foresight, comprises a multitude of constructs and is associated with a variety of psychiatric disorders. Dissecting different aspects of impulsive behaviour and relating these to specific neurobiological circuits would improve our understanding of the etiology of complex behaviours for which impulsivity is key, and advance genetic studies in this behavioural domain. In this review, we will discuss the heritability of some impulsivity constructs and their possible use as endophenotypes (heritable, disease-associated intermediate phenotypes). Several functional genetic variants associated with impulsive behaviour have been identified by the candidate gene approach and re-sequencing, and whole genome strategies can be implemented for discovery of novel rare and common alleles influencing impulsivity. Via deep sequencing an uncommon HTR2B stop codon, common in one population, was discovered, with implications for understanding impulsive behaviour in both humans and rodents and for future gene discovery.
PMCID: PMC3638385  PMID: 23440466
impulsivity; heritability; genes; sequencing; HTR2B
14.  DRD2/ANKK1 Taq1A polymorphism (rs1800497) has opposing effects on D2/3 receptor binding in healthy controls and patients with major depressive disorder 
The A1 allele of the DRD2/ANKK1 Taq1A polymorphism (rs1800497) is associated with reduced striatal D2/3 receptor binding in healthy individuals (Con) as well as depression and addiction. However, the effect of rs1800497 on D2/3 receptor binding in depressed patients as well as the SNP’s effect on D2/3 binding during reward-associated dopamine release is unknown. Twelve unmedicated patients with major depressive disorder (MDD) and 24 Con completed PET scans with [11C]raclopride, once without receiving monetary rewards (baseline) and once while winning money. In Con, the A1 allele was associated with reduced baseline binding potential (BPND) in the middle caudate and ventral striatum. However, in MDD patients the A1 allele was associated with increased baseline BPND in these regions. There were no significant associations between rs1800497 and change in BPND during reward-associated dopamine release. Conceivably, the A1 allele predisposes to depression and addiction via its effect on the post-synaptic D2 receptor.
PMCID: PMC3758772  PMID: 23683269
Depression; dopamine 2 receptor; positron emission tomography; reward; Taq1A
15.  Preservation of General Intelligence following Traumatic Brain Injury: Contributions of the Met66 Brain-Derived Neurotrophic Factor 
PLoS ONE  2014;9(2):e88733.
Brain-derived neurotrophic factor (BDNF) promotes survival and synaptic plasticity in the human brain. The Val66Met polymorphism of the BDNF gene interferes with intracellular trafficking, packaging, and regulated secretion of this neurotrophin. The human prefrontal cortex (PFC) shows lifelong neuroplastic adaption implicating the Val66Met BDNF polymorphism in the recovery of higher-order executive functions after traumatic brain injury (TBI). In this study, we examined the effect of this BDNF polymorphism on the preservation of general intelligence following TBI. We genotyped a sample of male Vietnam combat veterans (n = 156) consisting of a frontal lobe lesion group with focal penetrating head injuries for the Val66Met BDNF polymorphism. Val/Met did not differ from Val/Val genotypes in general cognitive ability before TBI. However, we found substantial average differences between these groups in general intelligence (≈ half a standard deviation or 8 IQ points), verbal comprehension (6 IQ points), perceptual organization (6 IQ points), working memory (8 IQ points), and processing speed (8 IQ points) after TBI. These results support the conclusion that Val/Met genotypes preserve general cognitive functioning, whereas Val/Val genotypes are largely susceptible to TBI.
PMCID: PMC3935849  PMID: 24586380
16.  Grey Matter Volume in Adolescent Anxiety: An Impact of the Brain-Derived Neurotropic Factor Val66Met Polymorphism? 
Minimal research links anxiety disorders in adolescents to regional gray matter volume (GMV) abnormalities and their modulation by genetic factors. Prior research suggests that a brain-derived neurotrophic factor (BNDF) Val66Met polymorphism may modulate such brain morphometry profiles.
Using voxel-based morphometry and magnetic resonance imaging, associations of BDNF and clinical anxiety with regional GMVs of anterior cingulate cortex, insula, amygdala, and hippocampus were examined in 39 affected (17 Met allele carriers, 22 Val/Val homozygotes) and 63 nonaffected adolescents (27 Met allele carriers, 36 Val/Val homozygotes).
Amygdala and anterior hippocampal GMVs were significantly smaller in patients than healthy adolescents, with a reverse pattern for the insula. Post-hoc regression analyses indicated a specific contribution of social phobia to the GMV reductions in the amygdala and hippocampus. Additionally, insula and dorsal– anterior cingulate cortex (ACC) GMVs were modulated by BDNF genotype. In both regions, GMVs were larger in the Val/Val homozygote patients than in those carrying the Met allele.
These results implicate reduced GMV in the amygdala and hippocampus in pediatric anxiety, particularly social phobia. In addition, the data suggest that genetic factors may modulate differences in the insula and dorsal ACC.
PMCID: PMC3570270  PMID: 23357445
BDNF; VBM; adolescence; anxiety; insula
17.  Genome-wide association study implicates NDST3 in schizophrenia and bipolar disorder 
Nature Communications  2013;4:2739.
Schizophrenia and bipolar disorder are major psychiatric disorders with high heritability and overlapping genetic variance. Here we perform a genome-wide association study in an ethnically homogeneous cohort of 904 schizophrenia cases and 1,640 controls drawn from the Ashkenazi Jewish population. We identify a novel genome-wide significant risk locus at chromosome 4q26, demonstrating the potential advantages of this founder population for gene discovery. The top single-nucleotide polymorphism (SNP; rs11098403) demonstrates consistent effects across 11 replication and extension cohorts, totalling 23, 191 samples across multiple ethnicities, regardless of diagnosis (schizophrenia or bipolar disorder), resulting in Pmeta=9.49 × 10−12 (odds ratio (OR)=1.13, 95% confidence interval (CI): 1.08–1.17) across both disorders and Pmeta=2.67 × 10−8 (OR=1.15, 95% CI: 1.08–1.21) for schizophrenia alone. In addition, this intergenic SNP significantly predicts postmortem cerebellar gene expression of NDST3, which encodes an enzyme critical to heparan sulphate metabolism. Heparan sulphate binding is critical to neurite outgrowth, axon formation and synaptic processes thought to be aberrant in these disorders.
Schizophrenia and bipolar disorder are important psychiatric disorders with overlapping genetic components. Here, the authors identify and replicate a genome-wide significant risk locus for the two disorders, and suggest a role for NDST3 in severe psychiatric disease.
PMCID: PMC3905728  PMID: 24253340
18.  A large-scale candidate gene analysis of mood disorders: evidence of neurotrophic tyrosine kinase receptor and opioid receptor signaling dysfunction 
Psychiatric genetics  2013;23(2):10.1097/YPG.0b013e32835d7028.
Despite proven heritability, little is known about the genetic architecture of mood disorders. Although a number of family and case–control studies have examined the genetics of mood disorders, none have carried out joint linkage-association studies and sought to validate the results with gene expression analyses in an independent cohort.
We present findings from a large candidate gene study that combines linkage and association analyses using families and singletons, providing a systematic candidate gene investigation of mood disorder. For this study, 876 individuals were recruited, including 83 families with 313 individuals and 563 singletons. This large-scale candidate gene analysis included 130 candidate genes implicated in addictive and other psychiatric disorders. These data showed significant genetic associations for 28 of these candidate genes, although none remained significant after correction for multiple testing. To evaluate the functional significance of these 28 candidate genes in mood disorders, we examined the transcriptional profiles of these genes within the dorsolateral prefrontal cortex and anterior cingulate for 21 cases with mood disorders and 25 nonpsychiatric controls, and carried out a pathway analysis to identify points of high connectivity suggestive of particular molecular pathways that may be dysregulated.
Two primary gene candidates were supported by the linkage-association, gene expression profiling, and network analysis: neurotrophic tyrosine kinase receptor, type 2 (NTRK2), and the opioid receptor, κ1 (OPRK1).
This study supports a role for NTRK2 and OPRK1 signaling in the pathophysiology of mood disorder. The unique approach incorporating evidence from multiple experimental and computational modalities enhances confidence in these findings.
PMCID: PMC3869619  PMID: 23277131
linkage and association; mood disorders; neurotrophic tyrosine kinase receptor; opioid receptor; type 2; κ1
19.  The Influence of Oxytocin Administration on Responses to Infant Faces and Potential Moderation by OXTR Genotype 
Psychopharmacology  2012;224(4):469-476.
Oxytocin is a neuropeptide that is associated with increases in social affiliative behaviors, particularly toward infants. However, no previous study has investigated healthy adults’ responses to infant faces following oxytocin administration. In addition, given that preliminary evidence suggests that a single nucleotide polymorphism (SNP) of the oxytocin receptor (OXTR) gene, rs53576, may influence behaviors associated with parental sensitivity, we assessed whether such responses vary according to OXTR rs53576 genotype.
The present study assessed the effects of intranasally administered oxytocin and OXTR genotype on human adults’ preferences for infant faces.
A double-blind, between-groups design was used, with 57 genotyped volunteers randomly assigned to receive intranasally administered oxytocin or placebo. Fifty minutes following the administration of oxytocin or placebo, participants viewed infants’ and adults’ faces showing neutral expressions and assessed how appealing they found each face.
Infants’ faces were more strongly preferred following oxytocin inhalation relative to placebo. When participants were separated according to genotype, this effect was only observed for participants homozygous for the rs53576G allele. Parallel effects were not seen for adults’ faces.
The present results are consistent with the hypothesis that acute oxytocin administration increases sensitivity to reward-relevant features of infants and/or reduces sensitivity to their aversive properties. The results also are consistent with suggestions of more efficient oxytocinergic function in rs53576G homozygotes.
PMCID: PMC3500580  PMID: 22763666
Oxytocin; OXTR; parental; faces; affiliation
20.  BDNF Polymorphism–Dependent OFC and DLPFC Plasticity Differentially Moderates Implicit and Explicit Bias 
Cerebral Cortex (New York, NY)  2011;22(11):2602-2609.
This study examined the role of orbitofrontal cortex (OFC) and dorsolateral prefrontal cortex (DLPFC) plasticity in controlling implicit and explicit social biases. Normal controls and patients with varied OFC and DLPFC lesion size and single nucleotide polymorphisms (SNPs) in the brain-derived neurotrophic factor (BDNF) gene, which promotes (methionine–valine [Met/Val] SNP) or stifles (valine–valine [Val/Val] SNP) plasticity in damaged PFC regions, completed measures of implicit and explicit social bias. Patients and controls demonstrated comparable levels of implicit bias, but patients with Met/Val SNPs exhibited less implicit bias when they had smaller OFC lesions compared with Val/Val patients with similar size lesions and those with large OFC lesions. Both patients and controls demonstrated patterns of explicit bias consistent with hypotheses. Patients with Met/Val SNPs exhibited less explicit bias when they had smaller DLPFC lesions sizes compared with Val/Val patients with similar size lesions and those with large DLPFC lesions. OFC lesion size and BDNF SNP type did not moderate explicit bias; DLPFC lesion size and BDNF SNP type did not moderate implicit bias (nor did other medial or lateral regions). Findings suggest that plasticity within specific PFC regions modulates the type and degree of social bias that individuals’ exhibit.
PMCID: PMC3464413  PMID: 22123938
BDNF; implicit and explicit bias; PFC plasticity; social neuroscience; TBI
21.  Brain Serotonin Transporter Binding in Depressed Patients With Bipolar Disorder Using Positron Emission Tomography 
Archives of general psychiatry  2007;64(2):201-208.
Depression in bipolar disorder is clinically indistinguishable from that observed in major depressive disorder. As in major depression, selective serotonin reuptake inhibitors targeting brain serotonin transporters are first-line treatments for bipolar depression. Associations of serotonin transporter promoter polymorphisms and bipolarity have been reported; however, research on alterations in serotonergic neurotransmission in bipolar depression remains scant.
To assess in vivo brain serotonin transporter binding potential (BP1, proportional to serotonin transporter number) in patients with bipolar depression and controls and to examine the relationship between serotonin transporter binding and genotype.
Case-control study.
University hospital.
A sample of 18 medication-free patients with bipolar depression and 41 controls.
Main Outcome Measures
In vivo brain serotonin transporter binding was measured using positron emission tomography and radiolabeled trans-1,2,3,5,6,10-β-hexahydro-6-[4-(methylthio) phenyl]pyrrolo-[2,1-a]-isoquinoline ([11C](+)-McNeil 5652). Participants were genotyped assessing biallelic and triallelic 5-HTTLPR polymorphisms.
Patients with bipolar disorder had 16% to 26% lower serotonin transporter BP1 in the midbrain, amygdala, hippocampus, thalamus, putamen, and anterior cingulate cortex. Triallelic 5-HTTLPR genotypes were unrelated to serotonin transporter BP1.
Lower serotonin transporter BP1 in bipolar depression overlaps with that observed in major depression and suggests that serotonergic dysfunction is common to depressive conditions.
PMCID: PMC3767993  PMID: 17283287
22.  Old Cryptococcus neoformans Cells Contribute to Virulence in Chronic Cryptococcosis 
mBio  2013;4(4):e00455-13.
Does cell age matter in virulence? The emergence of persister cells during chronic infections is critical for persistence of infection, but little is known how this occurs. Here, we demonstrate for the first time that the replicative age of the fungal pathogen Cryptococcus neoformans contributes to persistence during chronic meningoencephalitis. Generationally older C. neoformans cells are more resistant to hydrogen peroxide stress, macrophage intracellular killing, and antifungal agents. Older cells accumulate in both experimental rat infection and in human cryptococcosis. Mathematical modeling supports the concept that the presence of older C. neoformans cells emerges from in vivo selection pressures. We propose that advanced replicative aging is a new unanticipated virulence trait that emerges during chronic fungal infection and facilitates persistence. Therapeutic interventions that target old cells could help in the clearance of chronic infections.
Our findings that the generational age of Cryptococcus neoformans cells matters in pathogenesis introduces a novel concept to eukaryotic pathogenesis research. We propose that emerging properties of aging C. neoformans cells and possibly also other fungal pathogens contribute to persistence and virulence. Whereas the replicative life span of strains may not matter for virulence per se, age-related resilience and thus the generational age of individual C. neoformans cells within a pathogen population could greatly affect persistence of the pathogen population and therefore impact outcome.
PMCID: PMC3747583  PMID: 23943761
23.  Oxytocin Gene Polymorphisms Influence Human Dopaminergic Function in a Sex Dependent Manner 
Biological Psychiatry  2012;72(3):198-206.
Oxytocin, classically involved in social and reproductive activities, is increasingly recognized as an antinociceptive and anxiolytic agent, effects which may be mediated via oxytocin’s interactions with the dopamine system. Thus, genetic variation within the oxytocin gene (OXT) is likely to explain variability in dopamine-related stress responses. As such, we examined how OXT variation is associated with stress-induced dopaminergic neurotransmission in a healthy human sample.
Fifty-five young healthy volunteers were scanned using [11C] raclopride positron emission tomography while they underwent a standardized physical and emotional stressor that consisted of moderate levels of experimental sustained deep muscle pain, and a baseline, control state. Four haplotype tagging single nucleotide polymorphisms located in regions near OXT were genotyped. Measures of pain, affect, anxiety, well-being and interpersonal attachment were also assessed.
Female rs4813625 C allele carriers demonstrated greater stress-induced dopamine release, measured as reductions in receptor availability from baseline to the pain-stress condition relative to female GG homozygotes. No significant differences were detected among males. We also observed that female rs4813625 C allele carriers exhibited higher attachment anxiety, higher trait anxiety and lower emotional well-being scores. In addition, greater stress-induced dopamine release was associated with lower emotional well-being scores in female rs4813625 C allele carriers.
Our results suggest that variability within the oxytocin gene appear to explain interindividual differences in dopaminergic responses to stress, which are shown to be associated with anxiety traits, including those linked to attachment style, as well as emotional well-being in women.
PMCID: PMC3392442  PMID: 22418012
oxytocin; genetics; dopamine; positron emission tomography; humans; sex differences
24.  “Alcohol is Something That Been With Us Like a Common Cold”: Community Perceptions of American Indian Drinking 
Substance use & misuse  2010;45(12):1909-1929.
This study examined tribal members’ perspectives on alcohol, risk factors, consequences, and community responses. Focus groups were conducted with five American Indian tribes between 1997 and 2001. Participants were knowledgeable of the cultural lives of their reservation communities. Although there was agreement regarding the pervasiveness of heavy drinking, participants reported different opinions about the meaning of alcohol and appropriate intervention strategies. Three dilemmas were identified, suggesting that community ambivalence may serve as a barrier to reducing problem drinking. Implications, limitations, and future research directions are discussed. The study was funded by the National Institute on Alcohol Abuse and Alcoholism.
PMCID: PMC3703779  PMID: 20380555
American Indian; alcohol; prevention; qualitative research
25.  A Factor Analysis of Global GABAergic Gene Expression in Human Brain Identifies Specificity in Response to Chronic Alcohol and Cocaine Exposure 
PLoS ONE  2013;8(5):e64014.
Although expression patterns of GABAergic genes in rodent brain have largely been elucidated, no comprehensive studies have been performed in human brain. The purpose of this study was to identify global patterns of GABAergic gene expression in healthy adults, including trans and cis effects in the GABAA gene clusters, before determining the effects of chronic alcohol and cocaine exposure on gene expression in the hippocampus. RNA-Seq data from ‘BrainSpan’ was obtained across 16 brain regions from postmortem samples from nine adults. A factor analysis was performed on global expression of 21 GABAergic pathway genes. Factor specificity for response to chronic alcohol/cocaine exposure was subsequently determined from the analysis of RNA-Seq data from postmortem hippocampus of eight alcoholics, eight cocaine addicts and eight controls. Six gene expression factors were identified. Most genes loaded (≥0.5) onto one factor; six genes loaded onto two. The largest factor (0.30 variance) included the chromosome 5 gene cluster that encodes the most common GABAA receptor, α1β2γ2, and genes encoding the α3β3γ2 receptor. Genes within this factor were largely unresponsive to chronic alcohol/cocaine exposure. In contrast, the chromosome 4 gene cluster factor (0.14 variance) encoding the α2β1γ1 receptor was influenced by chronic alcohol/cocaine exposure. Two other factors (0.17 and 0.06 variance) showed expression changes in alcoholics/cocaine addicts; these factors included genes involved in GABA synthesis and synaptic transport. Finally there were two factors that included genes with exceptionally low (0.10 variance) and high (0.09 variance) expression in the cerebellum; the former factor was unaffected by alcohol/cocaine exposure. This study has shown that there appears to be specificity of GABAergic gene groups, defined by covariation in expression, for response to chronic alcohol/cocaine exposure. These findings might have implications for combating stress-related craving and relapse.
PMCID: PMC3661725  PMID: 23717525

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