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1.  Anatomical Characteristics of the Cerebral Surface in Bulimia Nervosa 
Biological psychiatry  2013;S0006-3223(13)00647-1 10.1016/j.biopsych.2013.07.017.
To examine morphometric features of the cerebral surface in adolescent and adult females with Bulimia Nervosa (BN).
Anatomical magnetic resonance images were acquired from 34 adolescent and adult females with BN and 34 healthy, age-matched controls. We compared the groups in the morphological characteristics of their cerebral surfaces while controlling for age and illness duration.
Significant reductions of local volumes on the brain surface were detected in frontal and temporoparietal areas in the BN compared to control participants. Reductions in inferior frontal regions correlated inversely with symptom severity, age, and Stroop interference scores in the BN group.
These findings suggest that local volumes of inferior frontal regions are smaller in individuals with BN compared to healthy individuals. These reductions along the cerebral surface may contribute to functional deficits in self-regulation and to the persistence of these deficits over development in BN.
PMCID: PMC3933456  PMID: 23978404
Bulimia Nervosa; MRI; surface morphology; frontal cortex; eating disorders; frontostriatal
2.  Levels-Of-Processing Effect on Word Recognition in Schizophrenia 
Biological psychiatry  2003;54(11):1154-1161.
Individuals with schizophrenia have difficulty organizing words semantically to facilitate encoding. This is commonly attributed to organizational rather than semantic processing limitations. By requiring participants to classify and encode words on either a shallow (e.g., uppercase/lowercase) or deep level (e.g., concrete/abstract), the levels-of-processing paradigm eliminates the need to generate organizational strategies.
This paradigm was administered to 30 patients with schizophrenia and 30 healthy comparison subjects to test whether providing a strategy would improve patient performance.
Word classification during shallow and deep encoding was slower and less accurate in patients. Patients also responded slowly during recognition testing and maintained a more conservative response bias following deep encoding; however, both groups showed a robust levels-of-processing effect on recognition accuracy, with unimpaired patient performance following both shallow and deep encoding.
This normal levels-of-processing effect in the patient sample suggests that semantic processing is sufficiently intact for patients to benefit from organizational cues. Memory remediation efforts may therefore be most successful if they focus on teaching patients to form organizational strategies during initial encoding.
PMCID: PMC4332587  PMID: 14643082
Schizophrenia; levels-of-processing; episodic memory; semantic processing; encoding strategy; neuropsychology
3.  General and Specific Cognitive Deficits in Schizophrenia: Goliath Defeats David? 
Biological psychiatry  2008;64(9):823-827.
Our earlier work suggested that the cognitive performance impairment in individuals with schizophrenia relative to healthy control subjects was generalized, cutting across narrower cognitive ability dimensions. Current analyses sought to extend these findings.
Seventeen neuropsychological variables, available for 148 schizophrenia subjects and 157 control subjects, were subjected to structural equation modeling. Analyses incorporated a hierarchical model, grouping the variables into six familiar cognitive domains and linking these to a higher-order, general cognitive ability factor. We added diagnosis to the model as a grouping factor and estimated loadings from diagnosis to the general cognitive factor and, separately, to the domain factors.
The fit of the final model was good (e.g., Non-Normed Fit Index [NNFI] = .988). Approximately 63.6% of the diagnosis-related variance in cognitive performance was mediated through the general factor, with smaller direct effects on verbal memory (13.8%) and processing speed (9.1%).
The schizophrenia cognitive deficit is largely generalized across performance domains, with small, direct effects of diagnostic group confined to selected domains. This generalized deficit sometimes has been seen as a function of the psychometric limitations of traditional cognitive test batteries. Alternatively, it may be a fundamental manifestation of schizophrenia, with similarly general neurobiological underpinnings.
PMCID: PMC4332801  PMID: 18472089
Cognitive deficit; neuropsychological testing; processing speed; schizophrenia; structural equation modeling; verbal memory
4.  Immune System Disturbances in Schizophrenia 
Biological psychiatry  2013;75(4):316-323.
Epidemiological, genetic, transcriptome, postmortem, peripheral biomarker, and therapeutic studies of schizophrenia all point to a dysregulation of both innate and adaptive immune systems in the disease, and it is likely that these immune changes actively contribute to disease symptoms. Gene expression disturbances in the brain of subjects with schizophrenia show complex, region-specific changes with consistently replicated and potentially interdependent induction of serpin peptidase inhibitor, clade A member 3 (SERPINA3) and interferon inducible transmembrane protein (IFITM) family transcripts in the prefrontal cortex. Recent data suggest that IFITM3 expression is a critical mediator of maternal immune activation. As the IFITM gene family is primarily expressed in the endothelial cells and meninges, and as the meninges play a critical role in interneuron development, we suggest that these two non-neuronal cell populations might play an important role in the disease pathophysiology. Finally, we propose that IFITM3 in particular might be a novel, appealing, knowledge-based drug target for treatment of schizophrenia.
Gene*environment interactions play a critical role in the emergence of schizophrenia pathophysiology. Epidemiological, genetic, transcriptome, postmortem, peripheral biomarker, and therapeutic studies of schizophrenia all point to a dysregulation of both innate and adaptive immune systems in the disease (1-3) and it is likely that these immune changes actively contribute to disease symptoms (1, 4, 5). Regardless of the abundance of data obtained to date, our understanding of the mechanism by which the immune system disturbances arise is limited: we do not have a good insight into the origin or sequence of events by which the immune dysregulation develops, and to date we have not taken full advantage of these changes as potential therapeutic targets.
PMCID: PMC3841236  PMID: 23890736
IFITM; IFITM3; SERPINA3; CHI3L1; CD14; postmortem; immune; schizophrenia; blood vessels; meninges; pia mater; blood-brain barrier
5.  The Cytokine Model of Schizophrenia: Emerging Therapeutic Strategies 
Biological psychiatry  2013;75(4):292-299.
We discuss the rationale for a trial of a novel biologic immunotherapy in schizophrenia (SZ). Available antipsychotic treatments for SZ are often limited by partial effectiveness and significant side effects. Thus, the search for novel medications is of high priority. All current antipsychotics function primarily by blocking D2-type dopamine receptors. An emerging theory of SZ postulates disturbances of cytokines and inflammatory mediators (i.e., the cytokine model), possibly originating in part from infectious exposures. Cytokines are one of the most important components of the immune system that orchestrate the response to infectious and other exogenous insults. Preclinical models of SZ support a convergence between a role for certain cytokines in the pathophysiology of SZ and major neurochemical postulates of the disorder, including the dopamine and glutamate hypotheses. Furthermore, several cytokines are elevated in plasma in SZ, and Positron Emission Tomography (PET) studies have shown active inflammation in the brains of individuals with psychosis. Treatment studies of certain anti-inflammatory agents, such as celecoxib and aspirin, in patients with SZ have provided further support for neuroinflammation in this disorder. The recent development of approved biological therapies for autoimmune diseases provides us with new opportunities to directly target cytokine signaling as a novel treatment strategy in SZ. In addition, advances in imaging, immunology, and psychopharmacology have paved the way for utilizing measures of target engagement of neuroimmune components that would facilitate the identification of patient subgroups who are most likely to benefit from cytokine modulation.
PMCID: PMC3931550  PMID: 24439555
schizophrenia; cytokine; inflammation; interleukin; microbial; neuroimmune
6.  [No title available] 
PMCID: PMC3864607  PMID: 23954107
7.  [No title available] 
PMCID: PMC3874248  PMID: 24041505
8.  [No title available] 
PMCID: PMC3874268  PMID: 23896203
9.  [No title available] 
PMCID: PMC3897253  PMID: 23954299
10.  Human stem cells and surrogate tissues for basic and translational study of mental disorders 
Biological psychiatry  2014;75(12):918-919.
PMCID: PMC4302385  PMID: 24862565
11.  The Long-Term Effects of Placebo in Patients with Chronic Schizophrenia 
Biological psychiatry  1999;46(8):1092-1105.
It has been hypothesized that placebo periods may increase long-term morbidity for patients with schizophrenia. In this study, the long-term effect of a placebo period was evaluated in a group of relatively treatment-refractory patients with chronic schizophrenia.
This retrospective study examined behavioral rating scores for 127 patients with chronic schizophrenia who were placed in a double-blind placebo study on the inpatient units of the National Institute of Mental Health Neuropsychiatric Research Hospital. Patients were rated daily with the Psychiatric Symptom Assessment Scale (PSAS), an extended and anchored version of the Brief Psychiatric Rating Scale (BPRS). At the end of the placebo phase, most patients were placed on haloperidol. Pre-placebo baseline PSAS ratings were compared with, first, discharge ratings and second, post-placebo ratings. To determine expected variability in the course of illness, patients in the placebo group were compared with patients hospitalized during the same time period, but who did not enter the placebo study.
By discharge, ratings for placebo patients had returned to baseline. Post-placebo ratings were quite variable. Although many of the placebo patients had returned to baseline by day 3 of the post-placebo phase, others had not returned to baseline by post-placebo day 42. PSAS Total Scores for patients who left the study early were no different at baseline, placebo, or through post-placebo day 35 compared with patients who completed the study.
The results indicate that given a sufficiently lengthy recovery period, patients with chronic schizophrenia who go through a placebo phase return to baseline, but that the speed with which they attain that recovery is highly variable.
PMCID: PMC4303345  PMID: 10536745
Schizophrenia; placebo; antipsychotic medications
12.  Reply To: The Liptak-Stouffer Test for Meta-Analyses 
Biological psychiatry  2014;77(1):e3-e4.
PMCID: PMC4300519  PMID: 24655597
14.  Ventral striatum lesions enhance stimulus and response encoding in dorsal striatum 
Biological psychiatry  2013;75(2):10.1016/j.biopsych.2013.05.023.
The development of addiction is thought to reflect a transition from goal-directed to stimulus-response driven behavior, functions attributed to ventral (VS) and dorsal striatum (DS), respectively. In line with this theory, neuroadaptations that occur during prolonged drug use progress from VS to DS. Here, we ask if VS dysfunction alone, independent of drug use, can impact neural selectivity in DS.
To address this issue we recorded from single neurons in DS while rats performed an odor-guided choice task for differently valued rewards in rats with and without unilateral VS lesions. In a separate group of animals we used bilateral VS lesions to determine if VS was critical for performance on this task.
We describe data showing that unilateral lesions of VS enhance neural representations in DS during performance of a task that is dependent on VS. Furthermore, we show VS is critical for reward-guided decision-making initially, but rats regain function after several days.
These results suggest that loss of VS function, independent of chronic drug use, can trigger stronger encoding in DS in a reward-guided decision-making task and that the transition from VS to DS governed behavior observed in addiction might be due, in part, to initial loss of VS function.
PMCID: PMC3796031  PMID: 23790313
striatum; nucleus accumbens; stimulus-response; value; single unit; rat
15.  Cocaine Self-Administration Abolishes Associative Neural Encoding in the Nucleus Accumbens Necessary for Higher-Order Learning 
Biological psychiatry  2013;75(2):10.1016/j.biopsych.2013.07.037.
Cocaine use is often associated with diminished cognitive function, persisting even after abstinence from the drug. Likely targets for these changes are the core and shell of the nucleus accumbens (NAc), which are critical for mediating the rewarding aspects of drugs of abuse as well as supporting associative learning. To understand this deficit, we recorded neural activity in the NAc of rats with either a history of cocaine self-administration or controls while they learned Pavlovian first- and second-order associations.
Rats were trained for 2 weeks to self-administer intravenous cocaine or water. Later, rats learned a first-order Pavlovian discrimination where a CS+ predicted food, and a control CS− did not. Rats then learned a second-order association where, absent any food reinforcement, a novel cue (SOC+) predicted the CS+ and another (SOC−) predicted the CS−. Electrophysiological recordings were taken during performance of these tasks in the NAc core and shell.
Both controls and cocaine-experienced rats learned the first-order association, but only controls learned the second-order association. Neural recordings indicated that core and shell neurons encoded task-relevant information that correlated with behavioral performance, while this type of encoding was abolished in cocaine-experienced rats.
NAc core and shell perform complementary roles in supporting normal associative learning, functions that are impaired following cocaine experience. This impoverished encoding of motivational behavior, even after abstinence from the drug, may provide a key mechanism to understand why addiction remains a chronically relapsing disorder despite repeated attempts at sobriety.
PMCID: PMC3865233  PMID: 24035479
natural reward; drug abuse; second-order conditioning; electrophysiology; striatum; dopamine
16.  Increased SK2 channel-mediated negative feedback on NMDAR impairs synaptic plasticity following context-dependent sensitization to morphine 
Biological psychiatry  2013;75(2):105-114.
Hippocampal long term potentiation (LTP) is impaired following repeated morphine administration paired with a novel context. This procedure produces locomotor sensitization that can be abolished by blocking Ca2+-permeable 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl) propanoic acid receptors (AMPARs) in the hippocampus. However, the mechanisms underlying LTP impairment remain unclear. Here, we investigate the role of N-methyl-D-aspartate receptors (NMDARs), AMPARs and small conductance Ca2+-activated potassium type 2 (SK2) channels in LTP induction after context-dependent sensitization to morphine.
Mice were treated with saline or escalating doses of morphine (5, 8, 10 and 15 mg/kg) every 12 hours in a locomotor activity (LMA) chamber and a challenge dose of 5mg/kg morphine was given one week later. After the challenge the hippocampi were removed to assay phosphatase 2A (PP2A) activity, NMDAR and SK2 channel synaptic expression or to perform electrophysiological recordings.
Impaired hippocampal LTP, which accompanied morphine-induced context-dependent sensitization, could not be restored by blocking Ca2+-permeable AMPARs. Context-dependent sensitization to morphine altered hippocampal NMDAR subunit composition and enhanced the SK2 channel-mediated negative feedback on NMDAR. Increased PP2A activity observed following context-dependent sensitization suggests that the potentiated SK2 channel effect on NMDAR was mediated by increased SK2 sensitivity to Ca2+. Finally, inhibition of SK2 channel or PP2A activity restored LTP.
Our studies demonstrate that the SK2 channel-NMDAR feedback loop plays a role in opiate-induced impairment of hippocampal plasticity and that the positive modulation of SK2 channels occurs via increases in PP2A activity. This provides further evidence that SK channels play a role in drug-induced plasticity.
PMCID: PMC3992971  PMID: 23735878
long term potentiation; hippocampus; PP2A; apamin; locomotor activity; SK2-NMDA loop
17.  Selective, Retrieval-Independent Disruption of Methamphetamine-Associated Memory by Actin Depolymerization 
Biological psychiatry  2013;75(2):96-104.
Memories associated with drugs of abuse, such as methamphetamine (METH), increase relapse vulnerability to substance use disorder. There is a growing consensus that memory is supported by structural and functional plasticity driven by F-actin polymerization in postsynaptic dendritic spines at excitatory synapses. However, the mechanisms responsible for the long-term maintenance of memories, after consolidation has occurred, are largely unknown.
Conditioned place preference (N=112) and context-induced reinstatement of self-administration (N=19) were used to assess the role of F-actin polymerization and myosin II, a molecular motor that drives memory-promoting dendritic spine actin polymerization, in the maintenance of METH-associated memories and related structural plasticity.
Memories formed through association with methamphetamine (METH), but not associations with foot shock or food reward, were disrupted by a highly-specific actin cycling inhibitor when infused into the amygdala during the post-consolidation maintenance phase. This selective effect of depolymerization on METH-associated memory was immediate, persistent and did not depend upon retrieval or strength of the association. Inhibition of non-muscle myosin II also resulted in a disruption of METH-associated memory.
Thus, drug-associated memories appear to be actively maintained by a unique form of cycling F-actin driven by myosin II. This finding provides a potential therapeutic approach for the selective treatment of unwanted memories associated with psychiatric disorders that is both selective and does not rely on retrieval of the memory. The results further suggest that memory maintenance depends upon the preservation of polymerized actin.
PMCID: PMC4023488  PMID: 24012327
memory maintenance; addiction; amygdala; structural plasticity; dendritic spine; myosin
18.  Biased Behaviors: Towards Understanding Vulnerability and Resilience Factors in Addictions 
Biological psychiatry  2014;75(2):94-95.
PMCID: PMC4088321  PMID: 24331645
stimulants; cocaine; attention; control; Stroop; fMRI
19.  Imaging glutamate homeostasis in cocaine addiction with the mGluR5 PET radiotracer [11C]ABP688 and Magnetic Resonance Spectroscopy 
Biological psychiatry  2013;75(2):165-171.
Preclinical studies demonstrate that glutamate homeostasis in the striatum is disrupted following cocaine exposure, including a decrease in metabotropic glutamate receptor type 5 (mGluR5) expression and reduced glutamate turnover. The goal of this study was to use imaging of the human brain to investigate alterations in the glutamate signaling in cocaine addiction.
Positron Emission tomography (PET) imaging with the radiotracer [11C]ABP688 was used to measure mGluR5 binding and magnetic resonance spectroscopy (MRS) was used to measure glutamate-glutamine levels in the striatum of cocaine addicted participants (n=15) compared to healthy controls (n=15). Following the scans, the cocaine addicted volunteers performed cocaine self-administration sessions in order to investigate the correlation between cocaine seeking behavior and mGluR5 receptor binding.
The results of the study showed that cocaine addiction was associated with a 20–22% reduction in [11C]ABP688 binding in the striatum. A secondary analysis of cortical and subcortical regions other than the striatum showed a similar reduction in [11C]ABP688 binding, suggesting that the decrease is widespread. No between-group differences were seen in the MRS measures of glutamate-glutamine in the left striatum. In addition, no correlation was seen between [11C]ABP688 binding in the striatum and the choice to self-administer cocaine.
Overall, these results show that long-term cocaine use is associated with a decrease in mGluR5 availability compared to matched healthy controls and suggests that this receptor may serve as a viable target for treatment development for this disorder.
PMCID: PMC4106018  PMID: 24035345
addiction; cocaine; magnetic resonance spectroscopy; positron emission tomography; metabotropic glutamate receptor 5; cocaine self-administration
20.  Nutrition and Depression: Implications for Improving Mental Health Among Childbearing-Aged Women 
Biological psychiatry  2005;58(9):679-685.
Adequate nutrition is needed for countless aspects of brain functioning. Poor diet quality, ubiquitous in the United States, may be a modifiable risk factor for depression. The objective was to review and synthesize the current knowledge of the role of nutrition in depression, and address implications for childbearing-aged women. Poor omega-3 fatty acid status increases the risk of depression. Fish oil and folic acid supplements each have been used to treat depression successfully. Folate deficiency reduces the response to antidepressants. Deficiencies of folate, vitamin B12, iron, zinc, and selenium tend to be more common among depressed than nondepressed persons. Dietary antioxidants have not been studied rigorously in relation to depression. Childbearing-aged women are particularly vulnerable to the adverse effects of poor nutrition on mood because pregnancy and lactation are major nutritional stressors to the body. The depletion of nutrient reserves throughout pregnancy and a lack of recovery postpartum may increase a woman’s risk of depression. Prospective research studies are needed to clarify the role of nutrition in the pathophysiology of depression among childbearing-aged women. Greater attention to nutritional factors in mental health is warranted given that nutrition interventions can be inexpensive, safe, easy to administer, and generally acceptable to patients.
PMCID: PMC4288963  PMID: 16040007
Depression; diet; nutrition; postpartum; pregnancy; women
21.  Correspondence 
Biological psychiatry  2014;76(4):e3-e4.
Follow-up and Extension of a Prior Genome-wide Association Study of Posttraumatic Stress Disorder: Gene × Environment Associations and Structural Magnetic Resonance Imaging in a Highly Traumatized African-American Civilian Population
PMCID: PMC4285665  PMID: 24576688
22.  Reduced Behavioral and Neural Activation in Stimulant Users To Different Error Rates During Decision-Making 
Biological psychiatry  2007;63(11):1054-1060.
Behavioral processes and neural systems dysfunctions that put individuals at risk for drug use in general—and stimulant use in particular—are poorly understood. Here, the hypothesis is examined that stimulant-using subjects adjust their decision-making less as a function of errors as evidenced by attenuated behavioral and neural substrate activation patterns.
Twelve young adults who had used stimulants were compared with 12 education-matched stimulant-naïve comparison subjects. Subjects completed the two-choice prediction task with three fixed error-rate conditions (20%, 50%, or 80% errors) during functional magnetic resonance imaging.
Stimulant users relative to comparison subjects showed less strategy adjustment to different error rates, e.g., they were less likely to stay with winning responses (win-stay) and to shift away from losing responses (lose-shift). These subjects also showed different activation patterns as a function of error rate in left insular and bilateral dorsolateral prefrontal cortex, but not anterior cingulate. The degree to which individuals adjusted switching rate, or win-stay/lose-shift consistent responses, as a function of errors was correlated with the difference in insular cortex activation differences between high and low error rates.
The behavior of stimulant users is less adaptive to the frequency of errors made and fewer brain processing resources are deployed during decision-making to anticipate erroneous performance. These findings could be markers for the predisposition of drug taking; however, their relevance for development of drug dependence needs further study.
PMCID: PMC4286246  PMID: 17949691
fMRI; stimulants; decision-making; error processing; insula
23.  Adolescent behavior and dopamine availability are uniquely sensitive to dietary omega-3 fatty acid deficiency 
Biological psychiatry  2013;75(1):10.1016/j.biopsych.2013.06.007.
Understanding the nature of environmental factors that contribute to behavioral health is critical for successful prevention strategies in individuals at-risk for psychiatric disorders. These factors are typically experiential in nature, such as stress and urbanicity, but nutrition, in particular dietary deficiency of omega-3 polyunsaturated fatty acids (n-3 PUFAs), has increasingly been implicated in the symptomatic onset of schizophrenia and mood disorders, which typically occurs during adolescence to early adulthood. Thus, adolescence may be the critical age range for the negative impact of diet as an environmental insult.
A rat model involving consecutive generations of n-3 PUFA deficiency was developed based on the assumption that dietary trends toward decreased consumption of these fats began four-five decades ago when the parents of current adolescents were born. Behavioral performance in a wide range of tasks, as well as markers of dopamine-related neurotransmission was compared in adolescents and adults fed n-3 PUFA adequate and deficient diets.
In adolescents, dietary n-3 PUFA deficiency across consecutive generations produced a modality-selective and task-dependent impairment in cognitive and motivated behavior distinct from the deficits observed in adults. While this dietary deficiency affected expression of dopamine-related proteins in both age groups, in adolescents, but not adults, there was an increase in tyrosine hydroxylase expression that was selective to the dorsal striatum.
These data support a nutritional contribution to optimal cognitive and affective functioning in adolescents. Furthermore, they suggest that n-3 PUFA deficiency disrupts adolescent behaviors through enhanced dorsal striatal dopamine availability.
PMCID: PMC3858419  PMID: 23890734
Schizophrenia; Addiction; Anxiety; Nutrition; Fatty Acids; Cognition
24.  Prenatal glucocorticoids and maternal smoking during pregnancy independently program adult nicotine dependence in daughters: A 40-year prospective study 
Biological psychiatry  2013;75(1):10.1016/j.biopsych.2013.07.024.
Maternal smoking during pregnancy (MSDP) is an independent risk factor for offspring nicotine dependence (ND), but mechanisms remain unknown. We investigated prenatal glucocorticoid (cortisol) and androgen (testosterone) associations with offspring ND over 40 years, and the possibility that prenatal glucocorticoids and androgens would mediate links between MSDP and offspring ND.
Participants were 1,086 mother-adult offspring pairs (59% female) from the New England Family Study, a 40-year longitudinal follow up of the Collaborative Perinatal Project. MSDP was assessed prospectively at each prenatal visit. Maternal cortisol, testosterone, and cotinine (nicotine metabolite), were assayed from third trimester maternal sera. Offspring lifetime ND was assessed via structured interview.
Significant bivariate associations emerged for: a) MSDP/cotinine and lifetime ND, and b) maternal cortisol and lifetime ND, for daughters only. In multivariate models, maternal cortisol and MSDP/cotinine remained significantly and independently associated with increased odds of daughters’ lifetime ND. However, cortisol did not mediate the MSDP-lifetime ND relation. No associations emerged between maternal testosterone and offspring ND.
Results provide the first evidence in support of prenatal glucocorticoid programming of adult ND over 40 years in daughters only. Our study highlights two independent prenatal pathways leading to increased risk for ND in daughters: elevated prenatal glucocorticoids and MSDP/nicotine exposure. Daughter-specific effects of glucocorticoid and MSDP programming over 40 years highlight the breadth and persistence of sexually dimorphic programming effects in humans. Results do not support androgen programming of offspring ND.
PMCID: PMC3858529  PMID: 24034414
Maternal smoking during pregnancy; nicotine dependence; cotinine; cortisol; testosterone; programming; glucocorticoid; androgen
25.  Gene-by-environment interaction studies have not properly controlled for potential confounders: The problem and the (simple) solution 
Biological psychiatry  2013;75(1):10.1016/j.biopsych.2013.09.006.
Candidate gene-by-environment (G×E) interaction research tests the hypothesis that the effects of some environmental variable (e.g., childhood maltreatment) on some outcome measure (e.g., depression) depend on a particular genetic polymorphism. Because this research is inherently non-experimental, investigators have been rightly concerned that detected interactions could be driven by confounders (e.g., ethnicity, gender, age, socioeconomic status, etc.) rather than by the specified genetic or environmental variables per se. In an attempt to eliminate such alternative explanations for detected G×E interactions, investigators routinely enter the potential confounders as covariates in general linear models. However, this practice does not control for the effects these variables might have on the G×E interaction. Rather, to properly control for confounders, researchers need to enter the covariate-by-environment and the covariate-by-gene interaction terms in the same model that tests the G×E term. In this manuscript, I demonstrate this point analytically and show that the practice of improperly controlling for covariates is the norm in the G×E interaction literature to date. Thus, many alternative explanations for G×E findings that investigators had thought were eliminated have not been.
PMCID: PMC3859520  PMID: 24135711
gene-by-environment interactions; confounders; adjustment; covariates; multiple regression; false positive rate; replication

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