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1.  Genetic variation in GABRA2 moderates peer influence on externalizing behavior in adolescents 
Brain and Behavior  2014;4(6):833-840.
Genetic predisposition and environmental influences are both important factors in the development of problematic behavior leading to substance use in adolescence. Involvement with delinquent peers also strongly predicts adolescent externalizing behavior. Several lines of evidence support a role of GABRA2 on externalizing behavior related to disinhibition. However, whether this genetic association is influenced by the environment such as peer behavior remains unknown.
We examined the moderating role of GABRA2 genetic variation on the socialization model of delinquent peer affiliation (at ages 12–14 years) on externalizing behavior (at ages 15–17 years) in the Michigan Longitudinal Study (MLS) adolescent sample.
The sample consisted of 244 adolescents (75 females and 152 with at least one parent with a DSM-IV lifetime alcohol dependence/abuse diagnosis). Peer delinquent activity reported by the participant and teacher-reported adolescent externalizing behavior (Teacher Report Form (TRF) were assessed.
No main effect of the GABRA2 SNP rs279826, which tags a large haplotype, on externalizing behavior was observed. However, there was a statistically reliable GABRA2 × peer delinquency interaction. The effect of peer delinquent involvement on externalizing scores and the rule breaking subscale is significantly stronger for those with the GG genotype compared to A-carriers, whereas there was no effect of genotype on externalizing in the absence of peer delinquent involvement. No interaction was observed for the aggression subscale.
Our results suggest that the genetic effect of GABRA2 on externalizing behavior, more specifically on rule breaking is, at least in part, due to its effect on susceptibility to environmental exposure (i.e., peer delinquency).
PMCID: PMC4212110  PMID: 25365806
Adolescence; externalizing; GABRA2; gene–environment interaction; peer delinquency
2.  Genetic variation in GABRA2 moderates peer influence on externalizing behavior in adolescents 
Brain and Behavior  2014;10.1002/brb3.291.
Genetic predisposition and environmental influences are both important factors in the development of problematic behavior leading to substance use in adolescence. Involvement with delinquent peers also strongly predicts adolescent externalizing behavior. Several lines of evidence support a role of GABRA2 on externalizing behavior related to disinhibition. However, whether this genetic association is influenced by the environment such as peer behavior remains unknown.
We examined the moderating role of GABRA2 genetic variation on the socialization model of delinquent peer affiliation (at ages 12–14 years) on externalizing behavior (at ages 15–17 years) in the Michigan Longitudinal Study (MLS) adolescent sample.
The sample consisted of 244 adolescents (75 females and 152 with at least one parent with a DSM‐IV lifetime alcohol dependence/abuse diagnosis). Peer delinquent activity reported by the participant and teacher‐reported adolescent externalizing behavior (Teacher Report Form (TRF) were assessed.
No main effect of the GABRA2 SNP rs279826, which tags a large haplotype, on externalizing behavior was observed. However, there was a statistically reliable GABRA2 × peer delinquency interaction. The effect of peer delinquent involvement on externalizing scores and the rule breaking subscale is significantly stronger for those with the GG genotype compared to A‐carriers, whereas there was no effect of genotype on externalizing in the absence of peer delinquent involvement. No interaction was observed for the aggression subscale.
Our results suggest that the genetic effect of GABRA2 on externalizing behavior, more specifically on rule breaking is, at least in part, due to its effect on susceptibility to environmental exposure (i.e., peer delinquency).
PMCID: PMC4212110  PMID: 25365806
Adolescence; externalizing; GABRA2; gene–environment interaction; peer delinquency
3.  Indirect Effect of Corticotropin-Releasing Hormone Receptor 1 Gene Variation on Negative Emotionality and Alcohol Use via Right Ventrolateral Prefrontal Cortex 
The Journal of Neuroscience  2014;34(11):4099-4107.
Variations in the corticotropin-releasing hormone receptor 1 (CRHR1) gene have been found to interact with stress in modulating excessive alcohol consumption. However, the neural mechanisms through which CRHR1 influences this risk in humans is largely unknown. This study examined the influence of an intronic CRHR1 gene variant, rs110402, on brain responses to negative emotional words, negative emotional traits, and alcohol use in adolescents and young adults at high risk for alcoholism. Childhood stress was investigated as a potential moderator. Using functional magnetic resonance imaging, we found that a region in the right ventrolateral prefrontal cortex (rVLPFC) was more engaged during negative emotional word processing in G homozygotes than in A allele carriers (p(FWE corrected) < 0.01, N = 77). Moreover, an indirect effect of genotype on negative emotionality via rVLPFC activation (p < 0.05, N = 69) was observed, which was further moderated by childhood stress (p < 0.05, N = 63). Specifically, with low childhood stress, G homozygotes exhibited lower levels of negative emotionality associated with greater rVLPFC activation, suggesting that the rVLPFC is involved in reappraisal that neutralizes negative emotional responses. In addition, we found that genotype indirectly modulated excessive alcohol consumption (p < 0.05, N = 69). Specifically, G homozygotes showed greater rVLPFC activation and had lower levels of negative emotionality, which were associated with fewer binge-drinking days and fewer alcohol related problems. This work provides support for a model in which CRHR1 gene variation modulates the risk of problem drinking via an internalizing/negative affect pathway involving rVLPFC and reappraisal of negative emotion.
PMCID: PMC3951705  PMID: 24623788
alcohol consumption; childhood stress; CRHR1; genetics; negative emotionality; prefrontal cortex
4.  Genes and Genetic Testing in Hereditary Ataxias 
Genes  2014;5(3):586-603.
Ataxia is a neurological cerebellar disorder characterized by loss of coordination during muscle movements affecting walking, vision, and speech. Genetic ataxias are very heterogeneous, with causative variants reported in over 50 genes, which can be inherited in classical dominant, recessive, X-linked, or mitochondrial fashion. A common mechanism of dominant ataxias is repeat expansions, where increasing lengths of repeated DNA sequences result in non-functional proteins that accumulate in the body causing disease. Greater understanding of all ataxia genes has helped identify several different pathways, such as DNA repair, ubiquitination, and ion transport, which can be used to help further identify new genes and potential treatments. Testing for the most common mutations in these genes is now clinically routine to help with prognosis and treatment decisions, but next generation sequencing will revolutionize how genetic testing will be done. Despite the large number of known ataxia causing genes, however, many individuals with ataxia are unable to obtain a genetic diagnosis, suggesting that more genes need to be discovered. Utilization of next generation sequencing technologies, expression studies, and increased knowledge of ataxia pathways will aid in the identification of new ataxia genes.
PMCID: PMC4198919  PMID: 25055202
ataxia; genetics; pathways; testing
5.  Mutations in KCND3 cause spinocerebellar ataxia type 22 
Annals of neurology  2012;72(6):859-869.
To identify the causative gene in SCA22, an autosomal dominant cerebellar ataxia mapped to chromosome 1p21-q23.
Subjects and Methods
We previously characterized a large Chinese family with progressive ataxia designated SCA22, which overlaps with the locus of SCA19. The disease locus in a French family and an Ashkenazi Jewish American family was also mapped to this region. Members from all three families were enrolled. Whole exome sequencing was performed to identify candidate mutations, which were narrowed by linkage analysis and confirmed by Sanger sequencing and co-segregation analyses. Mutational analyses were also performed in 105 Chinese and 55 Japanese families with cerebellar ataxia. Mutant gene products were examined in a heterologous expression system to address the changes in protein localization and electrophysiological functions.
We identified heterozygous mutations in the voltage-gated potassium channel Kv4.3-encoding gene KCND3: an in-frame three-nucleotide deletion c.679_681delTTC p.F227del in both the Chinese and French pedigrees, and a missense mutation c.1034G>T p.G345V in the Ashkenazi Jewish family. Direct sequencing of KCND3 further identified three mutations, c.1034G>T p.G345V, c.1013T>C p.V338E and c.1130C>T p.T377M, in three Japanese kindreds. Immunofluorescence analyses revealed that the mutant p.F227del Kv4.3 subunits were retained in the cytoplasm, consistent with the lack of A-type K+ channel conductance in whole-cell patch-clamp recordings.
Our data identify the cause of SCA19/22 in patients of diverse ethnic origins as mutations in KCND3. These findings further emphasize the important role of ion channels as key regulators of neuronal excitability in the pathogenesis of cerebellar degeneration.
PMCID: PMC4085146  PMID: 23280837
exome sequencing; next generation sequencing; spinocerebellar ataxia type 22; voltage-gated potassium channel; Kv4.3; KCND3
6.  Impulsiveness mediates the association between GABRA2 SNPs and lifetime alcohol problems 
Genes, brain, and behavior  2013;12(5):525-531.
Genetic variants in GABRA2 have previously been shown to be associated with alcohol measures, EEG β waves, and impulsiveness-related traits. Impulsiveness is a behavioral risk factor for alcohol and other substance abuse. Here, we tested association between 11 variants in GABRA2 with NEO- impulsiveness and problem drinking. Our sample of 295 unrelated adult subjects was from a community of families with at least one male with DSM-IV Alcohol use diagnosis, and from a socioeconomically comparable control group.
Ten GABRA2 SNPs were associated with the NEO-impulsiveness (p < 0.03). The alleles associated with higher impulsiveness correspond to the minor alleles identified in previous alcohol dependence studies. All ten SNPs are in LD with each other and represent one effect on impulsiveness. Four SNPs and the corresponding haplotype from intron 3 to intron 4 were also associated with Lifetime Alcohol Problems Score (LAPS, p < 0.03) (not corrected for multiple testing). Impulsiveness partially mediates (22.6% average) this relation between GABRA2 and LAPS. Our results suggest that GABRA2 variation in the region between introns 3 and 4 is associated with impulsiveness and this effect partially influences the development of alcohol problems, but a direct effect of GABRA2 on problem drinking remains. A potential functional SNP rs279827, located next to a splice site, is located in the most significant region for both impulsiveness and LAPS. The high degree of LD among nine of these SNPs and the conditional analyses we have performed suggest that all variants represent one signal.
PMCID: PMC3700576  PMID: 23566244
GABRA2; impulsiveness; alcohol problems; single nucleotide polymorphisms; mediation
7.  The CC genotype in the T102C HTR2A polymorphism predicts relapse in individuals after alcohol treatment 
Journal of psychiatric research  2013;47(4):527-533.
The serotonin system is hypothesized to contribute to predisposition and course of alcohol dependence. However, the potential association between the T102C polymorphism (rs6313) in the type 2A serotonin receptor (HTR2A) gene and treatment outcomes in alcohol dependence has not been investigated. The aim of the study was to assess the contribution of this genetic polymorphism as a predictor of relapse in relation to other previously identified predictors. A sample of 254 alcohol dependent subjects, were recruited in alcohol treatment centers in Warsaw, Poland and prospectively assessed at baseline and follow-up after 12 months. At baseline, information about demographics, psychopathological symptoms and alcohol problems was obtained. The stop-signal task was performed and blood samples for genetic analysis of HTR2A T102C (rs6313) were collected. Relapse was defined as any drinking during the follow-up period. The statistical analysis showed that the CC genotype was significantly associated with increased relapse. Other significant factors were baseline depressive symptoms, number of drinking days during the 3 months prior to the baseline assessment, severity of alcohol-related problems, and a lifetime history of impulsive suicide attempts. Logistic regression analysis with and without the genetic factor revealed that adding the genetic factor increased the R square value by about 4%, with the CC genotype in the T102C polymorphism being the strongest predictor of relapse (OR=2.32). The significant influence on relapse of the CC genotype, which is associated with fewer 5-HT2A receptors in the central nervous system, suggests the possibility that this genetic polymorphism could influence response to serotonergic medications.
PMCID: PMC3581721  PMID: 23321485
Alcohol dependence; Serotonin; HTR2A; Genetic polymorphism; Relapse
8.  Protocol for a collaborative meta-analysis of 5-HTTLPR, stress, and depression 
BMC Psychiatry  2013;13:304.
Debate is ongoing about what role, if any, variation in the serotonin transporter linked polymorphic region (5-HTTLPR) plays in depression. Some studies report an interaction between 5-HTTLPR variation and stressful life events affecting the risk for depression, others report a main effect of 5-HTTLPR variation on depression, while others find no evidence for either a main or interaction effect. Meta-analyses of multiple studies have also reached differing conclusions.
To improve understanding of the combined roles of 5-HTTLPR variation and stress in the development of depression, we are conducting a meta-analysis of multiple independent datasets. This coordinated approach utilizes new analyses performed with centrally-developed, standardized scripts. This publication documents the protocol for this collaborative, consortium-based meta-analysis of 5-HTTLPR variation, stress, and depression.
Study eligibility criteria: Our goal is to invite all datasets, published or unpublished, with 5-HTTLPR genotype and assessments of stress and depression for at least 300 subjects. This inclusive approach is to minimize potential impact from publication bias.
Data sources: This project currently includes investigators from 35 independent groups, providing data on at least N = 33,761 participants.
The analytic plan was determined prior to starting data analysis. Analyses of individual study datasets will be performed by the investigators who collected the data using centrally-developed standardized analysis scripts to ensure a consistent analytical approach across sites. The consortium as a group will review and interpret the meta-analysis results.
Variation in 5-HTTLPR is hypothesized to moderate the response to stress on depression. To test specific hypotheses about the role of 5-HTTLPR variation on depression, we will perform coordinated meta-analyses of de novo results obtained from all available data, using variables and analyses determined a priori. Primary analyses, based on the original 2003 report by Caspi and colleagues of a GxE interaction will be supplemented by secondary analyses to help interpret and clarify issues ranging from the mechanism of effect to heterogeneity among the contributing studies. Publication of this protocol serves to protect this project from biased reporting and to improve the ability of readers to interpret the results of this specific meta-analysis upon its completion.
PMCID: PMC3840571  PMID: 24219410
9.  The Serotonin Transporter Promoter Variant (5-HTTLPR), Stress, and Depression Meta-Analysis Revisited: Evidence of Genetic Moderation 
Archives of general psychiatry  2011;68(5):444-454.
The initial report of an interaction between a serotonin transporter promoter polymorphism (5-HTTLPR) and stress in the development of depression is perhaps the best-known and most cited finding in psychiatric genetics. Two recent meta-analyses explored the studies seeking to replicate this initial report and concluded that the evidence did not support the presence of the interaction. However, even the larger of the meta-analyses included only 14 of the 56 studies that have explored the relationship between 5-HTTLPR, stress and depression.
We sought to perform a meta-analysis including all relevant studies assessing whether 5-HTTLPR moderates the relationship between stress and depression.
Data Sources
We identified relevant articles from previous meta-analyses and reviews and a PubMed database search.
Study Selection
We excluded two studies presenting data that were included in other, larger, studies already included in our meta-analysis to avoid duplicate counting of subjects.
Data Extraction
In order to perform a more inclusive meta-analysis, we used the Liptak-Stouffer Z-score method to combine findings of primary studies at the significance test level rather than raw data level.
We included 54 studies and found strong evidence that 5-HTTLPR moderates the relationship between stress and depression, with the 5-HTTLPR s allele associated with an increased risk of developing depression under stress (p<0.0001). When restricting our analysis to the studies included in the previous meta-analyses, we found no evidence of association (Munafo studies p=0.16; Risch studies p=0.11). This suggests that the difference in results between previous meta-analyses and ours was not due to the difference in meta-analytic technique but instead to the expanded set of studies included in this analysis.
Contrary to the results of the smaller earlier meta-analyses, we find strong evidence that 5-HTTLPR moderates the relationship between stress and depression in the studies published to date.
PMCID: PMC3740203  PMID: 21199959
Graduate; Medical; Education; Residency; Serotonin; Transporter
10.  Diaphanous homolog 3 (Diap3) Overexpression Causes Progressive Hearing Loss and Inner Hair Cell Defects in a Transgenic Mouse Model of Human Deafness 
PLoS ONE  2013;8(2):e56520.
We previously demonstrated that a mutation in the 5′ untranslated region of Diaphanous homolog 3 (DIAPH3) results in 2 to 3-fold overexpression of the gene, leading to a form of delayed onset, progressive human deafness known as AUNA1 (auditory neuropathy, nonsyndromic, autosomal dominant, 1). To investigate the mechanism of deafness, we generated two lines of transgenic mice overexpressing Diap3, the murine ortholog of DIAPH3, on an FVB/NJ background. Line 771 exhibits a relatively mild 20 dB hearing loss at 12 kHz at 4 and 8 weeks of age, progressing to 40 dB and 60 dB losses at 16 and 24 weeks, respectively, at 12 and 24 kHz. Line 924 shows no hearing loss at 4 or 8 weeks, but manifests 35 and 50 dB threshold shifts at 16 and 24 weeks, respectively, at both 12 and 24 kHz. Notably, mice from the two transgenic lines retain distortion product otoacoustic emissions, indicative of normal cochlear outer hair cell (OHC) function despite elevation of auditory thresholds. Scanning electron microscopy of the organ of Corti demonstrates striking anomalies of the inner hair cell (IHC) stereocilia, while OHCs are essentially intact. Over time, IHCs of both lines develop elongated stereocilia that appear fused with neighboring stereocilia, in parallel to the time course of hearing loss in each line. Furthermore, we observe significant reduction in the number of IHC ribbon synapses over 24 weeks in both lines, although this reduction does not correlate temporally with onset and progression of hearing loss or stereociliary anomalies. In summary, overexpression of wild-type Diap3 in two lines of transgenic mice results in hearing loss that recapitulates human AUNA1 deafness. These findings suggest an essential role of Diap3 in regulating assembly and/or maintenance of actin filaments in IHC stereocilia, as well as a potential role at the IHC ribbon synapse.
PMCID: PMC3575478  PMID: 23441200
11.  The CC genotype in HTR2A T102C polymorphism is associated with behavioral impulsivity in alcohol-dependent patients 
High levels of impulsivity can increase the vulnerability for development of alcohol dependence. Moreover, impulsivity is considered to be a predictor of poor treatment outcomes. Few studies, however, have directly examined the genetics of impulsivity in alcohol-dependent patients. We analyzed the relationships between a well-recognized genetic marker of serotonin activity and levels of impulsivity as measured by both the Barratt Impulsiveness Scale (BIS-11) and the stop-signal task among 304 alcohol-dependent patients. The stop-signal task was used as an independent, objective method of estimating the level of behavioral impulsivity, and the BIS-11 as a self-report measure of global impulsivity. Blood was collected and analyzed for the T102C (rs6313) polymorphism in the serotonin type 2A receptor gene (HTR2A). Our results indicate a significant association between high levels of behavioral impulsivity and the C/C genotype of rs6313 in alcohol-dependent patients. The CC genotype has been previously found to be associated with a reduction in 5HT2A receptors in the central nervous system. These results support the hypothesis that genetic factors are important determinants of behavioral impulsivity in alcohol-dependent patients, and that the serotonin system plays an important role in establishing its level.
PMCID: PMC3224206  PMID: 21930285
alcohol dependence; genetic polymorphism; HTR2A; impulsivity; serotonin
12.  Expression of Caytaxin Protein in Cayman Ataxia Mouse Models Correlates with Phenotype Severity 
PLoS ONE  2012;7(11):e50570.
Caytaxin is a highly-conserved protein, which is encoded by the Atcay/ATCAY gene. Mutations in Atcay/ATCAY have been identified as causative of cerebellar disorders such as the rare hereditary disease Cayman ataxia in humans, generalized dystonia in the dystonic (dt) rat, and marked motor defects in three ataxic mouse lines. While several lines of evidence suggest that Caytaxin plays a critical role in maintaining nervous system processes, the physiological function of Caytaxin has not been fully characterized. In the study presented here, we generated novel specific monoclonal antibodies against full-length Caytaxin to examine endogenous Caytaxin expression in wild type and Atcay mutant mouse lines. Caytaxin protein is absent from brain tissues in the two severely ataxic Atcayjit (jittery) and Atcayswd (sidewinder) mutant lines, and markedly decreased in the mildly ataxic/dystonic Atcayji-hes (hesitant) line, indicating a correlation between Caytaxin expression and disease severity. As the expression of wild type human Caytaxin in mutant sidewinder and jittery mice rescues the ataxic phenotype, Caytaxin’s physiological function appears to be conserved between the human and mouse orthologs. Across multiple species and in several neuronal cell lines Caytaxin is expressed as several protein isoforms, the two largest of which are caused by the usage of conserved methionine translation start sites. The work described in this manuscript presents an initial characterization of the Caytaxin protein and its expression in wild type and several mutant mouse models. Utilizing these animal models of human Cayman Ataxia will now allow an in-depth analysis to elucidate Caytaxin’s role in maintaining normal neuronal function.
PMCID: PMC3511541  PMID: 23226316
13.  Tissue-Specific Functional Networks for Prioritizing Phenotype and Disease Genes 
PLoS Computational Biology  2012;8(9):e1002694.
Integrated analyses of functional genomics data have enormous potential for identifying phenotype-associated genes. Tissue-specificity is an important aspect of many genetic diseases, reflecting the potentially different roles of proteins and pathways in diverse cell lineages. Accounting for tissue specificity in global integration of functional genomics data is challenging, as “functionality” and “functional relationships” are often not resolved for specific tissue types. We address this challenge by generating tissue-specific functional networks, which can effectively represent the diversity of protein function for more accurate identification of phenotype-associated genes in the laboratory mouse. Specifically, we created 107 tissue-specific functional relationship networks through integration of genomic data utilizing knowledge of tissue-specific gene expression patterns. Cross-network comparison revealed significantly changed genes enriched for functions related to specific tissue development. We then utilized these tissue-specific networks to predict genes associated with different phenotypes. Our results demonstrate that prediction performance is significantly improved through using the tissue-specific networks as compared to the global functional network. We used a testis-specific functional relationship network to predict genes associated with male fertility and spermatogenesis phenotypes, and experimentally confirmed one top prediction, Mbyl1. We then focused on a less-common genetic disease, ataxia, and identified candidates uniquely predicted by the cerebellum network, which are supported by both literature and experimental evidence. Our systems-level, tissue-specific scheme advances over traditional global integration and analyses and establishes a prototype to address the tissue-specific effects of genetic perturbations, diseases and drugs.
Author Summary
Tissue specificity is an important aspect of many genetic diseases, reflecting the potentially different roles of proteins and pathways in diverse cell lineages. We propose an effective strategy to model tissue-specific functional relationship networks in the laboratory mouse. We integrated large scale genomics datasets as well as low-throughput tissue-specific expression profiles to estimate the probability that two proteins are co-functioning in the tissue under study. These networks can accurately reflect the diversity of protein functions across different organs and tissue compartments. By computationally exploring the tissue-specific networks, we can accurately predict novel phenotype-related gene candidates. We experimentally confirmed a top candidate gene, Mybl1, to affect several male fertility phenotypes, predicted based on male-reproductive system-specific networks and we predicted candidates related to a rare genetic disease ataxia, which are supported by experimental and literature evidence. The above results demonstrate the power of modeling tissue-specific dynamics of co-functionality through computational approaches.
PMCID: PMC3459891  PMID: 23028291
14.  Association of the DYX1C1 Dyslexia Susceptibility Gene with Orthography in the Chinese Population 
PLoS ONE  2012;7(9):e42969.
Several independent studies have supported the association of DYX1C1 with dyslexia, but its role in general reading development remains unclear. Here, we investigated the contribution of this gene to reading, with a focus on orthographic skills, in a sample of 284 unrelated Chinese children aged 5 to 11 years who were participating in the Chinese Longitudinal Study of Reading Development. We tested this association using a quantitative approach for Chinese character reading, Chinese character dictation, orthographic judgment, and visual skills. Significant or marginally significant associations were observed at the marker rs11629841 with children's orthographic judgments at ages 7 and 8 years (all P values<0.020). Significant associations with Chinese character dictation (all P values<0.013) were also observed for this single-nucleotide polymorphism (SNP) at ages 9, 10, and 11 years. Further analyses revealed that the association with orthographic skills was specific to the processing of specific components of characters (P values<0.046). No association was found at either SNP of rs3743205 or rs57809907. Our findings suggest that DYX1C1 influences reading development in the general Chinese population and supports a universal effect of this gene.
PMCID: PMC3441603  PMID: 23028439
15.  Influence of Threat and Serotonin Transporter Genotype on Interference Effects 
Emotion-cognition interactions are critical in goal-directed behavior and may be disrupted in psychopathology. Growing evidence also suggests that emotion-cognition interactions are modulated by genetic variation, including genetic variation in the serotonin system. The goal of the current study was to examine the impact of threat-related distracters and serotonin transporter promoter polymorphism (5-HTTLPR/rs25531) on cognitive task performance in healthy females. Using a novel threat-distracter version of the Multi-Source Interference Task specifically designed to probe emotion-cognition interactions, we demonstrate a robust and temporally dynamic modulation of cognitive interference effects by threat-related distracters relative to other distracter types and relative to no-distracter condition. We further show that threat-related distracters have dissociable and opposite effects on cognitive task performance in easy and difficult task conditions, operationalized as the level of response interference that has to be surmounted to produce a correct response. Finally, we present evidence that the 5-HTTLPR/rs25531 genotype in females modulates susceptibility to cognitive interference in a global fashion, across all distracter conditions, and irrespective of the emotional salience of distracters, rather than specifically in the presence of threat-related distracters. Taken together, these results add to our understanding of the processes through which threat-related distracters affect cognitive processing, and have implications for our understanding of disorders in which threat signals have a detrimental effect on cognition, including depression and anxiety disorders.
PMCID: PMC3349301  PMID: 22590463
cognition; emotion; interference resolution; threat; serotonin transporter gene; 5-HTTLPR; MSIT
16.  Impulsiveness and Insula activation during reward anticipation are associated with genetic variants in GABRA2 in a family sample enriched for alcoholism 
Molecular Psychiatry  2011;17(5):511-519.
Genetic factors, externalizing personality traits such as impulsivity, and brain processing of salient stimuli all can affect individual risk for alcoholism. One of very few confirmed genetic association findings differentiating alcoholics from non-alcoholics is with variants in the inhibitory gamma-amino butyric acid α2 receptor subunit (GABRA2) gene. Here we report the association of two of these GABRA2 variants with measures of alcohol symptoms, impulsivity and with insula cortex activation during anticipation of reward or loss using functional magnetic resonance imaging (fMRI).
In a sample of 173 families (449 subjects), 129 of whom had at least one member diagnosed with alcohol dependence or abuse, carriers for the G allele in two SNPs and haplotypes were more likely to have alcohol dependence symptoms (rs279858 p = 0.01; rs279826 p = 0.05; haplotype p = 0.02) and higher NEO-PI-R Impulsiveness scores (rs279858 p = 0.016; rs279826 p = 0.012; haplotype p = 0.032) with a stronger effect in females (rs279858 p = 0.011; rs279826 p = 0.002; haplotype p = 0.006), all p values are corrected for family history and age. A subset of offspring from these families (n = 44, 20 females), genotyped for GABRA2, participated in an fMRI study using a monetary incentive delay task. Increased insula activation during reward (r2 = 0.4; p = 0.026) and loss (r2 = 0.38; p = 0.039) anticipation was correlated with NEO-PI-R Impulsiveness and further associated with the GG genotype for both SNPs (ps’ < 0.04). Our results suggest that GABRA2 genetic variation is associated with Impulsiveness through variation of insula activity responses, here evidenced during anticipatory responses.
PMCID: PMC3166450  PMID: 21483437
Impulsiveness; GABRA2; SNP; alcohol dependence; Insula; fMRI
17.  Family-based association analysis to finemap bipolar linkage peak on chromosome 8q24 using 2,500 genotyped SNPs and 15,000 imputed SNPs 
Bipolar Disorders  2010;12(8):786-792.
Multiple linkage and association studies have suggested chromosome 8q24 as a promising candidate region for bipolar disorder (BP). We performed a detailed association analysis assessing the contribution of common genetic variation in this region to the risk of BP.
We analyzed 2,756 single nucleotide polymorphism (SNP) markers in the chromosome 8q24 region of 3,512 individuals from 737 families. In addition, we extended genotype imputation methods to family-based data and imputed 22,725 HapMap SNPs in the same region on 8q24. We applied a family-based method to test 15,552 high-quality genotyped or imputed SNPs for association with BP.
Our association analysis identified the most significant marker (p = 4.80 × 10−5), near the gene encoding potassium voltage-gated channel KQT-like protein (KCNQ3). Other marginally significant markers were located near adenylate cyclase 8 (ADCY8) and ST3 beta-galactoside alpha-2,3-sialyltransferase 1 (ST3GAL1).
We developed an approach to apply MACH imputation to family-based data, which can increase the power to detect association signals. Our association results showed suggestive evidence of association of BP with loci near KCNQ3, ADCY8, and ST3GAL1. Consistent with genes identified by genome-wide association studies for BP, our results are consistent with the involvement of ion channelopathy in BP pathogenesis. However, common variants are insufficient to explain linkage findings in 8q24; other genetic variations should be explored.
PMCID: PMC3290916  PMID: 21176025
8q24; bipolar disorder; imputation; ion channelopathy
18.  MicroRNA expression changes in lymphoblastoid cell lines in response to lithium treatment 
Lithium (Li) is commonly used in the treatment of bipolar disorder (BPD). However, the molecular mechanism of its action has not completely understood. MicroRNAs (miRNAs), a class of small RNA species are recognized as important regulators in post-transcription gene expression. To explore the role of miRNA in Li action, we quantitatively analyzed the expression patterns of 13 miRNAs in 20 lymphoblastoid cell lines (LCLs) with or without Li treatment in culture. Using paired t statistics in the analysis, we identified significant changes in seven of the 13 miRNAs tested in LCLs sampled at treatment day 4 (P < 0.05). Four of the seven significant miRNAs, miR-34a, miR-152, miR-155, and miR-221 consistently changed expression in the same LCLs at a longer treatment time point day 16 (Bonferroni P < 0.05). Interestingly, miR-221 and miR-34a also changed expression in rat hippocampus in response to Li treatment (Zhou et al., 2008), though in the opposite direction. We focused on the predicted target mRNAs of miR-221 and miR-34a, and identified 29 and ten targets that were strongly and inversely correlated in expression with the two miRNAs, respectively. At present we tested a subset of miRNAs, our results suggest that miRNAs are excellent candidates for the study of the molecular basis of Li’s treatment action in cell systems such as lymphocytes given limited access to the human brain.
PMCID: PMC3216398  PMID: 19254429
lithium; target gene; post-transcription regulation
19.  The Effect of Question Framing and Response Options on the Relationship between Racial Attitudes and Beliefs about Genes as Causes of Behavior 
Public opinion quarterly  2010;74(3):460-476.
Prior research suggests that the attribution of individual and group differences to genetic causes is correlated with prejudiced attitudes toward minority groups. Our study suggests that these findings may be due to the wording of the questions and to the choice of response options. Using a series of vignettes in an online survey, we find a relationship between racial attitudes and genetic attributions when respondents are asked to make causal attributions of differences between racial groups. However, when they are asked to make causal attributions for characteristics shown by individuals, no such relationship is found. The response scale used appears to make less, if any, difference in the results. These findings indicate that the way questions about genetic causation of behavior are framed makes a significant contribution to the answers obtained because it significantly changes the meaning of the questions. We argue that such framing needs to be carefully attended to, not only in posing research questions but also in discourse about genetics more generally.
PMCID: PMC3045778  PMID: 22476404
20.  SSRI response in depression may be influenced by SNPs in HTR1B and HTR1A 
Psychiatric genetics  2009;19(6):281-291.
Desensitization of serotonin 1A (HTR1A) and 1B (HTR1B) autoreceptors has been proposed to be involved in the delayed onset of response to SSRIs. Variations in gene expression in these genes may thus affect SSRI response. Here we test this hypothesis in two samples from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D), and show evidence for involvement of several genetic variants alone and in interaction. Initially, three functional SNPs in the HTR1B gene and in the HTR1A gene were analyzed in 153 depressed patients treated with citalopram. QIDS-C scores were evaluated over time with respect to genetic variation. Subjects homozygous for the - 1019 G allele (rs6295) in HTR1A showed higher baseline QIDS scores (p = 0.033), and by 12 weeks had a significantly lower response rate (p = 0.005). HTR1B haplotypes were estimated according to previously reported in-vitro expression levels. Individuals who were homozygous for the high-expression haplotype showed significantly slower response to citalopram (p = 0.034).
We then analyzed more SNPs in the extended overall STAR*D sample. Although we could not directly test the same functional SNPs, we found that homozygotes for the G allele at rs1364043 in HTR1A (p = 0.045) and the C allele of rs6298 in HTR1B showed better response to citalopram over time (p = 0.022). Test for interaction between rs6298 in HTR1B and rs1364043 in HTR1A was significant (overall p = 0.032)
Our data suggest that an enhanced capacity of HTR1B or HTR1A transcriptional activity may impair desensitization of the autoreceptors during SSRI treatment.
PMCID: PMC2783179  PMID: 19829169
SSRI; depression; haplotype; HTR1B; HTR1A; association
21.  Association between Val66Met Brain-Derived Neurotrophic Factor (BDNF) Gene Polymorphism and Post-Treatment Relapse in Alcohol Dependence 
The purpose of this study was to examine relationships between genetic markers of central serotonin and dopamine function, and risk for post-treatment relapse, in a sample of alcohol-dependent patients.
The study included 154 patients from addiction treatment programs in Poland, who met DSM-IV criteria for alcohol dependence. After assessing demographics, severity of alcohol use, suicidality, impulsivity, depression, hopelessness, and severity of alcohol use at baseline, patients were followed for approximately one year to evaluate treatment outcomes. Genetic polymorphisms in several genes (TPH2, SLC6A4, HTR1A, HTR2A, COMT, BDNF) were tested as predictors of relapse (defined as any drinking during follow-up) while controlling for baseline measures.
Of 154 eligible patients, 123 (80%) completed follow-up and 48% (n = 59) of these individuals relapsed. Patients with the Val allele in the Val66Met BDNF polymorphism and the Met allele in the Val158Met COMT polymorphism were more likely to relapse. Only the BDNF Val/Val genotype predicted post-treatment relapse (OR = 2.62; p = 0.019), and time to relapse (OR = 2.57; p = 0.002), after adjusting for baseline measures and other significant genetic markers. When the analysis was restricted to patients with a family history of alcohol dependence (n = 73), the associations between the BDNF Val/Val genotype and relapse (OR = 5.76, p = 0.0045) and time to relapse (HR = 4.93, p = 0.001) were even stronger.
The Val66Met BDNF gene polymorphism was associated with a higher risk and earlier occurrence of relapse among patients treated for alcohol dependence. The study suggests a relationship between genetic markers and treatment outcomes in alcohol dependence. Because a large number of statistical tests were conducted for this study and the literature on genetics and relapse is so novel, the results should be considered as hypothesis generating and need to be replicated in independent studies.
PMCID: PMC2928673  PMID: 19170664
alcohol dependence; genetic polymorphism; BDNF; relapse
22.  New insights into the genetics of addiction 
Nature reviews. Genetics  2009;10(4):225-231.
Drug addiction is a common brain disorder that is extremely costly to the individual and to society. Genetics contributes significantly to vulnerability to this disorder, but identification of susceptibility genes has been slow. Recent genome-wide linkage and association studies have implicated several regions and genes in addiction to various substances, including alcohol and, more recently, tobacco. Current efforts aim not only to replicate these findings in independent samples but also to determine the functional mechanisms of these genes and variants.
PMCID: PMC2879628  PMID: 19238175
23.  Genome-wide association scan for five major dimensions of personality 
Molecular psychiatry  2008;15(6):647-656.
Personality traits are summarized by five broad dimensions with pervasive influences on major life outcomes, strong links to psychiatric disorders, and clear heritable components. To identify genetic variants associated with each of the five dimensions of personality we performed a genome wide association (GWA) scan of 3,972 individuals from a genetically isolated population within Sardinia, Italy. Based on analyses of 362,129 single nucleotide polymorphisms (SNPs) we found several strong signals within or near genes previously implicated in psychiatric disorders. They include the association of Neuroticism with SNAP25 (rs362584, P = 5 × 10−5), Extraversion with BDNF and two cadherin genes (CDH13 and CDH23; Ps < 5 × 10−5), Openness with CNTNAP2 (rs10251794, P = 3 × 10−5), Agreeableness with CLOCK (rs6832769, P = 9 × 10−6), and Conscientiousness with DYRK1A (rs2835731, P = 3 × 10−5). Effect sizes were small (less than 1% of variance), and most failed to replicate in the follow-up independent samples (N up to 3,903), though the association between Agreeableness and CLOCK was supported in two of three replication samples (overall P = 2 × 10−5). We infer that a large number of loci may influence personality traits and disorders, requiring larger sample sizes for the GWA approach to identify significant genetic variants.
PMCID: PMC2874623  PMID: 18957941
personality; genome wide association; founder population; psychiatry; five-factor model
25.  Family-based SNP Association Study on 8q24 in Bipolar Disorder 
Previous linkage studies have identified chromosome 8q24 as a promising positional candidate region to search for bipolar disorder (BP) susceptibility genes. We, therefore, sought to identify BP susceptibility genes on chromosome 8q24 using a family-based association study of a dense panel of SNPs selected to tag the known common variation across the region of interest. A total of 1,458 SNPs across 16 Mb of 8q24 were examined in 3,512 subjects, 1,954 of whom were affected with BP, from 737 multiplex families. Single-locus tests were carried out with FBAT and Geno-PDT, and multi-locus test were carried out with HBAT and multi-locus Geno-PDT. None of the SNPs were associated with BP in the single-locus tests at a level that exceeded our threshold for study-wide significance (p<3.00×10−5). However, there was consistent evidence at our threshold for the suggestive level (p<7.00×10−4) from both the single locus and multi-locus tests of associations with SNPs in the genes ADCY8, ST3GAL1 and NSE2. Multi-locus analyses suggested joint effects between ADCY8 and ST3GAL1 (p=3.00×10−4), with at least one copy of the “high risk” allele required at both genes for association with BP, consistent with a jointly dominant-dominant model of action. These findings with ADCY8 and ST3GAL1 warrant further investigation in order to confirm the observed associations and their functional significance for BP susceptibility.
PMCID: PMC2700285  PMID: 18163389

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