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1.  A Preliminary Examination of the Relationship Between the 5-HTTLPR and Childhood Emotional Abuse on Depressive Symptoms in 10-to-12-Year-Old Youth 
Childhood emotional abuse (CEA) is a pervasive problem associated with negative sequelae such as elevated depressive symptoms. Key stress-related genes, such as the 5-HTTLPR polymorphism, interact with childhood abuse to produce elevated depressive symptoms in older adolescent girls, but not in older adolescent boys. To date, studies have not examined this relationship as a function of CEA specifically or among younger adolescents. To extend prior work, we examined the effects of the 5-HTTLPR and CEA on depressive symptoms among 10–12-year-old youth. Based on previous findings, we expected a main effect of CEA on depressive symptoms among all youth, but only expected an interactive effect between the 5-HTTLPR and CEA on depressive symptoms in girls. In the current study, 222 youth (mean age 11.02 years, 44.1% girls, 51.6% Caucasian, 33.0% African American, 2.7% Latino, and 12.7% other) and their parent(s)/guardian(s) completed the Revised Child Anxiety and Depression Scale and the Emotional Abuse subscale of the Childhood Trauma Questionnaire and provided saliva samples for genotyping the 5-HTTLPR. Results indicate that CEA, but not the 5-HTTLPR, was related to elevated depressive symptoms among boys. Among girls, each copy of the s allele of the 5-HTTLPR was related to increased depressive symptoms, but only for those who had experienced CEA. Our results extend prior findings by specifically examining CEA and by focusing on 10–12-year-old youth. These results, although preliminary, suggest that focusing on the interplay between putative genetic markers and a broader range of environmental events, such as CEA, might allow researchers to determine factors differentially influencing the later emergence of sex differences in depressive symptoms.
doi:10.1037/a0031121
PMCID: PMC4057058  PMID: 24932352
emotional abuse; depressive symptoms; 5-HTTLPR; sex differences; early adolescence
2.  COMT Val158Met modulates subjective responses to intravenous nicotine and cognitive performance in abstinent smokers 
The pharmacogenomics journal  2013;13(6):10.1038/tpj.2013.1.
The COMT Val158Met polymorphism may be a risk factor for nicotine addiction. This study examined the influence of the COMT Val158Met polymorphism on subjective, physiological, and cognitive effects of intravenous (IV) nicotine use in African American (AAs) (n=56) and European American (EAs) (n=68) smokers. Overnight abstinent smokers received saline followed by 0.5 and 1.0 mg/70 kg doses of nicotine, administered 30 minutes apart. Smokers with Val/Val genotype, compared to Met carriers, had greater negative subjective effects from IV nicotine and had more severe withdrawal severity following overnight abstinence from smoking. Women with Val/Val genotype reported greater difficulty concentrating and irritability than men with Val/Val or Met carrier genotypes. The Val/Val genotype was associated with better performance on the math task and in AA smokers it was associated with greater systolic blood pressure. These results support the rationale of pharmacologically inhibiting COMT to aid with smoking cessation among Val/Val genotype smokers.
doi:10.1038/tpj.2013.1
PMCID: PMC3675163  PMID: 23459442
Nicotine; Genetics; Pharmacogenetic; Smoking; Cigarette; COMT
3.  A Prospective Cohort Study Investigating Factors Associated with Depression during Medical Internship 
Archives of general psychiatry  2010;67(6):557-565.
Context
Although the prevalence of depression among medical interns substantially exceeds that of the general population, the specific factors responsible are not well understood. Recent reports of a moderating effect of a genetic polymorphism (5-HTTLPR) in the serotonin transporter protein gene on the likelihood that life stress will precipitate depression may help to understand the development of mood symptoms in medical interns.
Objective
To identify psychological, demographic and residency program factors that associate with depression among interns and use medical internship as a model to study the moderating effects of this polymorphism using a prospective, within-subject design that addresses the design limitations of earlier studies.
Design
Prospective cohort study
Setting
13 United States hospitals
Participants
740 interns entering participating residency programs
Main outcome measures
Subjects were assessed for depressive symptoms using the Patient Health Questionnaire (PHQ-9), a series of psychological traits and 5-HTTLPR genotype prior to internship and then assessed for depressive symptoms and potential stressors at 3-month intervals during internship.
Results
The PHQ-9 depression score increased from 2.4 prior to internship to a mean of 6.4 during internship (p<0.001). The proportion of participants who met PHQ-9 criteria for depression increased from 3.9% prior to internship to a mean of 25.7% during internship (p<0.001). A series of factors measured prior to internship (female sex, U.S. medical education, difficult early family environment, history of major depression, lower baseline depressive symptom score and higher neuroticism) and during internship (increased work hours, perceived medical errors and stressful life events) were associated with a greater increase in depressive symptoms during internship. In addition, subjects with at least one copy of a less transcribed 5-HTTLPR allele reported a greater increase in depressive symptoms under the stress of internship (p=0.002).
Conclusions
There is a marked increase in depressive symptoms during medical internship. Specific individual, internship and genetic factors are associated with the increase in depressive symptoms.
doi:10.1001/archgenpsychiatry.2010.41
PMCID: PMC4036806  PMID: 20368500
Graduate; Medical; Education; Residency; Serotonin; Transporter
4.  Examining the relation between the serotonin transporter 5-HTTPLR genotype x trauma exposure interaction on a contemporary phenotypic model of posttraumatic stress symptomatology: A pilot study 
Journal of affective disorders  2012;148(1):123-128.
Background
Little is known about the specificity of the interaction of serotonin transporter 5-HTTLPR genotype x trauma exposure in relation to contemporary structural models of PTSD symptomatology, which suggest that 4- or 5-factor models provide a better representation of this phenotypic expression of this disorder.
Methods
One hundred forty-nine respondents of a representative sample of adults affected by Hurricane Ike were interviewed 2 to 5 months after this 2008 disaster.
Results
After adjustment for age, sex, and ancestral proportion scores, the interaction of 5-HTTPLR genotype x trauma exposure was significantly associated with both severity (β=.40, p<.001) and probable diagnosis (Wald=4.55, p=.033; odds ratio=3.81, 95%CI=1.11–13.03) of Ike-related PTSD. Respondents with the low-expression variant of the 5-HTTPLR polymorphism (S allele) who were highly exposed to Hurricane Ike reported significantly greater severity of PTSD symptoms and were more likely to screen positive for PTSD than respondents homozygous for the L allele who were highly exposed to Hurricane Ike. Confirmatory factor analyses revealed that a 5-factor model of intercorrelated re-experiencing, avoidance, numbing, dysphoric arousal, and anxious arousal symptoms provided the best structural representation of PTSD symptomatology. The 5-HTTPLR genotype x exposure interaction was significant only for anxious arousal (β=.44, p<.001) and re-experiencing (β=.35, p<.001) symptoms, but not avoidance, numbing, or dysphoric arousal symptoms (all β’s≤.20, all p’s>.13).
Limitations
The small sample size and employment of self-report measures may limit generalizability of these findings.
Conclusions
Results of this pilot study suggest that the low-expression variant of the 5-HTTLPR polymorphism modifies risk for PTSD, but that this effect may be specific to anxious arousal and re-experiencing symptoms.
doi:10.1016/j.jad.2012.11.003
PMCID: PMC3604029  PMID: 23183127
Serotonin transporter gene; Posttraumatic stress disorder; Trauma; Disaster
5.  Ordered subset linkage analysis based on admixture proportion identifies new linkage evidence for alcohol dependence in African-Americans 
Human genetics  2012;132(4):397-403.
Genetic heterogeneity could reduce the power of linkage analysis to detect risk loci for complex traits such as alcohol dependence (AD). Previously, we performed a genomewide linkage analysis for AD in African-Americans (AAs) (Gelernter et al., 2009). The power of that linkage analysis could have been reduced by the presence of genetic heterogeneity owing to differences in admixture among AA families. We hypothesized that by examining a study sample whose genetic ancestry was more homogeneous we could increase the power to detect linkage. To test this hypothesis, we performed ordered subset linkage analysis (OSA) in 384 AA families using admixture proportion as a covariate to identify a more homogeneous subset of families and determine whether there is increased evidence for linkage with AD. Statistically significant increases in lod scores in subsets relative to the overall sample were identified on chromosomes 4 (P=0.0001), 12 (P=0.021), 15 (P=0.026) and 22 (P=0.0069). In a subset of 44 families with African ancestry proportions ranging from 0.858 to 0.996, we observed a genomewide significant linkage at 180 cM on chromosome 4 (lod=4.24, pointwise P<0.00001, empirical genomewide P=0.008). A promising candidate gene located there, GLRA3, which encodes a subunit of the glycine neurotransmitter receptor. Our results demonstrate that admixture proportion can be used as a covariate to reduce genetic heterogeneity and enhance the detection of linkage for AD in an admixed population such as AAs. This approach could be applied to any linkage analysis for complex traits conducted in an admixed population.
doi:10.1007/s00439-012-1255-2
PMCID: PMC3751162  PMID: 23239122
linkage; ordered subset linkage analysis; genetic heterogeneity; alcohol dependence; admixture
6.  A pilot multivariate parallel ICA study to investigate differential linkage between neural networks and genetic profiles in schizophrenia 
NeuroImage  2009;53(3):1007-1015.
Understanding genetic influences on both healthy and disordered brain function is a major focus in psychiatric neuroimaging. We utilized task-related imaging findings from an fMRI auditory oddball task known to be robustly associated with abnormal activation in schizophrenia, to investigate genomic factors derived from multiple single nucleotide polymorphisms (SNP’s) from genes previously shown to be associated with schizophrenia. Our major aim was to investigate the relationship of these genomic factors to normal/abnormal brain functionality between controls and schizophrenia patients. We studied a Caucasian-only sample of 35 healthy controls and 31 schizophrenia patients. All subjects performed an auditory oddball task, which consists of detecting an infrequent sound within a series of frequent sounds. Each subject was characterized on 24 different SNP markers spanning multiple risk genes previously associated with schizophrenia. We used a recently developed technique named parallel independent component analysis (para-ICA) to analyze this multimodal dataset (Liu et al., 2008). The method aims to identify simultaneously independent components of each modality (functional imaging, genetics) and the relationships between them. We detected 3 fMRI components significantly correlated with two distinct gene components. The fMRI components, along with their significant genetic profile (dominant SNP) correlations were as follows: 1) Inferior frontal- anterior/posterior cingulate-thalamus-caudate with SNPs from Brain derived neurotropic factor (BDNF) & Dopamine Transporter, (DAT) [r=−0.51; p<0.0001], 2) Superior/middle temporal gyrus-Cingulate-premotor with SLC6A4_PR and SLC6A4_PR_AG (Serotonin transporter promoter; 5HTTLPR) [r=0.27; p=0.03], 3) Default Mode-fronto-temporal gyrus with Brain derived neurotropic factor & Dopamine Transporter (BDNF, DAT) [r=−0.25; p=0.04]. Functional components comprised taskrelevant regions (including PFC, ACC, STG and MTG) frequently identified as abnormal in schizophrenia. Further, gene-fMRI combinations 1 (Z=1.75; p=0.03), 2 (Z=1.84;p=0.03) and 3 (Z=1.67; p=0.04) listed above showed significant differences between controls and patients, based on their correlated loading coefficients. We demonstrate a framework to identify interactions between “clusters” of brain function and of genetic information. Our results reveal the effect/influence of specific interactions, (perhaps epistastatic in nature), between schizophrenia risk genes on imaging endophenotypes representing attention/working memory and goal directed related brain function, thus establishing a useful methodology to probe multivariate genotype-phenotype relationships.
doi:10.1016/j.neuroimage.2009.11.052
PMCID: PMC3968678  PMID: 19944766
auditory oddball; DAT; BDNF; fMRI; gene; parallel ICA; multivariate; 5HTTLPR
7.  Distinct Loci in the CHRNA5/CHRNA3/CHRNB4 Gene Cluster Are Associated With Onset of Regular Smoking 
Stephens, Sarah H. | Hartz, Sarah M. | Hoft, Nicole R. | Saccone, Nancy L. | Corley, Robin C. | Hewitt, John K. | Hopfer, Christian J. | Breslau, Naomi | Coon, Hilary | Chen, Xiangning | Ducci, Francesca | Dueker, Nicole | Franceschini, Nora | Frank, Josef | Han, Younghun | Hansel, Nadia N. | Jiang, Chenhui | Korhonen, Tellervo | Lind, Penelope A. | Liu, Jason | Lyytikäinen, Leo-Pekka | Michel, Martha | Shaffer, John R. | Short, Susan E. | Sun, Juzhong | Teumer, Alexander | Thompson, John R. | Vogelzangs, Nicole | Vink, Jacqueline M. | Wenzlaff, Angela | Wheeler, William | Yang, Bao-Zhu | Aggen, Steven H. | Balmforth, Anthony J. | Baumeister, Sebastian E. | Beaty, Terri H. | Benjamin, Daniel J. | Bergen, Andrew W. | Broms, Ulla | Cesarini, David | Chatterjee, Nilanjan | Chen, Jingchun | Cheng, Yu-Ching | Cichon, Sven | Couper, David | Cucca, Francesco | Dick, Danielle | Foroud, Tatiana | Furberg, Helena | Giegling, Ina | Gillespie, Nathan A. | Gu, Fangyi | Hall, Alistair S. | Hällfors, Jenni | Han, Shizhong | Hartmann, Annette M. | Heikkilä, Kauko | Hickie, Ian B. | Hottenga, Jouke Jan | Jousilahti, Pekka | Kaakinen, Marika | Kähönen, Mika | Koellinger, Philipp D. | Kittner, Stephen | Konte, Bettina | Landi, Maria-Teresa | Laatikainen, Tiina | Leppert, Mark | Levy, Steven M. | Mathias, Rasika A. | McNeil, Daniel W. | Medland, Sarah E. | Montgomery, Grant W. | Murray, Tanda | Nauck, Matthias | North, Kari E. | Paré, Peter D. | Pergadia, Michele | Ruczinski, Ingo | Salomaa, Veikko | Viikari, Jorma | Willemsen, Gonneke | Barnes, Kathleen C. | Boerwinkle, Eric | Boomsma, Dorret I. | Caporaso, Neil | Edenberg, Howard J. | Francks, Clyde | Gelernter, Joel | Grabe, Hans Jörgen | Hops, Hyman | Jarvelin, Marjo-Riitta | Johannesson, Magnus | Kendler, Kenneth S. | Lehtimäki, Terho | Magnusson, Patrik K.E. | Marazita, Mary L. | Marchini, Jonathan | Mitchell, Braxton D. | Nöthen, Markus M. | Penninx, Brenda W. | Raitakari, Olli | Rietschel, Marcella | Rujescu, Dan | Samani, Nilesh J. | Schwartz, Ann G. | Shete, Sanjay | Spitz, Margaret | Swan, Gary E. | Völzke, Henry | Veijola, Juha | Wei, Qingyi | Amos, Chris | Cannon, Dale S. | Grucza, Richard | Hatsukami, Dorothy | Heath, Andrew | Johnson, Eric O. | Kaprio, Jaakko | Madden, Pamela | Martin, Nicholas G. | Stevens, Victoria L. | Weiss, Robert B. | Kraft, Peter | Bierut, Laura J. | Ehringer, Marissa A.
Genetic epidemiology  2013;37(8):846-859.
Neuronal nicotinic acetylcholine receptor (nAChR) genes (CHRNA5/CHRNA3/CHRNB4) have been reproducibly associated with nicotine dependence, smoking behaviors, and lung cancer risk. Of the few reports that have focused on early smoking behaviors, association results have been mixed. This meta-analysis examines early smoking phenotypes and SNPs in the gene cluster to determine: (1) whether the most robust association signal in this region (rs16969968) for other smoking behaviors is also associated with early behaviors, and/or (2) if additional statistically independent signals are important in early smoking. We focused on two phenotypes: age of tobacco initiation (AOI) and age of first regular tobacco use (AOS). This study included 56,034 subjects (41 groups) spanning nine countries and evaluated five SNPs including rs1948, rs16969968, rs578776, rs588765, and rs684513. Each dataset was analyzed using a centrally generated script. Meta-analyses were conducted from summary statistics. AOS yielded significant associations with SNPs rs578776 (beta = 0.02, P = 0.004), rs1948 (beta = 0.023, P = 0.018), and rs684513 (beta = 0.032, P = 0.017), indicating protective effects. There were no significant associations for the AOI phenotype. Importantly, rs16969968, the most replicated signal in this region for nicotine dependence, cigarettes per day, and cotinine levels, was not associated with AOI (P = 0.59) or AOS (P = 0.92). These results provide important insight into the complexity of smoking behavior phenotypes, and suggest that association signals in the CHRNA5/A3/B4 gene cluster affecting early smoking behaviors may be different from those affecting the mature nicotine dependence phenotype.
doi:10.1002/gepi.21760
PMCID: PMC3947535  PMID: 24186853
CHRNA5; CHRNA3; CHRNB4; meta-analysis; nicotine; smoke
8.  Autosomal Linkage Scan for Loci Predisposing to Comorbid Dependence on Multiple Substances 
Multiple substance dependence (MSD) trait comorbidity is common, and MSD patients are often severely affected clinically. While shared genetic risks have been documented, so far there has been no published report using the linkage scan approach to survey risk loci for MSD as a phenotype. A total of 1,758 individuals in 739 families [384 African American (AA) and 355 European American (EA) families] ascertained via affected sib-pairs with cocaine or opioid or alcohol dependence were genotyped using an array-based linkage panel of single-nucleotide polymorphism markers. Fuzzy clustering analysis was conducted on individuals with alcohol, cannabis, cocaine, opioid, and nicotine dependence for AAs and EAs separately, and linkage scans were conducted for the output membership coefficients using Merlin-regression. In EAs, we observed an autosome-wide significant linkage signal on chromosome 4 (peak lod = 3.31 at 68.3 cM; empirical autosome-wide P = 0.038), and a suggestive linkage signal on chromosome 21 (peak lod = 2.37 at 19.4 cM). In AAs, four suggestive linkage peaks were observed: two peaks on chromosome 10 (lod = 2.66 at 96.7 cM and lod = 3.02 at 147.6 cM] and the other two on chromosomes 3 (lod = 2.81 at 145.5 cM) and 9 (lod = 1.93 at 146.8 cM). Three particularly promising candidate genes, GABRA4, GABRB1, and CLOCK, are located within or very close to the autosome-wide significant linkage region for EAs on chromosome 4. This is the first linkage evidence supporting existence of genetic loci influencing risk for several comorbid disorders simultaneously in two major US populations.
doi:10.1002/ajmg.b.32037
PMCID: PMC3920832  PMID: 22354695
comorbidity; multiple substance dependence; fuzzy clustering; chromosome 4
9.  Child Abuse and Epigenetic Mechanisms of Disease Risk 
Background
Child abuse is highly prevalent and associated with increased risk for a range of health problems including: cancer, cardiovascular disease, diabetes, psychiatric disorders, and other health problems. Little is currently known about the mechanism by which early adversity confers risk for health problems later in life.
Purpose
To determine if there are epigenetic differences associated with child maltreatment that may help explain association between adverse childhood experiences and later health problems.
Methods
As part of a study examining genetic and environmental factors associated with depression, saliva DNA specimens were collected on 96 maltreated children removed from their parents due to abuse or neglect and 96 demographically-matched control children between 2003 and 2010. In 2011, the Illumina 450K BeadChip was used on stored DNA specimens and analyzed to examine whole-genome methylation differences between maltreated and control children.
Results
After controlling for multiple comparisons, maltreated and control children had significantly different methylation values at 2868 CpG sites (p< 5.0 × 10−7, all sites; average methylation difference per site=17%; range 1%–62%). The gene set contained numerous markers of diseases and biological processes related to the health problems associated with early childhood adversity.
Conclusions
While replication is required, this study suggests that epigenetic mechanisms may be associated with risk for health problems later in life in maltreated children. This study lays the groundwork for future studies examining health and methylation measures to further characterize the role of epigenetic mechanisms in conferring risk for medical problems in individuals with histories of early adversity.
doi:10.1016/j.amepre.2012.10.012
PMCID: PMC3758252  PMID: 23332324
10.  Array-based Profiling of DNA Methylation Changes Associated with Alcohol Dependence 
Background
Epigenetic regulation through DNA methylation may influence vulnerability to numerous disorders, including alcohol dependence (AD).
Methods
Peripheral blood DNA methylation levels of 384 CpGs in the promoter regions of 82 candidate genes were examined in 285 African Americans (AAs; 141 AD cases and 144 controls) and 249 European Americans (EAs; 144 AD cases and 105 controls) using Illumina GoldenGate Methylation Array assays. Association of AD and DNA methylation changes were analyzed using multivariate analyses of covariance with frequency of intoxication, sex, age and ancestry proportion as covariates. CpGs showing significant methylation alterations in AD cases were further examined in a replication sample (49 EA cases and 32 EA controls) using Sequenom’s MassARRAY EpiTYPER technology.
Results
In AAs, two CpGs in two genes (GABRB3 and POMC) were hypermethylated in AD cases compared to controls (P≤0.001). In EAs, six CpGs in six genes (HTR3A, NCAM1, DRD4, MBD3, HTR2B and GRIN1) were hypermethylated in AD cases compared to controls (P≤0.001); CpG cg08989585 in the HTR3A promoter region showed a significantly higher methylation level in EA cases than in EA controls after Bonferroni correction (P=0.00007). Additionally, methylation levels of six CpGs (including cg08989585) in the HTR3A promoter region were analyzed in the replication sample. Although the six HTR3A promoter CpGs did not show significant methylation differences between EA cases and EA controls (P=0.067–0.877), the methylation level of CpG cg08989585 was non-significantly higher in EA cases (26.9%) than in EA controls (18.6%) (P=0.139).
Conclusions
The findings from this study suggest that DNA methylation profile appears to be associated with AD in a population-specific way and the predisposition to AD may result from a complex interplay of genetic variation and epigenetic modifications.
doi:10.1111/j.1530-0277.2012.01928.x
PMCID: PMC3511647  PMID: 22924764
Illumna GoldenGate Methylation Array; Sequenom MassARRAY EpiTYPER; Promoter CpGs; Alcohol Dependence; Peripheral Blood DNA
11.  Prevalence of DSM-IV and DSM-5 Alcohol, Cocaine, Opioid, and Cannabis Use Disorders in a Largely Substance Dependent Sample 
Drug and alcohol dependence  2012;127(0):215-219.
BACKGROUND
The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) will soon replace the DSM-IV, which has existed for nearly two decades. The changes in diagnostic criteria have important implications for research and for the clinical care of individuals with Substance Use Disorders (SUDs).
METHODS
We used the Semi-Structured Assessment for Drug Dependence and Alcoholism to evaluate the lifetime presence of DSM-IV abuse and dependence diagnoses and DSM-5 mild, moderate, or severe SUDs for alcohol, cocaine, opioids, and cannabis in a sample of 7,543 individuals recruited to participate in genetic studies of substance dependence.
RESULTS
Switches between diagnostic systems consistently resulted in a modestly greater prevalence for DSM-5 SUDs, based largely on the assignment of DSM-5 diagnoses to DSM-IV “diagnostic ophans” (i.e., individuals meeting one or two criteria for dependence and none for abuse, and thus not receiving a DSM-IV SUD diagnosis). The vast majority of these diagnostic switches were attributable to the requirement that only two of 11 criteria be met for a DSM-5 SUD diagnosis. We found evidence to support the omission from DSM-5 of the legal criterion due to its limited diagnostic utility. The addition of craving as a criterion in DSM-5 did not substantially affect the likelihood of an SUD diagnosis.
CONCLUSION
The greatest advantage of DSM-5 appears to be its ability to capture diagnostic orphans. In this sample, changes reflected in DSM-5 had a minimal impact on the prevalence of SUD diagnoses.
doi:10.1016/j.drugalcdep.2012.07.009
PMCID: PMC3727225  PMID: 22884164
DSM-IV; DSM-5; Substance Use Disorders; Substance Abuse; Substance Dependence
12.  Association between polymorphisms in catechol-O-methyltransferase (COMT) and cocaine-induced paranoia in European-American and African-American populations 
Catechol-O-methyltransferase (genetic locus, COMT) is a major enzyme involved in catecholamine metabolism and has been associated with numerous psychiatric phenotypes. We studied COMT SNPs and haplotypes in cocaine-induced paranoia (CIP) in African-American (AA) and European-American (EA) populations. We genotyped 17 SNPs across the COMT locus in 319 AA pedigrees (848 individuals) and 302 EA pedigrees (707 individuals). Family-controlled association analyses were conducted using FBAT. We found SNP rs737865 to be nominally significantly associated in the AA family population (p=0.05). In EAs, the best-known marker, rs4680 (Val158Met), was nominally significant in additive models (p=0.03). SNP rs174696 also showed nominal significance in additive models (p=0.02). We considered the 3 SNPs (rs737866-rs4680-rs174696) together in haplotype analysis in both family populations, using HBAT. The A-A-T haplotype was significantly associated with CIP in EAs (Z=2.845; p=0.0044, global p=0.020). We then studied COMT SNPs in an additional 738 AA and 404 EA unrelated cocaine dependent individuals with and without paranoia. The A-A-T haplotype was significantly associated to CIP in the AA unrelated population (p=0.0015). Two haplotypes, A-G-C and A-A-C, were significant in the EA unrelated population (p=0.001 and p=0.0003). We also identified rs4680 and three other SNPs, rs933271, rs5993883, and rs740603, as potentially functional variants, as predicted by a signature of positive selection in unrelated EAs and AAs. Based on our robust family-controlled and unrelated-affected analyses, we conclude that COMT is associated with CIP, possibly as a result of its role in the metabolism of dopamine and norepinephrine.
doi:10.1002/ajmg.b.31205
PMCID: PMC3864552  PMID: 21656904
COMT; cocaine-induced paranoia; family-based analysis; haplotype; SNP; positive selection
13.  MAOA Genotype, Maltreatment, and Aggressive Behavior: The Changing Impac of Genotype at Varying Levels of Trauma 
Biological psychiatry  2008;65(5):10.1016/j.biopsych.2008.09.013.
Background:
Childhood adversity has been shown to interact with monoamine oxidase-A (MAOA) genotype to confer risk for antisocial behavior. Studies examining this gene-by-environment (G×E) association, however, have produced mixed results.
Methods:
Relevant research is reviewed, and results of a study with 114 children (73 maltreated and 41 control subjects) are presented. The maltreated children represent the extreme on a continuum of adversity and were assessed at a time of extreme stress—shortly after removal from their parents’ care due to abuse. Measures of aggressive behavior were obtained using standard research instruments, and monoamine oxidase-A MAOA genotypes were obtained from saliva-derived DNA specimens. Population structure was controlled for using ancestral proportion scores computed on the basis of genotypes of ancestry informative markers.
Results:
Many prior investigations appear to have had reduced power to detect the predicted G×E interaction because of low base rates of maltreatment and antisocial behavior in their samples and failure to use optimal procedures to control for population structure in ethnically diverse cohorts. In this investigation, a significant interaction was detected between exposure to moderate trauma and the “low-activity” MAOA genotype in conferring risk for aggression. Children with exposure to extreme levels of trauma, however, had high aggression scores regardless of genotype.
Conclusions:
Our study suggests that problems in aggressive behavior in maltreated children are moderated by MAOA genotype, but only up to moderate levels of trauma exposure. Extreme levels of trauma appear to overshadow the effect of MAOA genotype, especially in children assessed at time of acute crisis.
doi:10.1016/j.biopsych.2008.09.013
PMCID: PMC3816252  PMID: 18996506
Aggression; antisocial; child abuse; gene–environment interaction; maltreatment; MAOA
14.  Genome-wide Association Study Identifies New Susceptibility Loci for Posttraumatic Stress Disorder 
Biological psychiatry  2013;74(9):10.1016/j.biopsych.2013.04.013.
Background
Genetic factors influence the risk for posttraumatic stress disorder (PTSD), a potentially chronic and disabling psychiatric disorder that can arise after exposure to trauma. Candidate gene association studies have identified few genetic variants that contribute to PTSD risk.
Methods
We conducted genome-wide association analyses in 1578 European Americans (EAs), including 300 PTSD cases, and 2766 African Americans, including 444 PTSD cases, to find novel common risk alleles for PTSD. We used the Illumina Omni1-Quad microarray, which yielded approximately 870,000 single nucleotide polymorphisms (SNPs) suitable for analysis.
Results
In EAs, we observed that one SNP on chromosome 7p12, rs406001, exceeded genome-wide significance (p = 3.97×10−8). A SNP that maps to the first intron of the Tolloid-Like 1 gene (TLL1) showed the second strongest evidence of association, although no SNPs at this locus reached genome-wide significance. We then tested six SNPs in an independent sample of nearly 2000 EAs and successfully replicated the association findings for two SNPs in the first intron of TLL1, rs6812849 and rs7691872, with p values of 6.3×10−6 and 2.3×10−4, respectively. In the combined sample, rs6812849 had a p value of 3.1 ×10−9. No significant signals were observed in the African American part of the sample. Genome-wide association study analyses restricted to trauma-exposed individuals yielded very similar results.
Conclusions
This study identified TLL1 as a new susceptibility gene for PTSD.
doi:10.1016/j.biopsych.2013.04.013
PMCID: PMC3810148  PMID: 23726511
American populations; genome-wide association study; posttraumatic stress disorder; TLL1
15.  Improved Methods to Identify Stable, Highly Heritable Subtypes of Opioid Use and Related Behaviors 
Addictive Behaviors  2012;37(10):1138-1144.
Although there is evidence that opioid dependence (OD) is heritable, efforts to identify genes contributing to risk for the disorder have been hampered by its complex etiology and variable clinical manifestations. Decomposition of a complex set of opioid users into homogeneous subgroups could enhance genetic analysis. We applied a series of data mining techniques, including multiple correspondence analysis, variable selection and cluster analysis, to 69 opioid-related measures from 5,390 subjects aggregated from family-based and case-control genetic studies to identify homogeneous subtypes and estimate their heritability. Novel aspects of this work include our use of 1) heritability estimates of specific clinical features of OD to enhance the heritability of the subtypes and 2) a k-medoids clustering method in combination with hierarchical clustering to yield replicable clusters that are less sensitive to noise than previous methods. We identified five homogeneous groups, including two large groups comprised of 762 and 1,353 heavy opioid users, with estimated heritability of 0.69 and 0.76, respectively. These methods represent a promising approach to the identification of highly heritable subtypes in complex, heterogeneous disorders.
doi:10.1016/j.addbeh.2012.05.010
PMCID: PMC3395719  PMID: 22694982
Opioid dependence; Subtypes; Phenotype; k-medoids clustering; Hierarchical clustering; Heritability
16.  Meta-analyses of genome-wide linkage scans of anxiety-related phenotypes 
European Journal of Human Genetics  2012;20(10):1078-1084.
Genetic factors underlying trait neuroticism, reflecting a tendency towards negative affective states, may overlap genetic susceptibility for anxiety disorders and help explain the extensive comorbidity amongst internalizing disorders. Genome-wide linkage (GWL) data from several studies of neuroticism and anxiety disorders have been published, providing an opportunity to test such hypotheses and identify genomic regions that harbor genes common to these phenotypes. In all, 11 independent GWL studies of either neuroticism (n=8) or anxiety disorders (n=3) were collected, which comprised of 5341 families with 15 529 individuals. The rank-based genome scan meta-analysis (GSMA) approach was used to analyze each trait separately and combined, and global correlations between results were examined. False discovery rate (FDR) analysis was performed to test for enrichment of significant effects. Using 10 cM intervals, bins nominally significant for both GSMA statistics, PSR and POR, were found on chromosomes 9, 11, 12, and 14 for neuroticism and on chromosomes 1, 5, 15, and 16 for anxiety disorders. Genome-wide, the results for the two phenotypes were significantly correlated, and a combined analysis identified additional nominally significant bins. Although none reached genome-wide significance, an excess of significant PSRP-values were observed, with 12 bins falling under a FDR threshold of 0.50. As demonstrated by our identification of multiple, consistent signals across the genome, meta-analytically combining existing GWL data is a valuable approach to narrowing down regions relevant for anxiety-related phenotypes. This may prove useful for prioritizing emerging genome-wide association data for anxiety disorders.
doi:10.1038/ejhg.2012.47
PMCID: PMC3449070  PMID: 22473089
anxiety; neuroticism; panic disorder; linkage; meta-analysis
17.  Variant Callers for Next-Generation Sequencing Data: A Comparison Study 
PLoS ONE  2013;8(9):e75619.
Next generation sequencing (NGS) has been leading the genetic study of human disease into an era of unprecedented productivity. Many bioinformatics pipelines have been developed to call variants from NGS data. The performance of these pipelines depends crucially on the variant caller used and on the calling strategies implemented. We studied the performance of four prevailing callers, SAMtools, GATK, glftools and Atlas2, using single-sample and multiple-sample variant-calling strategies. Using the same aligner, BWA, we built four single-sample and three multiple-sample calling pipelines and applied the pipelines to whole exome sequencing data taken from 20 individuals. We obtained genotypes generated by Illumina Infinium HumanExome v1.1 Beadchip for validation analysis and then used Sanger sequencing as a “gold-standard” method to resolve discrepancies for selected regions of high discordance. Finally, we compared the sensitivity of three of the single-sample calling pipelines using known simulated whole genome sequence data as a gold standard. Overall, for single-sample calling, the called variants were highly consistent across callers and the pairwise overlapping rate was about 0.9. Compared with other callers, GATK had the highest rediscovery rate (0.9969) and specificity (0.99996), and the Ti/Tv ratio out of GATK was closest to the expected value of 3.02. Multiple-sample calling increased the sensitivity. Results from the simulated data suggested that GATK outperformed SAMtools and glfSingle in sensitivity, especially for low coverage data. Further, for the selected discrepant regions evaluated by Sanger sequencing, variant genotypes called by exome sequencing versus the exome array were more accurate, although the average variant sensitivity and overall genotype consistency rate were as high as 95.87% and 99.82%, respectively. In conclusion, GATK showed several advantages over other variant callers for general purpose NGS analyses. The GATK pipelines we developed perform very well.
doi:10.1371/journal.pone.0075619
PMCID: PMC3785481  PMID: 24086590
18.  Arguable Assumptions, Debatable Conclusions 
Biological psychiatry  2009;67(4):e19-e23.
doi:10.1016/j.biopsych.2009.07.041
PMCID: PMC3784000  PMID: 20006323
19.  Genetics of alcohol dependence 
Human genetics  2009;126(1):91-99.
Alcohol dependence (AD), a genetically influenced phenotype, is extremely costly to individuals and to society in the United States and throughout the world, contributing to morbidity and mortality and a host of economic, interpersonal, and societal problems. Although until recently the only genes established to affect risk for AD were those encoding several alcohol metabolizing enzymes, there are now several other genes that can be regarded as confirmed risk loci, discovered through linkage and candidate gene association studies. While the mechanism of action of the effects of alcohol-metabolizing enzymes on AD risk is thought to be well understood, we are still in the early stages of understanding the physiology of other risk loci. Further, it is clear that only a small number of the many genes that influence risk for AD have been identified. Newer methodologies (e.g., genomewide association, study of copy number variation, and deep sequencing of candidate loci to identify rare risk variants) that have improved our understanding of other complex traits hold the promise of identifying a greater set of AD susceptibility loci.
doi:10.1007/s00439-009-0701-2
PMCID: PMC3773848  PMID: 19533172
20.  GABRA2 Genotype, Impulsivity, and Body Mass 
Background
The goal of this study was to test a hypothesis associating impulsivity with an elevated body mass index (BMI).
Methods
To this end, we examined associations of BMI with putative genetic, neurophysiological, psychiatric, and psychological indicators of impulsivity in 78 women and 74 men formerly dependent on alcohol or drugs. A second analysis was designed to test the replicability of the genetic findings in an independent sample of 109 women and 111 men with a similar history of substance dependence.
Results
The results of the first analysis showed that BMI was positively correlated with Total and Nonplanning Scale Scores on the Barratt Impulsiveness Scale and the number of childhood symptoms of Attention-Deficit/Hyperactivity Disorder in women. It was also positively correlated, in women, with a GABRA2 variant previously implicated as a risk factor for substance dependence and an objective electroencephalographic feature previously associated with GABRA2 and relapse risk. The second analysis confirmed that the correlation between BMI and the substance-dependence-associated GABRA2 genotype was reliable and sex-specific.
Conclusions
We conclude that an elevated BMI is associated with genetic, neurophysiological, psychiatric, and psychological indicators of impulsivity. The sex difference may be explained by greater opportunities to eat and overeat, a preference for higher calorie foods, a longer duration of alcohol/drug abstinence, or previous pregnancies in women.
doi:10.1111/j.1521-0391.2012.00252.x
PMCID: PMC3773931  PMID: 22882390
21.  Serotonin transporter 5-HTTLPR genotype moderates the effects of childhood adversity on posttraumatic stress disorder risk: a replication study 
We reported that the 5-HTTLPR polymorphism in the promoter region of the serotonin transporter gene (SLC6A4) moderates the effect of childhood adversity on posttraumatic stress disorder (PTSD)risk (Xie and others 2009). In the present study, we considered 5178 subjects (a group with generally high substance dependence comorbidity, as for our previous study) using similar methodology to replicate our previous results.
We used logistic regression analyses to explore the interaction effect of 5-HTTLPR genotype and childhood adversity on PTSD risk. We found that, as reported in our previous study, in individuals with childhood adversity, the presence of one or two copies of the S allele of 5-HTTLPR increased the risk to develop PTSD. This gene-environment interaction effect was present in European Americans (EAs), but not in African Americans (AAs) (EAs, OR=1.49, 95% CI=1.07–2.08, P=0.019; AAs, OR=0.90, 95% CI=0.60–1.35, P=0.62). The statistical power to detect this interaction effect was increased when data were combined with those from our previous study (Xie and others 2009).
The findings reported here replicate those from our previous work, adding to a growing body of research demonstrating that the 5-HTTLPR genotype moderates risk for anxiety and depression phenotypes in the context of stress and adverse events.
doi:10.1002/ajmg.b.32068
PMCID: PMC3428016  PMID: 22693124
gene-environment interaction; PTSD; childhood adversity; 5-HTTLPR
22.  Biases and Errors on Allele Frequency Estimation and Disease Association Tests of Next Generation Sequencing of Pooled Samples 
Genetic epidemiology  2012;36(6):549-560.
Next generation sequencing is widely used to study complex diseases because of its ability to identify both common and rare variants without prior single nucleotide polymorphism (SNP) information. Pooled sequencing of implicated target regions can lower costs and allow more samples to be analyzed, thus improving statistical power for disease-associated variant detection. Several methods for disease association tests of pooled data and for optimal pooling designs have been developed under certain assumptions of the pooling process, e.g. equal/unequal contributions to the pool, sequencing depth variation, and error rate. However, these simplified assumptions may not portray the many factors affecting pooled sequencing data quality, such as PCR amplification during target capture and sequencing, reference allele preferential bias, and others. As a result, the properties of the observed data may differ substantially from those expected under the simplified assumptions. Here, we use real datasets from targeted sequencing of pooled samples, together with microarray SNP genotypes of the same subjects, to identify and quantify factors (biases and errors) affecting the observed sequencing data. Through simulations, we find that these factors have a significant impact on the accuracy of allele frequency estimation and the power of association tests. Furthermore, we develop a workflow protocol to incorporate these factors in data analysis to reduce the potential biases and errors in pooled sequencing data and to gain better estimation of allele frequencies. The workflow, Psafe, is available at http://bioinformatics.med.yale.edu/group/.
doi:10.1002/gepi.21648
PMCID: PMC3477622  PMID: 22674656
pooled sequencing; allele frequency estimation; next-generation sequencing; disease association tests
23.  The Role and Challenges of Exome Sequencing in Studies of Human Diseases 
Frontiers in Genetics  2013;4:160.
Recent advances in next-generation sequencing technologies have transformed the genetics study of human diseases; this is an era of unprecedented productivity. Exome sequencing, the targeted sequencing of the protein-coding portion of the human genome, has been shown to be a powerful and cost-effective method for detection of disease variants underlying Mendelian disorders. Increasing effort has been made in the interest of the identification of rare variants associated with complex traits in sequencing studies. Here we provided an overview of the application fields for exome sequencing in human diseases. We describe a general framework of computation and bioinformatics for handling sequencing data. We then demonstrate data quality and agreement between exome sequencing and exome microarray (chip) genotypes using data collected on the same set of subjects in a genetic study of panic disorder. Our results show that, in sequencing data, the data quality was generally higher for variants within the exonic target regions, compared to that outside the target regions, due to the target enrichment. We also compared genotype concordance for variant calls obtained by exome sequencing vs. exome genotyping microarrays. The overall consistency rate was >99.83% and the heterozygous consistency rate was >97.55%. The two platforms share a large amount of agreement over low frequency variants in the exonic regions, while exome sequencing provides much more information on variants not included on exome genotyping microarrays. The results demonstrate that exome sequencing data are of high quality and can be used to investigate the role of rare coding variants in human diseases.
doi:10.3389/fgene.2013.00160
PMCID: PMC3752524  PMID: 24032039
exome sequencing; exome arrays; Mendelian diseases; complex traits; whole-genome sequencing
24.  Association of CHRNA4 polymorphisms with smoking behavior in two populations 
CHRNA4, the gene that encodes the nicotinic acetylcholine receptor α4 subunit, is a potential candidate gene for nicotine dependence (ND). However, studies of the association of CHNRA4 with smoking behavior have shown inconsistent results. Our meta-analysis of linkage studies of smoking behavior identified a genome-wide significant linkage of the phenotype maximum number of cigarettes smoked in a 24-hour period to a region (20q13.12-q13.32) harboring CHRNA4. This motivated us to examine the association of CHRNA4 with smoking behavior in two independent samples. In this study, we examined five single nucleotide polymorphisms (SNPs) within CHRNA4 and three smoking-related behaviors: one quantitative trait [cigarettes smoked per day (CPD)], and two binary traits [DSM-IV diagnosis of ND and dichotomized Fagerstrom test of ND (FTND)], in 1,249 unrelated European-Americans (EAs) and 1,790 unrelated African-Americans (AAs). Using the combined sample with sex, age and race as covariates, the synonymous SNP rs1044394 was significantly associated with ND (P = 0.001) and FTND (P = 0.01). Rs2236196, which has a low correlation with rs1044394, was also significantly associated with CPD (P = 0.003). The pattern of association for these SNPs was similar in AAs and EAs. After correction for multiple testing, the association between rs1044394 and ND in the combined sample remained significant (P = 0.033). In summary, our study supports association between CHRNA4 common variation and ND in AA and EA samples. Additional studies will be necessary to evaluate the role of rare variants at CHRNA4 for ND.
doi:10.1002/ajmg.b.31177
PMCID: PMC3742073  PMID: 21445957
smoking behavior; nicotine dependence; FTND; SNP; association
25.  Increased Genetic Vulnerability to Smoking at CHRNA5 in Early-Onset Smokers 
Hartz, Sarah M. | Short, Susan E. | Saccone, Nancy L. | Culverhouse, Robert | Chen, LiShiun | Schwantes-An, Tae-Hwi | Coon, Hilary | Han, Younghun | Stephens, Sarah H. | Sun, Juzhong | Chen, Xiangning | Ducci, Francesca | Dueker, Nicole | Franceschini, Nora | Frank, Josef | Geller, Frank | Guđbjartsson, Daniel | Hansel, Nadia N. | Jiang, Chenhui | Keskitalo-Vuokko, Kaisu | Liu, Zhen | Lyytikäinen, Leo-Pekka | Michel, Martha | Rawal, Rajesh | Hum, Sc | Rosenberger, Albert | Scheet, Paul | Shaffer, John R. | Teumer, Alexander | Thompson, John R. | Vink, Jacqueline M. | Vogelzangs, Nicole | Wenzlaff, Angela S. | Wheeler, William | Xiao, Xiangjun | Yang, Bao-Zhu | Aggen, Steven H. | Balmforth, Anthony J. | Baumeister, Sebastian E. | Beaty, Terri | Bennett, Siiri | Bergen, Andrew W. | Boyd, Heather A. | Broms, Ulla | Campbell, Harry | Chatterjee, Nilanjan | Chen, Jingchun | Cheng, Yu-Ching | Cichon, Sven | Couper, David | Cucca, Francesco | Dick, Danielle M. | Foroud, Tatiana | Furberg, Helena | Giegling, Ina | Gu, Fangyi | Hall, Alistair S. | Hällfors, Jenni | Han, Shizhong | Hartmann, Annette M. | Hayward, Caroline | Heikkilä, Kauko | Lic, Phil | Hewitt, John K. | Hottenga, Jouke Jan | Jensen, Majken K. | Jousilahti, Pekka | Kaakinen, Marika | Kittner, Steven J. | Konte, Bettina | Korhonen, Tellervo | Landi, Maria-Teresa | Laatikainen, Tiina | Leppert, Mark | Levy, Steven M. | Mathias, Rasika A. | McNeil, Daniel W. | Medland, Sarah E. | Montgomery, Grant W. | Muley, Thomas | Murray, Tanda | Nauck, Matthias | North, Kari | Pergadia, Michele | Polasek, Ozren | Ramos, Erin M. | Ripatti, Samuli | Risch, Angela | Ruczinski, Ingo | Rudan, Igor | Salomaa, Veikko | Schlessinger, David | Styrkársdóttir, Unnur | Terracciano, Antonio | Uda, Manuela | Willemsen, Gonneke | Wu, Xifeng | Abecasis, Goncalo | Barnes, Kathleen | Bickeböller, Heike | Boerwinkle, Eric | Boomsma, Dorret I. | Caporaso, Neil | Duan, Jubao | Edenberg, Howard J. | Francks, Clyde | Gejman, Pablo V. | Gelernter, Joel | Grabe, Hans Jörgen | Hops, Hyman | Jarvelin, Marjo-Riitta | Viikari, Jorma | Kähönen, Mika | Kendler, Kenneth S. | Lehtimäki, Terho | Levinson, Douglas F. | Marazita, Mary L. | Marchini, Jonathan | Melbye, Mads | Mitchell, Braxton D. | Murray, Jeffrey C. | Nöthen, Markus M. | Penninx, Brenda W. | Raitakari, Olli | Rietschel, Marcella | Rujescu, Dan | Samani, Nilesh J. | Sanders, Alan R. | Schwartz, Ann G. | Shete, Sanjay | Shi, Jianxin | Spitz, Margaret | Stefansson, Kari | Swan, Gary E. | Thorgeirsson, Thorgeir | Völzke, Henry | Wei, Qingyi | Wichmann, H.-Erich | Amos, Christopher I. | Breslau, Naomi | Cannon, Dale S. | Ehringer, Marissa | Grucza, Richard | Hatsukami, Dorothy | Heath, Andrew | Johnson, Eric O. | Kaprio, Jaakko | Madden, Pamela | Martin, Nicholas G. | Stevens, Victoria L. | Stitzel, Jerry A. | Weiss, Robert B. | Kraft, Peter | Bierut, Laura J.
Archives of general psychiatry  2012;69(8):854-860.
Context
Recent studies have shown an association between cigarettes per day (CPD) and a nonsynonymous single-nucleotide polymorphism in CHRNA5, rs16969968.
Objective
To determine whether the association between rs16969968 and smoking is modified by age at onset of regular smoking.
Data Sources
Primary data.
Study Selection
Available genetic studies containing measures of CPD and the genotype of rs16969968 or its proxy.
Data Extraction
Uniform statistical analysis scripts were run locally. Starting with 94 050 ever-smokers from 43 studies, we extracted the heavy smokers (CPD >20) and light smokers (CPD ≤10) with age-at-onset information, reducing the sample size to 33 348. Each study was stratified into early-onset smokers (age at onset ≤16 years) and late-onset smokers (age at onset >16 years), and a logistic regression of heavy vs light smoking with the rs16969968 genotype was computed for each stratum. Meta-analysis was performed within each age-at-onset stratum.
Data Synthesis
Individuals with 1 risk allele at rs16969968 who were early-onset smokers were significantly more likely to be heavy smokers in adulthood (odds ratio [OR]=1.45; 95% CI, 1.36–1.55; n=13 843) than were carriers of the risk allele who were late-onset smokers (OR = 1.27; 95% CI, 1.21–1.33, n = 19 505) (P = .01).
Conclusion
These results highlight an increased genetic vulnerability to smoking in early-onset smokers.
doi:10.1001/archgenpsychiatry.2012.124
PMCID: PMC3482121  PMID: 22868939

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