Showing papers by "Joanna M. Biernacka published in 2016"
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United States Department of Health and Human Services1, Ludwig Maximilian University of Munich2, University of Göttingen3, University of Bonn4, Charité5, Dokkyo Medical University6, University of Barcelona7, Karolinska University Hospital8, State University of Campinas9, Medical University of Graz10, University of California, San Diego11, Mayo Clinic12, Paris Diderot University13, McGill University Health Centre14, University of Queensland15, National Taiwan University16, University Hospital of Basel17, University of Adelaide18, Newcastle University19, Douglas Mental Health University Institute20, Poznan University of Medical Sciences21, Geneva College22, French Institute of Health and Medical Research23, Neuroscience Research Australia24, University of New South Wales25, Dalhousie University26, Johns Hopkins University27, Osaka University28, University of Lorraine29, Goethe University Frankfurt30, Hokkaido University31, Karolinska Institutet32, University of Gothenburg33, Veterans Health Administration34, University of Antioquia35, University of Calgary36, University of Cagliari37, Aarhus University38, University of Cincinnati39, University of Salerno40, University of Naples Federico II41, Nagoya University42, Harvard University43, Dresden University of Technology44, Montreal Neurological Institute and Hospital45, United States Department of Veterans Affairs46, National Institutes of Health47, Roy J. and Lucille A. Carver College of Medicine48, University of Iowa49, Heidelberg University50, University of Toronto51, RIKEN Brain Science Institute52
TL;DR: A genome-wide association study of lithium response in 2,563 patients collected by 22 participating sites from the International Consortium on Lithium Genetics (ConLiGen); the largest attempted so far finds a single locus of four linked SNPs on chromosome 21 met genome- wide significance criteria for association with lithium response.
258 citations
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National Institutes of Health1, Broad Institute2, Karolinska Institutet3, University of Gothenburg4, Charité5, Dalhousie University6, University of Cagliari7, University of Barcelona8, University of Geneva9, University of Chicago10, Portland VA Medical Center11, Dresden University of Technology12, University of Adelaide13, Paris Diderot University14, Medical University of Graz15, University of Pennsylvania16, University of California, San Diego17, Mayo Clinic18, Scripps Health19, University of California, San Francisco20, McGill University21, University of Basel22, University of Bonn23, University of Iowa24, Translational Genomics Research Institute25, Douglas Mental Health University Institute26, Johns Hopkins University27, Indiana University28, University of Paris29, Ludwig Maximilian University of Munich30, University of New South Wales31, Neuroscience Research Australia32, University of Göttingen33, Howard University34, University of Lorraine35, Goethe University Frankfurt36, Heidelberg University37, United States Department of Veterans Affairs38, University of Illinois at Chicago39, Seconda Università degli Studi di Napoli40, University of Cincinnati41, University of Michigan42, University of Salerno43, Washington University in St. Louis44, Rush University Medical Center45
TL;DR: A two-stage meta-analysis of GWAS of bipolar disorder patients and controls revealed genome-wide significant associations at two novel loci, adding to a growing list of common autosomal variants involved in BD and illustrating the power of comparing well-characterized cases to an excess of controls in GWAS.
Abstract: Bipolar disorder (BD) is a genetically complex mental illness characterized by severe oscillations of mood and behaviour. Genome-wide association studies (GWAS) have identified several risk loci that together account for a small portion of the heritability. To identify additional risk loci, we performed a two-stage meta-analysis of >9 million genetic variants in 9,784 bipolar disorder patients and 30,471 controls, the largest GWAS of BD to date. In this study, to increase power we used ∼2,000 lithium-treated cases with a long-term diagnosis of BD from the Consortium on Lithium Genetics, excess controls, and analytic methods optimized for markers on the X-chromosome. In addition to four known loci, results revealed genome-wide significant associations at two novel loci: an intergenic region on 9p21.3 (rs12553324, P = 5.87 × 10 - 9; odds ratio (OR) = 1.12) and markers within ERBB2 (rs2517959, P = 4.53 × 10 - 9; OR = 1.13). No significant X-chromosome associations were detected and X-linked markers explained very little BD heritability. The results add to a growing list of common autosomal variants involved in BD and illustrate the power of comparing well-characterized cases to an excess of controls in GWAS.
176 citations
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TL;DR: Application of a pharmacometabolomics-informed pharmacogenomic research strategy, followed by functional validation, indicated that TSPAN5 and ERICH3 are associated with plasma serotonin concentrations and may have a role in SSRI treatment outcomes.
Abstract: Millions of patients suffer from major depressive disorder (MDD), but many do not respond to selective serotonin reuptake inhibitor (SSRI) therapy. We used a pharmacometabolomics-informed pharmacogenomics research strategy to identify genes associated with metabolites that were related to SSRI response. Specifically, 306 MDD patients were treated with citalopram or escitalopram and blood was drawn at baseline, 4 and 8 weeks for blood drug levels, genome-wide single nucleotide polymorphism (SNP) genotyping and metabolomic analyses. SSRI treatment decreased plasma serotonin concentrations (P<0.0001). Baseline and plasma serotonin concentration changes were associated with clinical outcomes (P<0.05). Therefore, baseline and serotonin concentration changes were used as phenotypes for genome-wide association studies (GWAS). GWAS for baseline plasma serotonin concentrations revealed a genome-wide significant (P=7.84E-09) SNP cluster on chromosome four 5’ of TSPAN5 and a cluster across ERICH3 on chromosome one (P=9.28E-08) that were also observed during GWAS for change in serotonin at 4 (P=5.6E-08 and P=7.54E-07, respectively) and 8 weeks (P=1.25E-06 and P=3.99E-07, respectively). The SNPs on chromosome four were expression quantitative trait loci for TSPAN5. Knockdown (KD) and overexpression (OE) of TSPAN5 in a neuroblastoma cell line significantly altered the expression of serotonin pathway genes (TPH1, TPH2, DDC and MAOA). Chromosome one SNPs included two ERICH3 nonsynonymous SNPs that resulted in accelerated proteasome-mediated degradation. In addition, ERICH3 and TSPAN5 KD and OE altered media serotonin concentrations. Application of a pharmacometabolomics-informed pharmacogenomic research strategy, followed by functional validation, indicated that TSPAN5 and ERICH3 are associated with plasma serotonin concentrations and may have a role in SSRI treatment outcomes.
87 citations
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TL;DR: DS-5-defined BED and BN are common in BP patients, possibly more common than DSM-IV- defined BEDand BN, and associated with greater psychiatric and general medical illness burden.
66 citations
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TL;DR: The study aimed to define thresholds of clinically significant change in 17‐item Hamilton Depression Rating Scale (HDRS‐17) scores using the Clinical Global Impression‐Improvement (CGI‐I) Scale as a gold standard.
Abstract: Objective
The study aimed to define thresholds of clinically significant change in 17-item Hamilton Depression Rating Scale (HDRS-17) scores using the Clinical Global Impression-Improvement (CGI-I) Scale as a gold standard.
Methods
We conducted a secondary analysis of individual patient data from the Pharmacogenomic Research Network Antidepressant Medication Pharmacogenomic Study, an 8-week, single-arm clinical trial of citalopram or escitalopram treatment of adults with major depression. We used equipercentile linking to identify levels of absolute and percent change in HDRS-17 scores that equated with scores on the CGI-I at 4 and 8 weeks. Additional analyses equated changes in the HDRS-7 and Bech-6 scale scores with CGI-I scores.
Results
A CGI-I score of 2 (much improved) corresponded to an absolute decrease (improvement) in HDRS-17 total score of 11 points and a percent decrease of 50–57%, from baseline values. Similar results were observed for percent change in HDRS-7 and Bech-6 scores. Larger absolute (but not percent) decreases in HDRS-17 scores equated with CGI-I scores of 2 in persons with higher baseline depression severity.
Conclusions
Our results support the consensus definition of response based on HDRS-17 scores (>50% decrease from baseline). A similar definition of response may apply to the HDRS-7 and Bech-6. Copyright © 2016 John Wiley & Sons, Ltd.
53 citations
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TL;DR: There appears to be a higher prevalence of comorbid depression and anxiety disorders as well as propensity to drink in negative emotional situations in female compared with male alcoholics, and Substance‐induced depression appears to have a sex‐specific effect on the increased risk for drinking in negativeotional situations in males.
Abstract: Background and Aims
Depression and anxiety are often comorbid with alcoholism and contribute to craving and relapse. We aimed to estimate the prevalence of life-time diagnoses of major depressive disorder (MDD), substance-induced depression (SID), anxiety disorder (AnxD) and substance-induced anxiety (SIA), the effects of these comorbidities on the propensity to drink in negative emotional states (negative craving), and test whether these effects differ by sex.
Design
Secondary analyses of baseline data collected in a single-arm study of pharmacogenetic predictors of acamprosate response.
Setting
Academic medical center and affiliated community-based treatment programs in the American upper mid-west.
Participants
A total of 287 males and 156 females aged 18–80 years, meeting DSM-IV criteria for alcohol dependence.
Measurements
The primary outcome measure was ‘propensity to drink in negative emotional situations’ (determined by the Inventory of Drug Taking Situations) and the key predictors/covariates were sex and psychiatric comorbidities, including MDD, SID, AnxD and SIA (determined by Psychiatric Research Interview of Substance and Mood Disorders).
Findings
The prevalence of the MDD, SID and AnxD was higher in females compared with males (33.1 versus 18.4%, 44.8 versus 26.4% and 42.2 versus 27.4%, respectively; P < 0.01, each), while SIA was rare (3.3%) and did not differ by sex. Increased propensity to drink in negative emotional situations was associated with comorbid MDD (β = 6.6, P = 0.013) and AnxD (β = 4.8, P = 0.042) as well as a SID × sex interaction effect (P = 0.003), indicating that the association of SID with propensity to drink in negative emotional situations differs by sex and is stronger in males (β = 7.9, P = 0.009) compared with females (β = −6.6, P = 0.091).
Conclusions
There appears to be a higher prevalence of comorbid depression and anxiety disorders as well as propensity to drink in negative emotional situations in female compared with male alcoholics. Substance-induced depression appears to have a sex-specific effect on the increased risk for drinking in negative emotional situations in males.
48 citations
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TL;DR: In adolescents, fully syndromal BD is associated with significant reductions in LPH Levels, and LPH levels decrease along the spectrum of risk for BD-I, and Quantifying lipid peroxidation in longitudinal studies may help clarify the role of LPH in BD risk progression.
41 citations
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TL;DR: Using an independent sample, 26 TCF7L2 single nucleotide polymorphisms (SNPs) are evaluated to explore further the association of BD with the TCF 7L2–BMI interaction.
Abstract: Objectives
Bipolar disorder (BD) is a complex disease associated with various hereditary traits, including a higher body mass index (BMI). In a prior genome-wide association study, we found that BMI modified the association of rs12772424 – a common variant in the gene encoding transcription factor 7-like 2 (TCF7L2) – with risk for BD. TCF7L2 is a transcription factor in the canonical Wnt pathway, involved in multiple disorders, including diabetes, cancer and psychiatric conditions. Here, using an independent sample, we evaluated 26 TCF7L2 single nucleotide polymorphisms (SNPs) to explore further the association of BD with the TCF7L2–BMI interaction.
Methods
Using a sample of 662 BD cases and 616 controls, we conducted SNP-level and gene-level tests to assess the evidence for an association between BD and the interaction of BMI and genetic variation in TCF7L2. We also explored the potential mechanism behind the detected associations using human brain expression quantitative trait loci (eQTL) analysis.
Results
The analysis provided independent evidence of an rs12772424–BMI interaction (p = 0.011). Furthermore, while overall there was no evidence for SNP marginal effects on BD, the TCF7L2–BMI interaction was significant at the gene level (p = 0.042), with seven of the 26 SNPs showing SNP–BMI interaction effects with p < 0.05. The strongest evidence of interaction was observed for rs7895307 (p = 0.006). TCF7L2 expression showed a significant enrichment of association with the expression of other genes in the Wnt canonical pathway.
Conclusions
The current study provides further evidence suggesting that TCF7L2 involvement in BD risk may be regulated by BMI. Detailed, prospective assessment of BMI, comorbidity, and other possible contributing factors is necessary to explain fully the mechanisms underlying this association.
30 citations
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TL;DR: Bipolar spectrum disorder with broadly-defined BE may not be as clinically relevant a sub-phenotype as bipolar spectrum Disorder with an ED but may be an adequate proxy for the latter when phenotyping large samples of individuals.
29 citations
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TL;DR: Although no significant interactions were identified, several of the genes with suggestive evidence of gene-environment interaction effects have biological plausibility for PD risk and further investigation of the role of those genes in PD risk is warranted.
28 citations
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TL;DR: A normalizing effect of acamprosate on a hyperglutamatergic state observed in recently withdrawn patients with alcohol dependence and a positive association between MACC glutamate levels and craving intensity in early abstinence are suggested.
Abstract: Although the precise drug mechanism of action of acamprosate remains unclear, its antidipsotropic effect is mediated in part through glutamatergic neurotransmission. We evaluated the effect of 4 weeks of acamprosate treatment in a cohort of 13 subjects with alcohol dependence (confirmed by a structured interview, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision) on proton magnetic resonance spectroscopy glutamate levels in the midline anterior cingulate cortex (MACC). We compared levels of metabolites with a group of 16 healthy controls. The Pennsylvania Alcohol Craving Scale was used to assess craving intensity. At baseline, before treatment, the mean cerebrospinal fluid-corrected MACC glutamate (Glu) level was significantly elevated in subjects with alcohol dependence compared with controls (P = 0.004). Four weeks of acamprosate treatment reduced glutamate levels (P = 0.025), an effect that was not observed in subjects who did not take acamprosate. At baseline, there was a significant positive correlation between cravings, measured by the Pennsylvania Alcohol Craving Scale, and MACC (Glu) levels (P = 0.019). Overall, these data would suggest a normalizing effect of acamprosate on a hyperglutamatergic state observed in recently withdrawn patients with alcohol dependence and a positive association between MACC glutamate levels and craving intensity in early abstinence. Further research is needed to evaluate the use of these findings for clinical practice, including monitoring of craving intensity and individualized selection of treatment with antidipsotropic medications in subjects with alcohol dependence.
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TL;DR: It is suggested that hormonal status may interact with genetic variants to influence cardiovascular phenotypes, specifically, the pharmacogenomic effects within the innate immunity pathway for CIMT.
Abstract: Prior to the initiation of menopausal hormone treatment (MHT), genetic variations in the innate immunity pathway were found to be associated with carotid artery intima-medial thickness (CIMT) and coronary arterial calcification (CAC) in women (n = 606) enrolled in the Kronos Early Estrogen Prevention Study (KEEPS). Whether MHT might affect these associations is unknown. The association of treatment outcomes with variation in the same 764 candidate genes was evaluated in the same KEEPS participants 4 yr after randomization to either oral conjugated equine estrogens (0.45 mg/day), transdermal 17β-estradiol (50 μg/day), each with progesterone (200 mg/day) for 12 days each month, or placebo pills and patch. Twenty SNPs within the innate immunity pathway most related with CIMT after 4 yr were not among those associated with CIMT prior to MHT. In 403 women who completed the study in their assigned treatment group, single nucleotide polymorphisms (SNPs) within the innate immunity pathway were found to alter the treatment effect on 4 yr change in CIMT (i.e., significant interaction between treatment and genetic variation in the innate immunity pathway; P 5 Agatston units after 4 yr. Results of this study suggest that hormonal status may interact with genetic variants to influence cardiovascular phenotypes, specifically, the pharmacogenomic effects within the innate immunity pathway for CIMT.
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TL;DR: It is suggested that glutamate levels in LDLPFC are associated with alcohol craving intensity in patients with AUD, and a larger sample size is needed to replicate this finding and evaluate the merits of glutamate spectroscopy as a biological correlate of alcohol cravingintensity and a guide to treatment interventions.
Abstract: Background
Quantifying craving longitudinally during the course of withdrawal, early abstinence, and relapse is essential for optimal management of alcohol use disorder (AUD). In an effort to identify biological correlates of craving, we used proton magnetic resonance spectroscopy (1H-MRS) to investigate the correlation between craving and glutamate levels in the left dorsolateral prefrontal cortex (LDLPFC) of patients with AUD.
Methods
Participants underwent 1H-MRS of the LDLPFC with 2-dimensional J-resolved (2DJ) averaged PRESS. MRS data were processed with LCModel and cerebrospinal fluid (CSF)-corrected to generate metabolite concentrations. The Penn Alcohol Craving Scale (PACS) and the 30-day time line follow-back (TLFB 30) were used to quantify craving for alcohol and drinking patterns, respectively.
Results
There was a statistically significant positive correlation between CSF-corrected glutamate ([Glu]) levels and PACS scores (n = 14; p = 0.005). When PACS scores were dichotomized (< or ≥median = 16), [Glu] levels were significantly higher in the high- versus low-craving group (p = 0.007). In addition, there was a significant negative correlation between CSF-corrected N-acetyl aspartic acid ([NAA]) levels and mean number of drinks per drinking day in the past month (n = 13; TLFB 30; p = 0.012). When mean TLFB 30 was dichotomized (< or ≥median = 7.86), [NAA] levels were significantly lower in subjects that consumed more alcoholic beverages. There was no significant correlation between [Glu] and [NAA] levels with other measures of drinking behavior and or depression symptom severity.
Conclusions
While limited by small sample size, these data suggest that glutamate levels in LDLPFC are associated with alcohol craving intensity in patients with AUD. Further study with larger sample size is needed to replicate this finding and evaluate the merits of glutamate spectroscopy as a biological correlate of alcohol craving intensity and a guide to treatment interventions.
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United States Department of Health and Human Services1, Karolinska Institutet2, University of Gothenburg3, Charité4, Dalhousie University5, University of Cagliari6, University of Barcelona7, Geneva College8, Karolinska University Hospital9, University of Chicago10, Veterans Health Administration11, Dresden University of Technology12, University of Adelaide13, Paris Diderot University14, Medical University of Graz15, University of Pennsylvania16, University of California, San Diego17, Mayo Clinic18, Scripps Health19, University of California, San Francisco20, McGill University Health Centre21, University Hospital of Basel22, University of Iowa Hospitals and Clinics23, Translational Genomics Research Institute24, McGill University25, Poznan University of Medical Sciences26, University of Bonn27, Johns Hopkins University28, Indiana University29, University of Paris30, Ludwig Maximilian University of Munich31, Neuroscience Research Australia32, University of Basel33, Howard University34, University of Lorraine35, National Institutes of Health36, Goethe University Frankfurt37, Heidelberg University38, University of Illinois at Chicago39, University of Naples Federico II40, University of Cincinnati41, University of Michigan42, University of New South Wales43, University of Salerno44, University of Iowa45, Washington University in St. Louis46, Rush University Medical Center47
TL;DR: The results add to a growing list of common autosomal variants involved in BD and illustrate the power of comparing well-characterized cases to an excess of controls in GWAS.
Abstract: Bipolar disorder (BD) is a genetically complex mental illness characterized by severe oscillations of mood and behavior. Genome-wide association studies (GWAS) have identified several risk loci that together account for a small portion of the heritability. To identify additional risk loci, we performed a two-stage meta-analysis of >9 million genetic variants in 9,784 bipolar disorder patients and 30,471 controls, the largest GWAS of BD to date. In this study, to increase power we used ~2,000 lithium-treated cases with a long-term diagnosis of BD from the Consortium on Lithium Genetics, excess controls, and analytic methods optimized for markers on the X-chromosome. In addition to four known loci, results revealed genome-wide significant associations at two novel loci: an intergenic region on 9p21.3 (rs12553324, p = 5.87×10-9; odds ratio = 1.12) and markers within ERBB2 (rs2517959, p = 4.53×10-9; odds ratio = 1.13). No significant X-chromosome associations were detected and X-linked markers explained very little BD heritability. The results add to a growing list of common autosomal variants involved in BD and illustrate the power of comparing well-characterized cases to an excess of controls in GWAS.
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TL;DR: The potential for EHR-based analyses of large cohorts to discover pleiotropic effects contributing to complex psychiatric traits and commonly co-occurring medical conditions is shown, particularly the association of the SVEP1 SNP with hypertension.
Abstract: Patients with bipolar disorder (BD) have a high prevalence of comorbid medical illness. However, the mechanisms underlying these comorbidities with BD are not well known. Certain genetic variants may have pleiotropic effects, increasing the risk of BD and other medical illnesses simultaneously. In this study, we evaluated the association of BD-susceptibility genetic variants with various medical conditions that tend to co-exist with BD, using electronic health records (EHR) data linked to genome-wide single-nucleotide polymorphism (SNP) data. Data from 7316 Caucasian subjects were used to test the association of 19 EHR-derived phenotypes with 34 SNPs that were previously reported to be associated with BD. After Bonferroni multiple testing correction, P<7.7 × 10−5 was considered statistically significant. The top association findings suggested that the BD risk alleles at SNP rs4765913 in CACNA1C gene and rs7042161 in SVEP1 may be associated with increased risk of ‘cardiac dysrhythmias’ (odds ratio (OR)=1.1, P=3.4 × 10−3) and ‘essential hypertension’ (OR=1.1, P=3.5 × 10−3), respectively. Although these associations are not statistically significant after multiple testing correction, both genes have been previously implicated with cardiovascular phenotypes. Moreover, we present additional evidence supporting these associations, particularly the association of the SVEP1 SNP with hypertension. This study shows the potential for EHR-based analyses of large cohorts to discover pleiotropic effects contributing to complex psychiatric traits and commonly co-occurring medical conditions.
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TL;DR: Simulations showed that the new RF methods eliminate the bias in standard RF variable importance for XSNPs when sex is associated with the trait, and are able to detect causal autosomal and X SNPs.
Abstract: Machine learning methods, including Random Forests (RF), are increasingly used for genetic data analysis. However, the standard RF algorithm does not correctly model the effects of X chromosome single nucleotide polymorphisms (SNPs), leading to biased estimates of variable importance. We propose extensions of RF to correctly model X SNPs, including a stratified approach and an approach based on the process of X chromosome inactivation. We applied the new and standard RF approaches to case-control alcohol dependence data from the Study of Addiction: Genes and Environment (SAGE), and compared the performance of the alternative approaches via a simulation study. Standard RF applied to a case-control study of alcohol dependence yielded inflated variable importance estimates for X SNPs, even when sex was included as a variable, but the results of the new RF methods were consistent with univariate regression-based approaches that correctly model X chromosome data. Simulations showed that the new RF methods eliminate the bias in standard RF variable importance for X SNPs when sex is associated with the trait, and are able to detect causal autosomal and X SNPs. Even in the absence of sex effects, the new extensions perform similarly to standard RF. Thus, we provide a powerful multimarker approach for genetic analysis that accommodates X chromosome data in an unbiased way. This method is implemented in the freely available R package "snpRF" (http://www.cran.r-project.org/web/packages/snpRF/).