Publications by authors named "Jeffrey R Bishop"

108 Publications

Impact of polygenic risk for coronary artery disease and cardiovascular medication burden on cognitive impairment in psychotic disorders.

Prog Neuropsychopharmacol Biol Psychiatry 2021 Oct 29;113:110464. Epub 2021 Oct 29.

Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, United States of America; Department of Psychiatry and Behavioral Sciences, University of Minnesota Medical School, Minneapolis, MN, United States of America. Electronic address:

Background: Cognitive impairment is a core deficit across psychotic disorders, the causes and therapeutics of which remain unclear. Epidemiological observations have suggested associations between cognitive dysfunction in psychotic disorders and cardiovascular risk factors, but an underlying etiology has not been established.

Methods: Neuropsychological performance using the Brief Assessment of Cognition in Schizophrenia (BACS) was assessed in 616 individuals of European ancestry (403 psychosis, 213 controls). Polygenic risk scores for coronary artery disease (PRS) were quantified for each participant across 13 p-value thresholds (P 0.5-5e). Cardiovascular and psychotropic medications were categorized for association analyses. Each PRS was examined in relation to the BACS and the optimized P was confirmed with five-fold cross-validation and independent validation. Functional enrichment analyses were used to identify biological mechanisms linked to PRS-cognition associations. Multiple regression analyses examined PRS under the optimal P and medication burden in relation to the BACS composite and subtest scores.

Results: Higher PRS was associated with lower BACS composite scores (p = 0.001) in the psychosis group, primarily driven by the Verbal Memory subtest (p < 0.001). Genes linked to multiple nervous system related processes and pathways were significantly enriched in PRS. After controlling for PRS, a greater number of cardiovascular medications was also correlated with worse BACS performance in patients with psychotic disorders (p = 0.029).

Conclusions: Higher PRS and taking more cardiovascular medications were both significantly associated with cognitive impairment in psychosis. These findings indicate that cardiovascular factors may increase the risk for cognitive dysfunction and related functional outcomes among individuals with psychotic disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pnpbp.2021.110464DOI Listing
October 2021

Association of CYP2B6 genetic polymorphisms with bupropion and hydroxybupropion exposure: A systematic review and meta-analysis.

Pharmacotherapy 2021 Nov 9. Epub 2021 Nov 9.

Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota, USA.

Introduction: Bupropion is metabolized to its active metabolite, hydroxybupropion (HB), by the genetically polymorphic cytochrome P450 2B6 (CYP2B6) enzyme. Despite its significant role in bupropion metabolism, the magnitude of the impact of CYP2B6 genotype on the exposure of bupropion has not been quantified.

Objectives: A systematic review and meta-analysis was conducted to quantify the association of bupropion and HB exposure with CYP2B6 variant alleles and genotype-defined metabolizer phenotypes.

Methods: MEDLINE, EMBASE, Web of Science, Scifinder, PsycINFO, and CENTRAL were screened to identify studies that met the following inclusion criteria (search updated on February 2021): (1) area under the plasma drug concentration-time curve (AUC) of bupropion and/or HB in relation to CYP2B6 genotypes was studied, and (2) study participants were genotyped for common CYP2B6 variant alleles including at least CYP2B6*6. The Newcastle Ottawa Scale was used to assess risk of bias in each included study. The ratio of means (RoM) between CYP2B6 genotype or genotype-defined phenotype groups for bupropion exposure was calculated for each study and combined in a meta-analysis.

Results: Eleven studies met the inclusion criteria for this systematic review, and 10 (including N = 413 participants) were included in the meta-analysis. All 10 studies involved healthy adult volunteers, where other medications were not allowed. The AUCs of HB and the active moiety (bupropion + HB) were significantly reduced in CYP2B6*6 carriers compared with the non-carriers (HB: RoM 0.77, 95% CI 0.71-0.83; active moiety: RoM 0.81, 95% CI 0.75-0.88). Both CYP2B6 poor and intermediate metabolizers had significantly decreased exposures to HB and the active moiety than normal metabolizers.

Conclusion: The CYP2B6*6 allele and genotype-determined CYP2B6 poor and intermediate metabolizer phenotypes are associated with significantly lower exposures to HB and the total active moiety. The findings of this study suggest opportunities to further study precision dosing strategies for bupropion therapy based on CYP2B6 genotype.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/phar.2644DOI Listing
November 2021

Development and Implementation of In-House Pharmacogenomic Testing Program at a Major Academic Health System.

Front Genet 2021 20;12:712602. Epub 2021 Oct 20.

Institute for Health Informatics, University of Minnesota, Minneapolis, MN, United States.

Pharmacogenomics (PGx) studies how a person's genes affect the response to medications and is quickly becoming a significant part of precision medicine. The clinical application of PGx principles has consistently been cited as a major opportunity for improving therapeutic outcomes. Several recent studies have demonstrated that most individuals (> 90%) harbor PGx variants that would be clinically actionable if prescribed a medication relevant to that gene. In multiple well-conducted studies, the results of PGx testing have been shown to guide therapy choice and dosing modifications which improve treatment efficacy and reduce the incidence of adverse drug reactions (ADRs). Although the value of PGx testing is evident, its successful implementation in a clinical setting presents a number of challenges to molecular diagnostic laboratories, healthcare systems, providers and patients. Different molecular methods can be applied to identify PGx variants and the design of the assay is therefore extremely important. Once the genotyping results are available the biggest technical challenge lies in turning this complex genetic information into phenotypes and actionable recommendations that a busy clinician can effectively utilize to provide better medical care, in a cost-effective, efficient and reliable manner. In this paper we describe a successful and highly collaborative implementation of the PGx testing program at the University of Minnesota and MHealth Fairview Molecular Diagnostic Laboratory and selected Pharmacies and Clinics. We offer detailed descriptions of the necessary components of the pharmacogenomic testing implementation, the development and technical validation of the in-house SNP based multiplex PCR based assay targeting 20 genes and 48 SNPs as well as a separate CYP2D6 copy number assay along with the process of PGx report design, results of the provider and pharmacists usability studies, and the development of the software tool for genotype-phenotype translation and gene-phenotype-drug CPIC-based recommendations. Finally, we outline the process of developing the clinical workflow that connects the providers with the PGx experts within the Molecular Diagnostic Laboratory and the Pharmacy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fgene.2021.712602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8564018PMC
October 2021

Sexual Functioning in Adolescents With Major Depressive Disorder: A Prospective Study.

J Clin Psychiatry 2021 Oct 5;82(6). Epub 2021 Oct 5.

Menninger Department of Psychiatry and Behavioral Sciences and Department of Pediatrics, Baylor College of Medicine-Texas Children's Hospital, Houston, Texas.

To examine the association between sexual functioning, depression and anxiety severity, and selective serotonin reuptake inhibitor (SSRI) use in adolescents.

From September 2010 to December 2014, 15- to 20-year-old participants, either unmedicated or within a month of beginning SSRI treatment, completed the Beck Depression Inventory-II (BDI-II), Beck Anxiety Inventory (BAI), and Changes in Sexual Functioning Questionnaire (CSFQ) at baseline and every 4 months for up to 2 years. The - was used to determine presence of psychiatric disorders. Data regarding use of medications and hormonal contraception were collected. Polymorphisms of the and genes were genotyped. Linear mixed-effects regression models examined the association between depression and anxiety symptom severity, SSRI use, and sexual functioning, accounting for relevant covariates.

A total of 263 participants (59% female, mean ± SD age = 18.9 ± 1.6 years, 70% with major depressive disorder) contributed to this analysis. After adjusting for age, sex, and duration in the study, depression severity, but not anxiety severity, was associated with lower CSFQ total scores (β = -0.13,  < .0001) and lower arousal, orgasm, and pleasure subscale scores (all β = -0.03,  < .003). Higher SSRI doses were associated with lower orgasm subscale scores (β = -0.30,  < .03). Hormonal contraceptive use was associated with higher CSFQ total scores (β = 0.97,  < .003) and higher arousal (β = 0.25,  < .009), desire (β = 0.24,  < .001), orgasm (β = 0.27,  < .02), and pleasure (β = 0.15,  < .004) subscale scores. No significant genetic moderating effect was found.

In adolescents, depression is associated with lower sexual functioning while SSRI use impairs orgasm.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4088/JCP.21m13892DOI Listing
October 2021

Subtypes of schizophrenia identified by multi-omic measures associated with dysregulated immune function.

Mol Psychiatry 2021 Sep 29. Epub 2021 Sep 29.

Huaxi MR Research Center, Department of Radiology and National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, China.

Epigenetic modifications are plausible molecular sources of phenotypic heterogeneity across schizophrenia patients. The current study investigated biological heterogeneity in schizophrenia using peripheral epigenetic profiles to delineate illness subtypes independent of their phenomenological manifestations. We applied epigenome-wide profiling with a DNA methylation array from blood samples of 63 schizophrenia patients and 59 healthy controls. Non-negative matrix factorization (NMF) and k-means clustering were performed to identify DNA methylation-related patient subtypes. The validity of the partition was tested by assessing the profile of the T cell receptor (TCR) repertoires. The uniqueness of the identified subtypes in relation to brain structural and clinical measures were evaluated. Two distinct patterns of DNA methylation profiles were identified in patients. One subtype (60.3% of patients) showed relatively limited changes in methylation levels and cell composition compared to controls, while a second subtype (39.7% of patients) exhibited widespread methylation level alterations among genes enriched in immune cell activity, as well as a higher proportion of neutrophils and lower proportion of lymphocytes. Differentiation of the two patient subtypes was validated by TCR repertoires, which paralleled the partition based on DNA methylation profiles. The subtype with widespread methylation modifications had higher symptom severity, performed worse on cognitive measures, and displayed greater reductions in fractional anisotropy of white matter tracts and evidence of gray matter thickening compared to the other subtype. Identification of a distinct subtype of schizophrenia with unique molecular, cerebral, and clinical features provide a novel parcellation of the schizophrenia syndrome with potential to guide development of individualized therapeutics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41380-021-01308-6DOI Listing
September 2021

Multisite evaluation of institutional processes and implementation determinants for pharmacogenetic testing to guide antidepressant therapy.

Clin Transl Sci 2021 Sep 25. Epub 2021 Sep 25.

University of Minnesota Medical School, Minneapolis, Minnesota, USA.

There is growing interest in utilizing pharmacogenetic (PGx) testing to guide antidepressant use, but there is lack of clarity on how to implement testing into clinical practice. We administered two surveys at 17 sites that had implemented or were in the process of implementing PGx testing for antidepressants. Survey 1 collected data on the process and logistics of testing. Survey 2 asked sites to rank the importance of Consolidated Framework for Implementation Research (CFIR) constructs using best-worst scaling choice experiments. Of the 17 sites, 13 had implemented testing and four were in the planning stage. Thirteen offered testing in the outpatient setting, and nine in both outpatient/inpatient settings. PGx tests were mainly ordered by psychiatry (92%) and primary care (69%) providers. CYP2C19 and CYP2D6 were the most commonly tested genes. The justification for antidepressants selected for PGx guidance was based on Clinical Pharmacogenetics Implementation Consortium guidelines (94%) and US Food and Drug Administration (FDA; 75.6%) guidance. Both institutional (53%) and commercial laboratories (53%) were used for testing. Sites varied on the methods for returning results to providers and patients. Sites were consistent in ranking CFIR constructs and identified patient needs/resources, leadership engagement, intervention knowledge/beliefs, evidence strength and quality, and the identification of champions as most important for implementation. Sites deployed similar implementation strategies and measured similar outcomes. The process of implementing PGx testing to guide antidepressant therapy varied across sites, but key drivers for successful implementation were similar and may help guide other institutions interested in providing PGx-guided pharmacotherapy for antidepressant management.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cts.13154DOI Listing
September 2021

Genome-wide association study accounting for anticholinergic burden to examine cognitive dysfunction in psychotic disorders.

Neuropsychopharmacology 2021 09 18;46(10):1802-1810. Epub 2021 Jun 18.

Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN, USA.

Identifying genetic contributors to cognitive impairments in psychosis-spectrum disorders can advance understanding of disease pathophysiology. Although CNS medications are known to affect cognitive performance, they are often not accounted for in genetic association studies. In this study, we performed a genome-wide association study (GWAS) of global cognitive performance, measured as composite z-scores from the Brief Assessment of Cognition in Schizophrenia (BACS), in persons with psychotic disorders and controls (N = 817; 682 cases and 135 controls) from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) study. Analyses accounting for anticholinergic exposures from both psychiatric and non-psychiatric medications revealed five significantly associated variants located at the chromosome 3p21.1 locus, with the top SNP rs1076425 in the inter-alpha-trypsin inhibitor heavy chain 1 (ITIH1) gene (P = 3.25×E-9). The inclusion of anticholinergic burden improved association models (P < 0.001) and the number of significant SNPs identified. The effect sizes and direction of effect of the top variants remained consistent when investigating findings within individuals receiving specific antipsychotic drugs and after accounting for antipsychotic dose. These associations were replicated in a separate study sample of untreated first-episode psychosis. The chromosome 3p21.1 locus was previously reported to have association with the risk for psychotic disorders and cognitive performance in healthy individuals. Our findings suggest that this region may be a psychosis risk locus that is associated with cognitive mechanisms. Our data highlight the general point that the inclusion of medication exposure information may improve the detection of gene-cognition associations in psychiatric genetic research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41386-021-01057-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8358015PMC
September 2021

Pharmacogenomics education, research and clinical implementation in the state of Minnesota.

Pharmacogenomics 2021 07 17;22(11):681-691. Epub 2021 Jun 17.

Essentia Institute of Rural Health, Duluth, MN 55805, USA.

Several healthcare organizations across Minnesota have developed formal pharmacogenomic (PGx) clinical programs to increase drug safety and effectiveness. Healthcare professional and student education is strong and there are multiple opportunities in the state for learners to gain workforce skills and develop advanced competency in PGx. Implementation planning is occurring at several organizations and others have incorporated structured utilization of PGx into routine workflows. Laboratory-based and translational PGx research in Minnesota has driven important discoveries in several therapeutic areas. This article reviews the state of PGx activities in Minnesota including educational programs, research, national consortia involvement, technology, clinical implementation and utilization and reimbursement, and outlines the challenges and opportunities in equitable implementation of these advances.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/pgs-2021-0058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8265281PMC
July 2021

Pharmacists as facilitators of pharmacogenomic guidance for antidepressant drug selection and dosing.

Authors:
Jeffrey R Bishop

Clin Transl Sci 2021 07 31;14(4):1206-1209. Epub 2021 May 31.

Department of Experimental and Clinical Pharmacology, University of Minnesota College of Pharmacy, Minneapolis, Minnesota, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cts.13057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301590PMC
July 2021

Current strategies for predicting side effects from second generation antipsychotics in youth.

Expert Opin Drug Metab Toxicol 2021 Jun 2;17(6):655-664. Epub 2021 May 2.

Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA.

: Antipsychotic medications are used to treat a number of conditions in children and adolescents. While side effect profiles from second generation antipsychotics (SGAs) may differ from older antipsychotics, they do not come without risk. Knowing which children may be at higher risk for specific outcomes is important clinical information for prescribers. Common side effects and toxicities of SGAs in children include movement disorders, weight gain, and hormonal changes. There are also rare, but potentially dangerous adverse events including neuroleptic malignant syndrome, hypersensitivity and suicidal ideation.: This review will summarize and comment on clinical, pharmacological, and genetic factors having evidence as predictors of SGA-associated side effects and toxicities in children.: Observations across studies note that older children and those that do not respond early in treatment may be more at risk for movement disorders, while younger, antipsychotic naive children are at increased risk for weight gain. Relatively fewer studies have looked at pharmacogenetic relationships, although variations in pharmacokinetic and pharmacodynamic genes hold promise to advance drug dosing or selection strategies. Future efforts to assimilate multiple clinical, pharmacological, and genetic factors to facilitate predictive analytics and clinical decision support for prescribers will advance precision care to patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/17425255.2021.1922668DOI Listing
June 2021

Corrigendum: Methylation of and in Relation to Treatment Response to Mindfulness Based Stress Reduction for Posttraumatic Stress Disorder.

Front Psychiatry 2021 4;12:642245. Epub 2021 Mar 4.

Department of Psychiatry, University of Minnesota Medical School, Minneapolis, MN, United States.

[This corrects the article DOI: 10.3389/fpsyt.2018.00418.].
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fpsyt.2021.642245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7970629PMC
March 2021

Prescribing Prevalence of Medications With Potential Genotype-Guided Dosing in Pediatric Patients.

JAMA Netw Open 2020 12 1;3(12):e2029411. Epub 2020 Dec 1.

Personalized Medicine Initiative, Nicklaus Children's Health System, Miami, Florida.

Importance: Genotype-guided prescribing in pediatrics could prevent adverse drug reactions and improve therapeutic response. Clinical pharmacogenetic implementation guidelines are available for many medications commonly prescribed to children. Frequencies of medication prescription and actionable genotypes (genotypes where a prescribing change may be indicated) inform the potential value of pharmacogenetic implementation.

Objective: To assess potential opportunities for genotype-guided prescribing in pediatric populations among multiple health systems by examining the prevalence of prescriptions for each drug with the highest level of evidence (Clinical Pharmacogenetics Implementation Consortium level A) and estimating the prevalence of potential actionable prescribing decisions.

Design, Setting, And Participants: This serial cross-sectional study of prescribing prevalences in 16 health systems included electronic health records data from pediatric inpatient and outpatient encounters from January 1, 2011, to December 31, 2017. The health systems included academic medical centers with free-standing children's hospitals and community hospitals that were part of an adult health care system. Participants included approximately 2.9 million patients younger than 21 years observed per year. Data were analyzed from June 5, 2018, to April 14, 2020.

Exposures: Prescription of 38 level A medications based on electronic health records.

Main Outcomes And Measures: Annual prevalence of level A medication prescribing and estimated actionable exposures, calculated by combining estimated site-year prevalences across sites with each site weighted equally.

Results: Data from approximately 2.9 million pediatric patients (median age, 8 [interquartile range, 2-16] years; 50.7% female, 62.3% White) were analyzed for a typical calendar year. The annual prescribing prevalence of at least 1 level A drug ranged from 7987 to 10 629 per 100 000 patients with increasing trends from 2011 to 2014. The most prescribed level A drug was the antiemetic ondansetron (annual prevalence of exposure, 8107 [95% CI, 8077-8137] per 100 000 children). Among commonly prescribed opioids, annual prevalence per 100 000 patients was 295 (95% CI, 273-317) for tramadol, 571 (95% CI, 557-586) for codeine, and 2116 (95% CI, 2097-2135) for oxycodone. The antidepressants citalopram, escitalopram, and amitriptyline were also commonly prescribed (annual prevalence, approximately 250 per 100 000 patients for each). Estimated prevalences of actionable exposures were highest for oxycodone and ondansetron (>300 per 100 000 patients annually). CYP2D6 and CYP2C19 substrates were more frequently prescribed than medications influenced by other genes.

Conclusions And Relevance: These findings suggest that opportunities for pharmacogenetic implementation among pediatric patients in the US are abundant. As expected, the greatest opportunity exists with implementing CYP2D6 and CYP2C19 pharmacogenetic guidance for commonly prescribed antiemetics, analgesics, and antidepressants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamanetworkopen.2020.29411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737091PMC
December 2020

Differences in Predicted Warfarin Dosing Requirements Between Hmong and East Asians Using Genotype-Based Dosing Algorithms.

Pharmacotherapy 2021 03 21;41(3):265-276. Epub 2020 Dec 21.

Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota, USA.

Introduction: Warfarin's narrow therapeutic index and high variability in dosage requirements make dosage selection critical. Genetic factors are known to impact warfarin dosage selection. The Hmong are a unique Asian subpopulation numbering over 278,000 in the United States whose participation in genetics-based research is virtually nonexistent. The translational significance of early reports of warfarin pharmacogene differences in Hmong has not been evaluated.

Objectives: (i) To validate previously identified allele frequency differences relevant to warfarin dosing in Hmong versus East Asians and (ii) to compare predicted warfarin sensitivity and maintenance doses between a Hmong population and an East Asian cohort.

Method: DNA collected from two independent cohorts (n=236 and n=198) of Hmong adults were genotyped for CYP2C9 (*2, *3), VKORC1 (G-1639A), and CYP4F2 (*3). Allele frequencies between the combined Hmong cohort (n=433) and East Asians (n=1165) from the 2009 International Warfarin Pharmacogenetics Consortium (IWPC) study were compared using a χ test. Percentages of Hmong and East Asian participants predicted to be very sensitive to warfarin were compared using a χ test, and the predicted mean warfarin maintenance dose was compared with a t test.

Results: The allele frequencies of CYP2C9*3 in the combined Hmong cohort and CYP4F2*3 in the VIP-Hmong cohort are significantly different from those in East Asians (18.9% vs 3.0%, p<0.001 and 9.8% vs 22.1%, p<0.001, respectively). Comparing the combined Hmong cohort to the East Asian cohort, the percentage of participants predicted to be very sensitive to warfarin was significantly higher (28% vs 5%, p<0.01) and the mean predicted warfarin maintenance dose was significantly lower (19.8 vs 21.3 mg/week, p<0.001), respectively.

Conclusion: The unique allele frequencies related to warfarin when combined with nongenetic factors observed in the Hmong translate into clinically relevant differences in predicted maintenance dose requirements for Hmong versus East Asians.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/phar.2487DOI Listing
March 2021

Review and Consensus on Pharmacogenomic Testing in Psychiatry.

Pharmacopsychiatry 2021 Jan 4;54(1):5-17. Epub 2020 Nov 4.

Division of Clinical Pharmacology, Toxicology & Therapeutic Innovation, Children's Mercy Kansas City, Kansas City and School of Medicine, University of Missouri-Kansas City, Kansas City, MO, USA.

The implementation of pharmacogenomic (PGx) testing in psychiatry remains modest, in part due to divergent perceptions of the quality and completeness of the evidence base and diverse perspectives on the clinical utility of PGx testing among psychiatrists and other healthcare providers. Recognizing the current lack of consensus within the field, the International Society of Psychiatric Genetics assembled a group of experts to conduct a narrative synthesis of the PGx literature, prescribing guidelines, and product labels related to psychotropic medications as well as the key considerations and limitations related to the use of PGx testing in psychiatry. The group concluded that to inform medication selection and dosing of several commonly-used antidepressant and antipsychotic medications, current published evidence, prescribing guidelines, and product labels support the use of PGx testing for 2 cytochrome P450 genes (). In addition, the evidence supports testing for human leukocyte antigen genes when using the mood stabilizers carbamazepine (), oxcarbazepine (), and phenytoin (CYP2C9, HLA-B). For valproate, screening for variants in certain genes () is recommended when a mitochondrial disorder or a urea cycle disorder is suspected. Although barriers to implementing PGx testing remain to be fully resolved, the current trajectory of discovery and innovation in the field suggests these barriers will be overcome and testing will become an important tool in psychiatry.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/a-1288-1061DOI Listing
January 2021

Multivariate relationships between peripheral inflammatory marker subtypes and cognitive and brain structural measures in psychosis.

Mol Psychiatry 2021 Jul 15;26(7):3430-3443. Epub 2020 Oct 15.

Department of Experimental and Clinical Pharmacology and Department of Psychiatry, University of Minnesota, Minneapolis, MN, USA.

Elevations in peripheral inflammatory markers have been reported in patients with psychosis. Whether this represents an inflammatory process defined by individual or subgroups of markers is unclear. Further, relationships between peripheral inflammatory marker elevations and brain structure, cognition, and clinical features of psychosis remain unclear. We hypothesized that a pattern of plasma inflammatory markers, and an inflammatory subtype established from this pattern, would be elevated across the psychosis spectrum and associated with cognition and brain structural alterations. Clinically stable psychosis probands (Schizophrenia spectrum, n = 79; Psychotic Bipolar disorder, n = 61) and matched healthy controls (HC, n = 60) were assessed for 15 peripheral inflammatory markers, cortical thickness, subcortical volume, cognition, and symptoms. A combination of unsupervised exploratory factor analysis and hierarchical clustering was used to identify inflammation subtypes. Levels of IL6, TNFα, VEGF, and CRP were significantly higher in psychosis probands compared to HCs, and there were marker-specific differences when comparing diagnostic groups. Individual and/or inflammatory marker patterns were associated with neuroimaging, cognition, and symptom measures. A higher inflammation subgroup was defined by elevations in a group of 7 markers in 36% of Probands and 20% of HCs. Probands in the elevated inflammatory marker group performed significantly worse on cognitive measures of visuo-spatial working memory and response inhibition, displayed elevated hippocampal, amygdala, putamen and thalamus volumes, and evidence of gray matter thickening compared to the proband group with low inflammatory marker levels. These findings specify the nature of peripheral inflammatory marker alterations in psychotic disorders and establish clinical, neurocognitive and neuroanatomic associations with increased inflammatory activation in psychosis. The identification of a specific subgroup of patients with inflammatory alteration provides a potential means for targeting treatment with anti-inflammatory medications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41380-020-00914-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046847PMC
July 2021

Biotyping in psychosis: using multiple computational approaches with one data set.

Neuropsychopharmacology 2021 01 26;46(1):143-155. Epub 2020 Sep 26.

Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, 60637, USA.

Focusing on biomarker identification and using biomarkers individually or in clusters to define biological subgroups in psychiatry requires a re-orientation from behavioral phenomenology to quantifying brain features, requiring big data approaches for data integration. Much still needs to be accomplished, not only to refine but also to build support for the application and customization of such an analytical phenotypic approach. In this review, we present some of what Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP) has learned so far to guide future applications of multivariate phenotyping and their analyses to understanding psychosis. This paper describes several B-SNIP projects that use phenotype data and big data computations to generate novel outcomes and glimpse what phenotypes contribute to disease understanding and, with aspiration, to treatment. The source of the phenotypes varies from genetic data, structural neuroanatomic localization, immune markers, brain physiology, and cognition. We aim to see guiding principles emerge and areas of commonality revealed. And, we will need to demonstrate not only data stability but also the usefulness of biomarker information for subgroup identification enhancing target identification and treatment development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41386-020-00849-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689458PMC
January 2021

Assessing the enrichment of dietary supplement coverage in the Unified Medical Language System.

J Am Med Inform Assoc 2020 10;27(10):1547-1555

Institute for Health Informatics, University of Minnesota, Minneapolis, Minnesota, USA.

Objective: We sought to assess the need for additional coverage of dietary supplements (DS) in the Unified Medical Language System (UMLS) by investigating (1) the overlap between the integrated DIetary Supplements Knowledge base (iDISK) DS ingredient terminology and the UMLS and (2) the coverage of iDISK and the UMLS over DS mentions in the biomedical literature.

Materials And Methods: We estimated the overlap between iDISK and the UMLS by mapping iDISK to the UMLS using exact and normalized strings. The coverage of iDISK and the UMLS over DS mentions in the biomedical literature was evaluated via a DS named-entity recognition (NER) task within PubMed abstracts.

Results: The coverage analysis revealed that only 30% of iDISK terms can be matched to the UMLS, although these cover over 99% of iDISK concepts. A manual review revealed that a majority of the unmatched terms represented new synonyms, rather than lexical variants. For NER, iDISK nearly doubles the precision and achieves a higher F1 score than the UMLS, while maintaining a competitive recall.

Discussion: While iDISK has significant concept overlap with the UMLS, it contains many novel synonyms. Furthermore, almost 3000 of these overlapping UMLS concepts are missing a DS designation, which could be provided by iDISK. The NER experiments show that the specialization of iDISK is useful for identifying DS mentions.

Conclusions: Our results show that the DS representation in the UMLS could be enriched by adding DS designations to many concepts and by adding new synonyms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jamia/ocaa128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566420PMC
October 2020

Thoughtful Clinical Use of Pharmacogenetics in Child and Adolescent Psychopharmacology.

J Am Acad Child Adolesc Psychiatry 2021 06 26;60(6):660-664. Epub 2020 Aug 26.

University of Cincinnati, Ohio. Electronic address:

AACAP's recent policy statement on Clinical Use of Pharmacogenetic Tests in Prescribing Psychotropic Medications for Children and Adolescents recommends that "clinicians avoid using pharmacogenetic testing to select psychotropic medications in children and adolescents." We agree that there are limitations to the nascent evidence base for using pharmacogenetics, especially in combinatorial form (eg, test results that bin medications based on multiple genes). However, all-or-nothing recommendations fail to recognize the nuance and context of this testing and contrast with the AACAP Facts for Families on pharmacogenetic testing. Moreover, pharmacogenetic testing may inform dosing for antidepressants that are commonly used in child and adolescent psychiatry (eg, sertraline, escitalopram, citalopram, fluvoxamine) as well as the tolerability of some psychotropic medications. With this in mind, we wish to remind the AACAP community of the accumulating evidence and to highlight important principles of pharmacogenetic testing in youths. Specifically: 1) pharmacogenetic testing is not always performed by commercial companies and is not always combinatorial; 2) dosing recommendations or assessment of risk for severe hypersensitivity reactions are based on pharmacogenetics in the Food and Drug Administration (FDA)-approved product inserts for several medications commonly prescribed to children (eg, citalopram, aripiprazole, atomoxetine, carbamazepine, oxcarbazepine at www.fda.gov/drugs/science-and-research-drugs/table-pharmacogenomic-biomarkers-drug-labeling); 3) expert consensus guidelines for dosing or identifying hypersensitivity risk for these drugs are available from the National Institutes of Health (NIH)-supported Clinical Pharmacogenetics Implementation Consortium (CPIC, www.cpicpgx.org/), which provides transparent, regularly updated, and evidence-based evaluations of pharmacogenetic data; and 4) randomized trials are not required for clinical dose adjustments; for example, dose adjustments because of decreased hepatic function or concomitant interacting medications are based on pharmacokinetic data, similar to many pharmacokinetic gene-based recommendations from CPIC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaac.2020.08.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141104PMC
June 2021

Catechol-O-methyltransferase genotype differentially contributes to the flexibility and stability of cognitive sets in patients with psychotic disorders and their first-degree relatives.

Schizophr Res 2020 09 21;223:236-241. Epub 2020 Aug 21.

Department of Psychology, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States. Electronic address:

Dopaminergic activity in prefrontal cortex is modulated by the low (Met) and high (Val) activity of the rs4680 Val158Met single nucleotide polymorphism (SNP) in the Catechol-O-Methyltransferase (COMT) gene. While this has been related to working memory maintenance in patients with schizophrenia, the familial pattern, impact across the psychosis spectrum, and the role of this genotype on other aspects of behavior, such as cognitive flexibility, remains unclear. The relationship between COMT Val158Met genotype and both cognitive stability and flexibility were assessed using the Penn Conditional Exclusion Test (PCET) in healthy controls (n = 241), patients with psychotic disorders (n = 542), and their first-degree relatives (n = 613) from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) consortium. Higher rates of perseverative errors (poor flexibility) were associated with the low-activity COMT genotype (Met allele carriers) in probands compared to their first-degree relatives with the same genotype. Probands and first-degree relatives homozygous for the high-activity COMT enzyme (Val/Val) showed elevated rates of regressive errors (poor stability) compared to controls. Conversely, heterozygous relatives had comparable regressive error rates to controls, with probands showing elevated errors in comparison. These findings suggest that impaired suppression of learned response patterns and reduced stability of mental sets may be a familial intermediate cognitive phenotype related to Val COMT allele genotype.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.schres.2020.08.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704884PMC
September 2020

Using pharmacogenomics and therapeutic drug monitoring to guide drug selection and dosing in outpatient mental health comprehensive medication management.

Ment Health Clin 2020 Jul 2;10(4):254-258. Epub 2020 Jul 2.

Associate Professor, Department of Pharmaceutical Sciences and Pharmacy Practice, University of Minnesota College of Pharmacy, Duluth, Minnesota; Psychiatry Provider, Human Development Center, Duluth, Minnesota.

Pharmacogenomic (PGx) testing aided by therapeutic drug monitoring (TDM) has the potential to improve medication-related outcomes in some individuals prescribed psychiatric medications. Many commonly prescribed psychiatric medications are metabolized through polymorphic drug metabolizing enzymes such as cytochrome p450 (CYP) 2D6 (CYP2D6) and CYP2C19. Through PGx testing, clinicians can make biologically informed choices when selecting a new medication, and TDM may help inform dose adjustments or assess exposures to current treatments. Herein, we describe 2 complex case reports of individuals with multiple psychiatric diagnoses and extensive histories of medication failures who underwent PGx testing in addition to TDM as part of a pharmacist-led comprehensive medication therapy management evaluation in a community mental health clinic setting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.9740/mhc.2020.07.254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7337998PMC
July 2020

CYP2D6 Genetic Polymorphisms and Risperidone Pharmacokinetics: A Systematic Review and Meta-analysis.

Pharmacotherapy 2020 07 12;40(7):632-647. Epub 2020 Jul 12.

Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota, USA.

Background: Risperidone is a second-generation antipsychotic drug metabolized to an active metabolite, 9-hydroxyrisperidone, primarily by cytochrome P450 (CYP) 2D6 and to a lesser extent by CYP3A4. The extent to which drug metabolism genetics impacts risperidone and 9-hydroxyrisperidone exposure has not been clarified.

Objective: A systematic review and meta-analysis evaluated the impact of genetically defined CYP2D6 function on risperidone pharmacokinetics applying a standardized genotype-phenotype translation system.

Methods: A comprehensive electronic database search identified studies reporting relationships between genetically determined CYP2D6 metabolism and risperidone pharmacokinetic properties. The exposure of risperidone or active moiety (risperidone + 9-hydroxyrisperidone) was measured by dose-adjusted steady-state serum or plasma concentration or area under the concentration-time curve as primary outcomes. Subjects were assigned to CYP2D6 poor metabolizer, intermediate metabolizer, normal metabolizer, or ultrarapid metabolizer groups using a standardized genotype-phenotype translation method. Effect sizes between groups were pooled and stratified by single or multiple dosing regimens.

Results: A total of 15 studies involving 2125 adult subjects were included in the meta-analysis. Following multiple-dose oral administration, compared with CYP2D6 normal metabolizers, the risperidone dose-adjusted steady-state serum/plasma concentration was 2.35-fold higher in intermediate metabolizers (95% confidence interval [CI] 1.77-3.13, p<0.0001) and 6.20-fold higher in poor metabolizers (95% CI 5.05-7.62, p<0.0001); the active moiety dose-adjusted steady-state concentration was 1.18-fold higher in intermediate metabolizers (95% CI 1.11-1.25, p<0.0001) and 1.44-fold higher in poor metabolizers (95% CI 1.23-1.69, p<0.0001). Higher area under the concentration-time curve of risperidone and active moiety was also found in single-dose studies.

Conclusion: Genetically defined impaired CYP2D6 activity is associated with increased exposure of both risperidone and risperidone + 9-hydroxyrisperidone in adults receiving oral formulations. Additional studies are needed to quantify the clinical impact of these relationships.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/phar.2434DOI Listing
July 2020

Pharmacogenomics: an Update for Child and Adolescent Psychiatry.

Curr Psychiatry Rep 2020 05 6;22(5):26. Epub 2020 May 6.

Division of Child and Adolescent Psychiatry, Institute of Living/Hartford Hospital, 200 Retreat Ave, Hartford, CT, 06019, USA.

Purpose Of Review: This paper aims to acquaint child and adolescent psychiatrists with the field of pharmacogenomics (PGX) and review the most up-to-date evidence-based practices to guide the application of this field in clinical care.

Recent Findings: Despite much research being done in this area, the field of PGX continues to yield controversial findings. In the adult world, studies have focused on the impact of combinatorial gene panels that guide medication selection by providing reports that estimate the impact of multiple pharmacodynamic and pharmacokinetic genes, but to date, these have not been directly examined in younger patient populations. Pharmacokinetic genes, CYP2D6 and CYP2C19, and hypersensitivity genes, HLA-A and HLA-B, have the strongest evidence base for application to pharmacotherapy in children. Although the field is evolving, and the evidence is mixed, there may be a role for PGX testing in children to help guide dosing and monitoring strategies. However, evidence-based medicine, rather than PGX testing, continues to play the lead role in guiding medication selection in pediatric psychopharmacology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11920-020-01145-4DOI Listing
May 2020

Once-Monthly Subcutaneously Administered Risperidone in the Treatment of Schizophrenia: Patient Considerations.

Patient Prefer Adherence 2019 31;13:2233-2241. Epub 2019 Dec 31.

Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA.

Adherence to antipsychotic medications is a major challenge in schizophrenia. Long-acting injectable antipsychotics have been shown to offer advantages over oral formulations. A new extended release formulation of risperidone for subcutaneous injection was developed to address issues of non-adherence. The aim of this manuscript was to compare the new subcutaneous formulation to currently available formulations of injectable risperidone and paliperidone to determine whether the novel delivery by subcutaneous injection may provide substantial benefits. A literature search was conducted using PubMed, OVID, and Cochrane Library electronic databases to assess the advantages and disadvantages of long-acting formulations of risperidone. Potential advantages of risperidone for subcutaneous injection include a simplified dosing and ease of administration. Potential disadvantages include injection site pain and medication cost.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/PPA.S192418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053417PMC
December 2019

iDISK: the integrated DIetary Supplements Knowledge base.

J Am Med Inform Assoc 2020 04;27(4):539-548

Institute for Health Informatics, University of Minnesota, Minneapolis, Minnesota, USA.

Objective: To build a knowledge base of dietary supplement (DS) information, called the integrated DIetary Supplement Knowledge base (iDISK), which integrates and standardizes DS-related information from 4 existing resources.

Materials And Methods: iDISK was built through an iterative process comprising 3 phases: 1) establishment of the content scope, 2) development of the data model, and 3) integration of existing resources. Four well-regarded DS resources were integrated into iDISK: The Natural Medicines Comprehensive Database, the "About Herbs" page on the Memorial Sloan Kettering Cancer Center website, the Dietary Supplement Label Database, and the Natural Health Products Database. We evaluated the iDISK build process by manually checking that the data elements associated with 50 randomly selected ingredients were correctly extracted and integrated from their respective sources.

Results: iDISK encompasses a terminology of 4208 DS ingredient concepts, which are linked via 6 relationship types to 495 drugs, 776 diseases, 985 symptoms, 605 therapeutic classes, 17 system organ classes, and 137 568 DS products. iDISK also contains 7 concept attribute types and 3 relationship attribute types. Evaluation of the data extraction and integration process showed average errors of 0.3%, 2.6%, and 0.4% for concepts, relationships and attributes, respectively.

Conclusion: We developed iDISK, a publicly available standardized DS knowledge base that can facilitate more efficient and meaningful dissemination of DS knowledge.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jamia/ocz216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7075538PMC
April 2020

Closing the Classroom Theory to Practice Gap by Simulating a Psychiatric Pharmacy Practice Experience.

Am J Pharm Educ 2019 12;83(10):7276

University of Minnesota, College of Pharmacy, Minneapolis, Minnesota.

To examine the feasibility and effectiveness of combining whole-task and guided reflection educational design principles with cloud-based learning technologies to simulate the clinical psychiatric advanced pharmacy practice experience (APPE) in the classroom to begin to close the theory to practice gap. Components of the typical student experience while completing an APPE were integrated into the course experience, ie, patient case work-ups, facilitated sessions with a preceptor, personal statement of goals and progress with feedback, and intentional interaction with peer-learners. Multiple sources of quantitative and qualitative data were collected and analyzed. Twelve third-year pharmacy students from two campuses participated in and successfully completed this one-credit elective advanced psychiatric pharmacotherapy course. Eleven board-certified psychiatric pharmacists (BCPP) served as visiting experts, some participating for multiple weeks, and provided preceptor-like feedback to the case presentations in spring 2017. All BCPP pharmacists plus an additional geriatric pharmacist specialist participated in the course in spring 2018. Results of the quantitative and qualitative analyses demonstrated that students progressed in their readiness for APPEs and gained additional psychiatric pharmacy knowledge and evidence-based medicine decision making skills. Pharmacy programs are challenged to find additional ways to improve student readiness for APPEs and expand psychiatric learning opportunities to meet the increasing mental health needs across clinical settings. This example provides a feasible and effective strategy to do both without the requirement to create extensive new learning materials or add significant faculty workload.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5688/ajpe7276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6983905PMC
December 2019

Potential Clinical Relevance of Differences in Allele Frequencies Found within Very Important Pharmacogenes between Hmong and East Asian Populations.

Pharmacotherapy 2020 02 14;40(2):142-152. Epub 2020 Jan 14.

Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota.

Objectives: Implementing pharmacogenetics for very important pharmacogenes (VIPs) holds the promise of improving clinical outcomes through optimal medication selection and dosing. However, significant differences in the frequency of actionable variants in VIPs may exist within subpopulations of a given ancestral group. Furthermore, these differences can potentially impact drug selection and dosing. The purpose of this study was to ascertain allele frequencies for VIPs and to predict medication requirements using Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines in Hmong and compare with published data for East Asians.

Methods: Using a community-based participatory action research approach, DNA collected from 194 Hmong adults living in the United States was analyzed for 22 genetic variants within eight VIPs (CYP2C9, CYP2C19, CYP4F2, DPYD, G6PD, SLCO1B1, TPMT, VKORC1). Allele frequencies for VIPs and predicted medication requirements using CPIC guidelines were compared between Hmong participants and East Asians.

Results: Significant differences in allele frequencies between the Hmong and East Asians were found for 23% (5/22) of the CPIC-actionable variants tested. Allele frequencies for VIPs in Hmong versus East Asians were 16.6% versus 3.4% in CYP2C9*3A, 42.2% versus 29.0% for CYP2C19*2, 0.3% versus 8.3% in CYP2C19*3, 6.5% versus 22.1% in CYP4F2*3, and 3.6% versus 0.1% in SLCO1B1*5, respectively. These differences significantly influenced predicted medication usage recommendations in warfarin, simvastatin, and phenytoin between Hmong and East Asians.

Conclusions: Important differences in allele frequencies for key genetic variants influencing selection of medications and dosages were found between the Hmong and East Asians. The magnitude and nature of these differences can be expected to result in different medication recommendations for the Hmong relative to East Asians.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/phar.2360DOI Listing
February 2020

Brain gray matter network organization in psychotic disorders.

Neuropsychopharmacology 2020 03 7;45(4):666-674. Epub 2019 Dec 7.

Huaxi MR Research Center (HMRRC), Department of Radiology, Functional and Molecular Imaging Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, China.

Abnormal neuroanatomic brain networks have been reported in schizophrenia, but their characterization across patients with psychotic disorders, and their potential alterations in nonpsychotic relatives, remain to be clarified. Participants recruited by the Bipolar and Schizophrenia Network for Intermediate Phenotypes consortium included 326 probands with psychotic disorders (107 with schizophrenia (SZ), 87 with schizoaffective disorder (SAD), 132 with psychotic bipolar disorder (BD)), 315 of their nonpsychotic first-degree relatives and 202 healthy controls. Single-subject gray matter graphs were extracted from structural MRI scans, and whole-brain neuroanatomic organization was compared across the participant groups. Compared with healthy controls, psychotic probands showed decreased nodal efficiency mainly in bilateral superior temporal regions. These regions had altered morphological relationships primarily with frontal lobe regions, and their network-level alterations were associated with positive symptoms of psychosis. Nonpsychotic relatives showed lower nodal centrality metrics in the prefrontal cortex and subcortical regions, and higher nodal centrality metrics in the left cingulate cortex and left thalamus. Diagnosis-specific analysis indicated that individuals with SZ had lower nodal efficiency in bilateral superior temporal regions than controls, probands with SAD only exhibited lower nodal efficiency in the left superior and middle temporal gyrus, and individuals with psychotic BD did not show significant differences from healthy controls. Our findings provide novel evidence of clinically relevant disruptions in the anatomic association of the superior temporal lobe with other regions of whole-brain networks in patients with psychotic disorders, but not in their unaffected relatives, suggesting that it is a disease-related trait. Network disorganization primarily involving frontal lobe and subcortical regions in nonpsychotic relatives may be related to familial illness risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41386-019-0586-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7021697PMC
March 2020

NRXN1 is associated with enlargement of the temporal horns of the lateral ventricles in psychosis.

Transl Psychiatry 2019 09 17;9(1):230. Epub 2019 Sep 17.

Yale University Departments of Psychiatry & Neuroscience, New Haven, USA.

Schizophrenia, Schizoaffective, and Bipolar disorders share behavioral and phenomenological traits, intermediate phenotypes, and some associated genetic loci with pleiotropic effects. Volumetric abnormalities in brain structures are among the intermediate phenotypes consistently reported associated with these disorders. In order to examine the genetic underpinnings of these structural brain modifications, we performed genome-wide association analyses (GWAS) on 60 quantitative structural brain MRI phenotypes in a sample of 777 subjects (483 cases and 294 controls pooled together). Genotyping was performed with the Illumina PsychChip microarray, followed by imputation to the 1000 genomes multiethnic reference panel. Enlargement of the Temporal Horns of Lateral Ventricles (THLV) is associated with an intronic SNP of the gene NRXN1 (rs12467877, P = 6.76E-10), which accounts for 4.5% of the variance in size. Enlarged THLV is associated with psychosis in this sample, and with reduction of the hippocampus and enlargement of the choroid plexus and caudate. Eight other suggestively significant associations (P < 5.5E-8) were identified with THLV and 5 other brain structures. Although rare deletions of NRXN1 have been previously associated with psychosis, this is the first report of a common SNP variant of NRXN1 associated with enlargement of the THLV in psychosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41398-019-0564-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6748921PMC
September 2019
-->