TOPMed imputed genomics enhances genomic atlas of the human proteome in brain, cerebrospinal fluid, and plasma
(2024) Scientific Data, 11 (1), art. no. 387, .
Yi, H.a b , Yang, Q.b , Repaci, C.b c , Lee, C.M.b d , Heo, G.a b , Timsina, J.a b , Gorijala, P.a b , Yang, C.a b , Budde, J.a b , Wang, L.a b , Cruchaga, C.a b e , Sung, Y.J.a b c
a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
b NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, United States
c Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States
d Institute for Informatics, Washington University School of Medicine, St. Louis, MO, United States
e Hope Center for Neurologic Diseases, Washington University, St. Louis, MO, United States
Abstract
Comprehensive expression quantitative trait loci studies have been instrumental for understanding tissue-specific gene regulation and pinpointing functional genes for disease-associated loci in a tissue-specific manner. Compared to gene expressions, proteins more directly affect various biological processes, often dysregulated in disease, and are important drug targets. We previously performed and identified tissue-specific protein quantitative trait loci in brain, cerebrospinal fluid, and plasma. We now enhance this work by analyzing more proteins (1,300 versus 1,079) and an almost twofold increase in high quality imputed genetic variants (8.4 million versus 4.4 million) by using TOPMed reference panel. We identified 38 genomic regions associated with 43 proteins in brain, 150 regions associated with 247 proteins in cerebrospinal fluid, and 95 regions associated with 145 proteins in plasma. Compared to our previous study, this study newly identified 12 loci in brain, 30 loci in cerebrospinal fluid, and 22 loci in plasma. Our improved genomic atlas uncovers the genetic control of protein regulation across multiple tissues. These resources are accessible through the Online Neurodegenerative Trait Integrative Multi-Omics Explorer for use by the scientific community. © The Author(s) 2024.
Document Type: Article
Publication Stage: Final
Source: Scopus
Characterization of early markers of disease in the mouse model of mucopolysaccharidosis IIIB
(2024) Journal of Neurodevelopmental Disorders, 16 (1), art. no. 16, .
McCullough, K.B.a b , Titus, A.a , Reardon, K.a , Conyers, S.a , Dougherty, J.D.a b c , Ge, X.d , Garbow, J.R.c d , Dickson, P.c e , Yuede, C.M.a c f g , Maloney, S.E.a b c
a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
b Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, United States
c Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine, St. Louis, MO 63110, United States
d Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States
e Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, United States
f Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
g Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, United States
Abstract
Background: Mucopolysaccharidosis (MPS) IIIB, also known as Sanfilippo Syndrome B, is a devastating childhood disease. Unfortunately, there are currently no available treatments for MPS IIIB patients. Yet, animal models of lysosomal storage diseases have been valuable tools in identifying promising avenues of treatment. Enzyme replacement therapy, gene therapy, and bone marrow transplant have all shown efficacy in the MPS IIIB model systems. A ubiquitous finding across rodent models of lysosomal storage diseases is that the best treatment outcomes resulted from intervention prior to symptom onset. Therefore, the aim of the current study was to identify early markers of disease in the MPS IIIB mouse model as well as examine clinically-relevant behavioral domains not yet explored in this model. Methods: Using the MPS IIIB mouse model, we explored early developmental trajectories of communication and gait, and later social behavior, fear-related startle and conditioning, and visual capabilities. In addition, we examined brain structure and function via magnetic resonance imaging and diffusion tensor imaging. Results: We observed reduced maternal isolation-induced ultrasonic vocalizations in MPS IIIB mice relative to controls, as well as disruption in a number of the spectrotemporal features. MPS IIIB also exhibited disrupted thermoregulation during the first two postnatal weeks without any differences in body weight. The developmental trajectories of gait were largely normal. In early adulthood, we observed intact visual acuity and sociability yet a more submissive phenotype, increased aggressive behavior, and decreased social sniffing relative to controls. MPS IIIB mice showed greater inhibition of startle in response to a pretone with a decrease in overall startle response and reduced cued fear memory. MPS IIIB also weighed significantly more than controls throughout adulthood and showed larger whole brain volumes and normalized regional volumes with intact tissue integrity as measured with magnetic resonance and diffusion tensor imaging, respectively. Conclusions: Together, these results indicate disease markers are present as early as the first two weeks postnatal in this model. Further, this model recapitulates social, sensory and fear-related clinical features. Our study using a mouse model of MPS IIIB provides essential baseline information that will be useful in future evaluations of potential treatments. © The Author(s) 2024.
Author Keywords
Aggression; Dominance; Fear conditioning; Gait; Lysosomal storage disorder; MRI/DTI; Mucopolysaccharidosis IIIB; Sanfilippo B; Startle response; Ultrasonic vocalization
Document Type: Article
Publication Stage: Final
Source: Scopus
The Brain Gene Registry: a data snapshot
(2024) Journal of Neurodevelopmental Disorders, 16 (1), art. no. 17, .
Baldridge, D.a , Kaster, L.b , Sancimino, C.c , Srivastava, S.d e , Molholm, S.f , Gupta, A.b , Oh, I.b , Lanzotti, V.g , Grewal, D.b , Riggs, E.R.h , Savatt, J.M.i , Hauck, R.b , Sveden, A.e , Constantino, J.N.j , Piven, J.k , Gurnett, C.A.l , Chopra, M.d e , Hazlett, H.k , Payne, P.R.O.b
a Department of Pediatrics, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
b Institute for Informatics, Data Science and Biostatistics, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
c Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY, United States
d Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States
e Rosamund Stone Zander Translational Neuroscience Center, Boston Children’s Hospital, Boston, MA, United States
f Departments of Pediatrics and Neuroscience, Albert Einstein College of Medicine, Bronx, NY, United States
g Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
h Autism and Developmental Medicine Institute, Geisinger, Danville, PA, United States
i Department of Genomic Health, Geisinger, Danville, PA, United States
j Division of Behavioral and Mental Health, Departments of Psychiatry and Pediatrics, Children’s Healthcare of Atlanta, Emory University, Atlanta, GA, United States
k The Carolina Institute for Developmental Disabilities, University of North Carolina, Chapel Hill, NC, United States
l Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
Abstract
Monogenic disorders account for a large proportion of population-attributable risk for neurodevelopmental disabilities. However, the data necessary to infer a causal relationship between a given genetic variant and a particular neurodevelopmental disorder is often lacking. Recognizing this scientific roadblock, 13 Intellectual and Developmental Disabilities Research Centers (IDDRCs) formed a consortium to create the Brain Gene Registry (BGR), a repository pairing clinical genetic data with phenotypic data from participants with variants in putative brain genes. Phenotypic profiles are assembled from the electronic health record (EHR) and a battery of remotely administered standardized assessments collectively referred to as the Rapid Neurobehavioral Assessment Protocol (RNAP), which include cognitive, neurologic, and neuropsychiatric assessments, as well as assessments for attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Co-enrollment of BGR participants in the Clinical Genome Resource’s (ClinGen’s) GenomeConnect enables display of variant information in ClinVar. The BGR currently contains data on 479 participants who are 55% male, 6% Asian, 6% Black or African American, 76% white, and 12% Hispanic/Latine. Over 200 genes are represented in the BGR, with 12 or more participants harboring variants in each of these genes: CACNA1A, DNMT3A, SLC6A1, SETD5, and MYT1L. More than 30% of variants are de novo and 43% are classified as variants of uncertain significance (VUSs). Mean standard scores on cognitive or developmental screens are below average for the BGR cohort. EHR data reveal developmental delay as the earliest and most common diagnosis in this sample, followed by speech and language disorders, ASD, and ADHD. BGR data has already been used to accelerate gene-disease validity curation of 36 genes evaluated by ClinGen’s BGR Intellectual Disability (ID)-Autism (ASD) Gene Curation Expert Panel. In summary, the BGR is a resource for use by stakeholders interested in advancing translational research for brain genes and continues to recruit participants with clinically reported variants to establish a rich and well-characterized national resource to promote research on neurodevelopmental disorders. © The Author(s) 2024.
Author Keywords
Brain gene registry; Electronic health records; Neurodevelopmental disorders
Funding details
Boston Children’s HospitalBCH
School of Medicine, Washington University in St. LouisWUSM
Albert Einstein College of Medicine, Yeshiva UniversityAECOM
Alvin J. Siteman Cancer CenterSCC
Children’s National Hospital
National Institutes of HealthNIH
University of North Carolina WilmingtonUNCW
Baylor College of Medicine
National Center for Advancing Translational SciencesNCATS
U24HG006834
National Cancer InstituteNCIP30CA091842
P50HD103573
National Human Genome Research InstituteNHGRIUL1TR002345
Intellectual and Developmental Disabilities Research Center, School of Medicine, Washington University in St. LouisIDDRCP50HD105351
P50HD103525
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHDP50HD105352
Document Type: Article
Publication Stage: Final
Source: Scopus
Characteristics of women concordant and discordant for urine drug screens for cannabis exposure and self-reported cannabis use during pregnancy
(2024) Neurotoxicology and Teratology, 103, art. no. 107351, .
Bogdan, R.a , Leverett, S.D.b c , Constantino-Petit, A.M.c , Lashley-Simms, N.c , Liss, D.B.d , Johnson, E.C.c , Lenze, S.N.c , Lean, R.E.c , Smyser, T.A.c , Carter, E.B.e , Smyser, C.D.f , Rogers, C.E.c , Agrawal, A.c
a Psychological & Brain Sciences, Washington University in Saint Louis, United States
b Division of Biology & Biomedical Sciences, Neurosciences Program, Washington University in Saint Louis, United States
c Department of Psychiatry, Washington University in Saint Louis, United States
d Department of Emergency Medicine, Washington University in Saint Louis, United States
e Department of Obstetrics & Gynecology, Washington University in Saint Louis, United States
f Department of Neurology, Washington University in Saint Louis, United States
Abstract
Background: Increasing cannabis use among pregnant people and equivocal evidence linking prenatal cannabis exposure to adverse outcomes in offspring highlights the need to understand its potential impact on pregnancy and child outcomes. Assessing cannabis use during pregnancy remains a major challenge with potential influences of stigma on self-report as well as detection limitations of easily collected biological matrices. Objective: This descriptive study examined the concordance between self-reported (SR) cannabis use and urine drug screen (UDS) detection of cannabis exposure during the first trimester of pregnancy and characterized concordant and discordant groups for sociodemographic factors, modes of use, secondhand exposure to cannabis and tobacco, and alcohol use and cotinine positivity. Study design: The Cannabis Use During Development and Early Life (CUDDEL) Study is an ongoing longitudinal study that recruits pregnant individuals presenting for obstetric care, who report lifetime cannabis use as well as using (n = 289) or not using cannabis (n = 169) during pregnancy. During the first trimester pregnancy visit, SR of cannabis use and a UDS for cannabis, other illicit drugs and nicotine are acquired from eligible participants, of whom 333 as of 05/01/2023 had both. Results: Using available CUDDEL Study data on both SR and UDS (n = 333; age 26.6 ± 4.7; 88.6% Black; 45.4% below federal poverty threshold; 56.5% with paid employment; 89% with high school education; 22% first pregnancy; 12.3 ± 3.6 weeks gestation), we classified pregnant individuals with SR and UDS data into 4 groups based on concordance (k = 0.49 [95% C.I. 0.40–0.58]) between SR cannabis use and UDS cannabis detection during the first trimester: 1) SR+/UDS+ (n = 107); 2) SR-/UDS- (n = 142); 3) SR+/UDS- (n = 44); 4) SR-/UDS+ (n = 40). Those who were SR+/UDS- reported less frequent cannabis use and fewer hours under the influence of cannabis during their pregnancy. Those who were SR-/UDS+ were more likely to have joined the study at a lower gestational age with 62.5% reporting cannabis use during their pregnancy prior to being aware that they were pregnant. Of the 40 SR-/UDS+ women, 14 (i.e., 35%) reported past month secondhand exposure, or blunt usage. In the subset of individuals with SR and UDS available at trimester 2 (N = 160) and 3 (N = 140), concordant groups were mostly stable and > 50% of those in the discordant groups became concordant by the second trimester. Classifying individuals as exposed or not exposed who were SR+ and/or UDS+ resulted in minor changes in group status based on self-report at screening. Conclusion: Overall, there was moderate concordance between SR and UDS for cannabis use/exposure during pregnancy. Instances of SR+/UDS- discordancy may partially be attributable to lower levels of use that are not detected on UDS. SR-/UDS+ discordancy may arise from recent use prior to knowledge of pregnancy, extreme secondhand exposure, deception, and challenges with completing questionnaires. Acquiring both self-report and biological detection of cannabis use/exposure allows for the examination of convergent evidence. Classifying those who are SR+ and/or UDS+ as individuals who used cannabis during their first trimester after being aware of their pregnancy resulted in only a minor change in exposure status; thus, relying on self-report screening, at least in this population and within this sociocultural context likely provides an adequate approximation of cannabis use during pregnancy. © 2024 Elsevier Inc.
Author Keywords
cannabis; Pregnancy; Prenatal; Urine
Funding details
National Institutes of HealthNIHR01MH113570, 5T32NS121881, U01 DA055367, R21 AA027827, U01NS107486, R01 DA054750, K01MH122735, R01 AG061162
Document Type: Article
Publication Stage: Final
Source: Scopus
Pharmacogenetic Influence on Stereoselective Steady-State Disposition of Bupropion
(2024) Drug Metabolism and Disposition: The Biological Fate of Chemicals, 52 (5), pp. 455-466.
Kharasch, E.D., Lenze, E.J.
Department of Anesthesiology, Duke University, Durham, North Carolina (E.D.K.); Bermaride, LLC (E.D.K.); and Department of Psychiatry, Washington University in St. Louis, St. Louis, Missouri (E.J.L.)
Abstract
Bupropion is used for treating depression, obesity, and seasonal affective disorder, and for smoking cessation. Bupropion is commonly prescribed, but has complex pharmacokinetics and interindividual variability in metabolism and bioactivation may influence therapeutic response, tolerability, and safety. Bupropion is extensively and stereoselectively metabolized, the metabolites are pharmacologically active, and allelic variation in cytochrome P450 (CYP) 2B6 affects clinical hydroxylation of single-dose bupropion. Genetic effects on stereoselective disposition of steady-state bupropion are not known. In this preplanned secondary analysis of a prospective, randomized, double-blinded, crossover study which compared brand and generic bupropion XL 300 mg drug products, we measured steady-state enantiomeric plasma and urine parent bupropion and primary and secondary metabolite concentrations. This investigation evaluated the influence of genetic polymorphisms in CYP2B6, CYP2C19, and P450 oxidoreductase on the disposition of Valeant Pharmaceuticals Wellbutrin brand bupropion in 67 participants with major depressive disorder. We found that hydroxylation of both bupropion enantiomers was lower in carriers of the CYP2B6*6 allele and in carriers of the CYP2B6 516G>T variant, with correspondingly greater bupropion and lesser hydroxybupropion plasma concentrations. Hydroxylation was 25-50% lower in CYP2B6*6 carriers and one-third to one-half less in 516T carriers. Hydroxylation of the bupropion enantiomers was comparably affected by CYP2B6 variants. CYP2C19 polymorphisms did not influence bupropion plasma concentrations or hydroxybupropion formation but did influence the minor pathway of 4′-hydroxylation of bupropion and primary metabolites. P450 oxidoreductase variants did not influence bupropion disposition. Results show that CYP2B6 genetic variants affect steady-state metabolism and bioactivation of Valeant brand bupropion, which may influence therapeutic outcomes. SIGNIFICANCE STATEMENT: Bupropion, used for depression, obesity, and smoking cessation, undergoes metabolic bioactivation, with incompletely elucidated interindividual variability. We evaluated cytochrome P450 (CYP) 2B6, CYP2C19 and P450 oxidoreductase genetic variants and steady-state bupropion and metabolite enantiomers disposition. Both enantiomers hydroxylation was lower in CYP2B6*6 and CYP2B6 516G>T carriers, with greater bupropion and lesser hydroxybupropion plasma concentrations. CYP2C19 polymorphisms did not affect bupropion or hydroxybupropion but did influence minor 4′-hydroxylation of bupropion and primary metabolites. CYP2B6 variants affect steady-state bupropion bioactivation, which may influence therapeutic outcomes. Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.
Document Type: Article
Publication Stage: Final
Source: Scopus
Cognitive and functional performance and plasma biomarkers of early Alzheimer’s disease in Down syndrome
(2024) Alzheimer’s and Dementia: Diagnosis, Assessment and Disease Monitoring, 16 (2), art. no. e12582, .
Schworer, E.K.a , Handen, B.L.b , Petersen, M.c , O’Bryant, S.c , Peven, J.C.b , Tudorascu, D.L.b , Lee, L.b , Krinsky-McHale, S.J.d , Hom, C.L.e , Clare, I.C.H.f , Christian, B.T.a , Schupf, N.g , Lee, J.H.g , Head, E.h , Mapstone, M.i , Lott, I.i , Ances, B.M.j , Zaman, S.f , Brickman, A.M.g , Lai, F.k , Rosas, H.D.k l , Hartley, S.L.a m
a Waisman Center, University of Wisconsin-Madison, Madison, WI, United States
b Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States
c Department of Family Medicine and Institute for Translational Research, University of North Texas Health Science Center, Fort Worth, TX, United States
d New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, United States
e Department of Psychiatry and Human Behavior, University of California, Irvine, CA, United States
f Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
g Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Sergievsky Center, and Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, United States
h Department of Pathology & Laboratory Medicine, University of California, Irvine School of Medicine, Irvine, CA, United States
i Department of Neurology, University of California, Irvine School of Medicine, Irvine, CA, United States
j Department of Neurology, Washington University at St. Louis, St. Louis, MO, United States
k Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
l Center for Neuro-imaging of Aging and Neurodegenerative Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
m School of Human Ecology, University of Wisconsin-Madison, Madison, WI, United States
Abstract
INTRODUCTION: People with Down syndrome (DS) have a 75% to 90% lifetime risk of Alzheimer’s disease (AD). AD pathology begins a decade or more prior to onset of clinical AD dementia in people with DS. It is not clear if plasma biomarkers of AD pathology are correlated with early cognitive and functional impairments in DS, and if these biomarkers could be used to track the early stages of AD in DS or to inform inclusion criteria for clinical AD treatment trials. METHODS: This large cross-sectional cohort study investigated the associations between plasma biomarkers of amyloid beta (Aβ)42/40, total tau, and neurofilament light chain (NfL) and cognitive (episodic memory, visual–motor integration, and visuospatial abilities) and functional (adaptive behavior) impairments in 260 adults with DS without dementia (aged 25–81 years). RESULTS: In general linear models lower plasma Aβ42/40 was related to lower visuospatial ability, higher total tau was related to lower episodic memory, and higher NfL was related to lower visuospatial ability and lower episodic memory. DISCUSSION: Plasma biomarkers may have utility in tracking AD pathology associated with early stages of cognitive decline in adults with DS, although associations were modest. Highlights: Plasma Alzheimer’s disease (AD) biomarkers correlate with cognition prior to dementia in Down syndrome. Lower plasma amyloid beta 42/40 was related to lower visuospatial abilities. Higher plasma total tau and neurofilament light chain were associated with lower cognitive performance. Plasma biomarkers show potential for tracking early stages of AD symptomology. © 2024 The Authors. Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.
Author Keywords
adaptive behavior; adults; cognitive performance; functional abilities; neurofilament light chain; plasma amyloid beta; plasma total tau; trisomy 21
Document Type: Article
Publication Stage: Final
Source: Scopus