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Office of Neuroscience Research > Resources and Facilities > WUSTL Neuroscience Publications for the week

WUSTL Neuroscience Publications for the week


The publications below include authors at Washington University and were identified by Scopus search.  These are the most current publications.  For previous lists, visit the WUSTL Neuroscience publications archive.

March 17, 2017


Shany, E.a b , Inder, T.E.c , Goshen, S.b , Lee, I.d , Neil, J.J.e , Smyser, C.D.d f j , Doyle, L.W.g h i , Anderson, P.J.h i , Shimony, J.S.j 
Diffusion Tensor Tractography of the Cerebellar Peduncles in Prematurely Born 7-Year-Old Children
(2017) Cerebellum, 16 (2), pp. 314-325. 

DOI: 10.1007/s12311-016-0796-7

a Department of Neonatology, Soroka Medical Center, P.O. Box 151, Beer Sheva, Israel
b Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel
c Department of Pediatric Newborn Medicine, Brigham and Women’s Hospital, Boston, MA, United States
d Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
e Department of Neurology, Boston Children’s Hospital, Boston, MA, United States
f Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
g Department of Obstetrics and Gynaecology, The Royal Women’s Hospital, Melbourne, Australia
h Clinical Sciences, Murdoch Children’s Research Institute, Melbourne, Australia
i Department of Paediatrics, The University of Melbourne, Melbourne, Australia
j Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States

The objective of this study was to correlate neurodevelopmental outcome of preterm-born children and their perinatal clinical and imaging characteristics with diffusion magnetic resonance imaging (MRI) measures of the three cerebellar peduncles at age 7. Included in this prospective longitudinal study were 140 preterm-born children (<30 weeks gestation) who underwent neurodevelopmental assessment (IQ, motor, language, working memory) and diffusion-weighted imaging (DWI) at age 7 years. White matter tracts in the superior, middle, and inferior cerebellar peduncles were delineated using regions of interest drawn on T2-weighted images and fractional anisotropy (FA) maps. Diffusion measures (mean diffusivity (MD) and FA) and tract volumes were calculated. Linear regression was used to assess relationships with outcome. The severity of white matter injury in the neonatal period was associated with lower FA in the right superior cerebellar peduncle (SCP) and lower tract volumes of both SCPs and middle cerebellar peduncles (MCPs). In the MCP, higher IQ was associated with lower MD in the whole group and higher FA in right-handed children. In the SCP, lower motor scores were associated with higher MD and higher language scores were associated with higher FA. These associations remained significant in multivariable models. This study adds to the body of literature detailing the importance of cerebellar involvement in cognitive function related to reciprocal connections with supratentorial structures. © 2016, Springer Science+Business Media New York.

Author Keywords
Cerebellum;  Magnetic resonance imaging;  Neurodevelopmental outcome;  Premature infants

Document Type: Article
Source: Scopus


Yokoyama, J.S.a , Karch, C.M.b , Fan, C.C.c , Bonham, L.W.a , Kouri, N.d , Ross, O.A.d , Rademakers, R.d , Kim, J.d , Wang, Y.e , Höglinger, G.U.f , Müller, U.g , Ferrari, R.h , Hardy, J.h , International Ftd-Genomics Consortium (Ifgc)p , Momeni, P.i , Sugrue, L.P.j , Hess, C.P.j , James Barkovich, A.j , Boxer, A.L.a , Seeley, W.W.a , Rabinovici, G.D.a , Rosen, H.J.a , Miller, B.L.a , Schmansky, N.J.k , Fischl, B.k l , Hyman, B.T.m , Dickson, D.W.d , Schellenberg, G.D.n , Andreassen, O.A.f , Dale, A.M.c o , Desikan, R.S.j 
Shared genetic risk between corticobasal degeneration, progressive supranuclear palsy, and frontotemporal dementia
(2017) Acta Neuropathologica, pp. 1-13. Article in Press. 

DOI: 10.1007/s00401-017-1693-y

a Department of Neurology, Memory and Aging Center, University of California, San Francisco, 675 Nelson Rising Lane, Suite 190, San Francisco, CA, United States
b Department of Psychiatry, Washington University, St. Louis, MO, United States
c Department of Cognitive Sciences, University of California, San Diego, La Jolla, CA, United States
d Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL, United States
e NORMENT; Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
f Department of Neurology, Technical University of Munich, Munich, Germany and German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
g Institut for Humangenetik, Justus-Liebig-Universität, Giessen, Germany
h Department of Molecular Neuroscience, Institute of Neurology, UCL, London, United Kingdom
i Laboratory of Neurogenetics, Department of Internal Medicine, Texas Tech University Health Science Center, Lubbock, TX, United States
j Neuroradiology Section, L-352, Department of Radiology and Biomedical Imaging, University of California, San Francisco, 505 Parnassus Avenue, San Francisco, CA, United States
k Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, MA, United States
l Computer Science and Artificial Intelligence Laboratory (CSAIL), Massachusetts Institute of Technology, Cambridge, MA, United States
m Department of Neurology, Massachusetts General Hospital, Charlestown, MA, United States
n Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
o Departments of Radiology and Neurosciences, University of California, San Diego, La Jolla, CA, United States

Corticobasal degeneration (CBD), progressive supranuclear palsy (PSP) and a subset of frontotemporal dementia (FTD) are neurodegenerative disorders characterized by tau inclusions in neurons and glia (tauopathies). Although clinical, pathological and genetic evidence suggests overlapping pathobiology between CBD, PSP, and FTD, the relationship between these disorders is still not well understood. Using summary statistics (odds ratios and p values) from large genome-wide association studies (total n = 14,286 cases and controls) and recently established genetic methods, we investigated the genetic overlap between CBD and PSP and CBD and FTD. We found up to 800-fold enrichment of genetic risk in CBD across different levels of significance for PSP or FTD. In addition to NSF (tagging the MAPT H1 haplotype), we observed that SNPs in or near MOBP, CXCR4, EGFR, and GLDC showed significant genetic overlap between CBD and PSP, whereas only SNPs tagging the MAPT haplotype overlapped between CBD and FTD. The risk alleles of the shared SNPs were associated with expression changes in cis-genes. Evaluating transcriptome levels across adult human brains, we found a unique neuroanatomic gene expression signature for each of the five overlapping gene loci (omnibus ANOVA p &lt; 2.0 × 10−16). Functionally, we found that these shared risk genes were associated with protein interaction and gene co-expression networks and showed enrichment for several neurodevelopmental pathways. Our findings suggest: (1) novel genetic overlap between CBD and PSP beyond the MAPT locus; (2) strong ties between CBD and FTD through the MAPT clade, and (3) unique combinations of overlapping genes that may, in part, influence selective regional or neuronal vulnerability observed in specific tauopathies. © 2017 Springer-Verlag Berlin Heidelberg

Document Type: Article in Press
Source: Scopus


Pappa, K., Doty, T., Taff, S.D., Kniepmann, K., Foster, E.R.
Self-Management Program Participation and Social Support in Parkinson's Disease: Mixed Methods Evaluation
(2017) Physical and Occupational Therapy in Geriatrics, pp. 1-18. Article in Press. 

DOI: 10.1080/02703181.2017.1288673

Program in Occupational Therapy, Washington University School of Medicine, St. Louis, Missouri, USA

Aims: To explore the potential influence of the Stanford Chronic Disease Self-Management Program (CDSMP) on social support in Parkinson's disease (PD). Methods: This was a quasi-experimental mixed methods design. Volunteers with PD (n = 27) and care partners (n = 6) completed the CDSMP, questionnaires of social support and self-management outcomes, and an interview about social support in relation to CDSMP participation. PD participants (n = 19) who did not participate in the CDSMP completed the questionnaires for quantitative comparison purposes. Results: Regarding the quantitative data, there were no significant effects of CDSMP participation on social support questionnaire scores; however, there were some positive correlations between changes in social support and changes in self-management outcomes from pre- to post-CDSMP participation. Three qualitative themes emerged from the interviews: lack of perceived change in amount and quality of social support, positive impact on existing social networks, and benefit from participating in a supportive PD community. Conclusions: Although participants did not acknowledge major changes in social support, there were some social support-related benefits of CDSMP participation for PD participants and care partners. These findings provide a starting point for more in-depth studies of social support and self-management in this population. © 2017 Taylor & Francis Group, LLC

Author Keywords
caregiving;  Parkinson's disease;  self-management;  Social support

Document Type: Article in Press
Source: Scopus


Elsamadicy, A.A.a b , Chongsathidkiet, P.a b c , Desai, R.d , Woroniecka, K.a b c , Farber, S.H.a b , Fecci, P.E.a b c , Sampson, J.H.a b c 
Prospect of rindopepimut in the treatment of glioblastoma
(2017) Expert Opinion on Biological Therapy, 17 (4), pp. 507-513. 

DOI: 10.1080/14712598.2017.1299705

a Duke Brain Tumor Immunotherapy Program, Department of Neurosurgery, Duke University Medical Center, Durham, NC, United States
b The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, United States
c Department of Pathology, Duke University Medical Center, Durham, NC, United States
d Department of Neurosurgery, Washington University School of Medicine in St. Louis, St. Louis, MO, United States

Introduction: Rindopepimut (CDX-110) is a peptide vaccine that targets epidermal growth factor receptor variant III (EGFRvIII), a tumor-specific epitope expressed in the most common and lethal primary malignant neoplasm of the brain–glioblastoma (GBM). Areas covered: The EGFRvIII mutation introduces an 801 base pair in-frame deletion of the extracellular domain of the transmembrane tyrosine kinase, resulting in constitutive kinase activity, amplification of cell growth, and inhibition of apoptosis. Rindopepimut contains a 14mer amino acid peptide spanning the EGFRvIII mutation site that is conjugated to keyhole limpet hemocyanin (KLH). The EGFRvIII neoantigen is exclusively present on GBM cells, providing rindopepimut tumor-specific activity. The authors review rindopepimut’s clinical efficacy, administration, safety, and prospects in the treatment of GBM. Expert opinion: Rindopepimut showed clinical benefit and significant efficacy in phase II clinical trials, including as part of a multi-immunotherapy approach. A phase III clinical trial was terminated early, however, as it was deemed likely the study would fail to meet its primary endpoint. Longer term and sub-group analyses will be necessary to better understand rindopepimut’s future role in GBM therapy. © 2017 Informa UK Limited, trading as Taylor & Francis Group.

Author Keywords
clinical trials;  EGFRvIII;  Glioblastoma;  immunotherapy;  peptide vaccine;  rindopepimut

Document Type: Article
Source: Scopus


Hughes, A.E.O., Enright, J.M., Myers, C.A., Shen, S.Q., Corbo, J.C.
Cell Type-Specific Epigenomic Analysis Reveals a Uniquely Closed Chromatin Architecture in Mouse Rod Photoreceptors
(2017) Scientific Reports, 7, art. no. 43184, . 

DOI: 10.1038/srep43184

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MI, United States

Rod photoreceptors are specialized neurons that mediate vision in dim light and are the predominant photoreceptor type in nocturnal mammals. The rods of nocturnal mammals are unique among vertebrate cell types in having an â € inverted' nuclear architecture, with a dense mass of heterochromatin in the center of the nucleus rather than dispersed clumps at the periphery. To test if this unique nuclear architecture is correlated with a unique epigenomic landscape, we performed ATAC-seq on mouse rods and their most closely related cell type, cone photoreceptors. We find that thousands of loci are selectively closed in rods relative to cones as well as >60 additional cell types. Furthermore, we find that the open chromatin profile of photoreceptors lacking the rod master regulator Nrl is nearly indistinguishable from that of native cones, indicating that Nrl is required for selective chromatin closure in rods. Finally, we identified distinct enrichments of transcription factor binding sites in rods and cones, revealing key differences in the cis-regulatory grammar of these cell types. Taken together, these data provide insight into the development and maintenance of photoreceptor identity, and highlight rods as an attractive system for studying the relationship between nuclear organization and local changes in gene regulation.

Document Type: Article
Source: Scopus


Ramsey,, A.T., Phda , Baumann, A.b , Patterson Silver Wolf, D.b , Yan, Y.c , Cooper, B.d , Proctor, E.b 
The need for data-informed clinical supervision in substance use disorder treatment
(2017) Journal of Addictive Diseases, pp. 1-10. Article in Press. 

DOI: 10.1080/10550887.2017.1291051

a Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA
b Brown School of Social Work, Washington University, St. Louis, Missouri, USA
c Division of Public Health Sciences, Washington University School of Medicine, St. Louis, Missouri, USA
d Institute for Public Health, Washington University, St. Louis, Missouri, USA

Effective clinical supervision is necessary for high-quality care in community-based substance use disorder treatment settings, yet little is known about current supervision practices. Some evidence suggests that supervisors and counselors differ in their experiences of clinical supervision; however, the impact of this misalignment on supervision quality is unclear. Clinical information monitoring systems may support supervision in substance use disorder treatment, but the potential use of these tools must first be explored. First, the current study examines the extent to which misaligned supervisor–counselor perceptions impact supervision satisfaction and emphasis on evidence-based treatments. This study also reports on formative work to develop a supervision-based clinical dashboard, an electronic information monitoring system and data visualization tool providing real-time clinical information to engage supervisors and counselors in a coordinated and data-informed manner, help align supervisor–counselor perceptions about supervision, and improve supervision effectiveness. Clinical supervisors and frontline counselors (N = 165) from five Midwestern agencies providing substance abuse services completed an online survey using Research Electronic Data Capture software, yielding a 75% response rate. Valid quantitative measures of supervision effectiveness were administered, along with qualitative perceptions of a supervision-based clinical dashboard. Through within-dyad analyses, misalignment between supervisor and counselor perceptions of supervision practices was negatively associated with satisfaction of supervision and reported frequency of discussing several important clinical supervision topics, including evidence-based treatments and client rapport. Participants indicated the most useful clinical dashboard functions and reported important benefits and challenges to using the proposed tool. Clinical supervision tends to be largely an informal and unstructured process in substance abuse treatment, which may compromise the quality of care. Clinical dashboards may be a well-targeted approach to facilitate data-informed clinical supervision in community-based treatment agencies. © 2017 Taylor & Francis Group, LLC

Author Keywords
clinical informatics;  service quality;  substance use disorder treatment;  Supervision

Document Type: Article in Press
Source: Scopus


Kharasch, E.D.a b c 
Current Concepts in Methadone Metabolism and Transport
(2017) Clinical Pharmacology in Drug Development, 6 (2), pp. 125-134. Cited 1 time.

DOI: 10.1002/cpdd.326

a Department of Anesthesiology, Washington University in St. Louis, St. Louis, MO, United States
b Department of Biochemistry and Biophysics, Washington University in St. Louis, St. Louis, MO, United States
c The Center for Clinical Pharmacology, St. Louis College of Pharmacy and Washington University in St. Louis School of Medicine, St. Louis, MO, United States

Methadone is a cornerstone therapy for opioid addiction and a public health strategy for HIV/AIDS and hepatitis C reduction. Methadone is also used for acute and chronic pain. As use for chronic pain has grown, so too have adverse events. Constitutive and acquired (drug interactions) inter- and intraindividual variability in methadone pharmacokinetics and pharmacodynamics confounds reliable clinical use. Identification of enzymes and transporters responsible for methadone disposition has been a long-sought ideal. Initial in vitro studies identified CYP3A4 as metabolizing methadone. Subsequently, by extrapolation, CYP3A4 was long assumed to be responsible for clinical methadone disposition. However, CYP2B6 is also a major catalyst of methadone metabolism in vitro. It has now been unequivocally established that CYP2B6, not CYP3A4, is the principal determinant of methadone metabolism, clearance, elimination, and plasma concentrations in humans. Methadone disposition is susceptible to inductive and inhibitory drug interactions. CYP2B6 genetics also influences methadone metabolism and clearance, which were diminished in CYP2B6*6 carriers and increased in CYP2B6*4 carriers. CYP2B6 genetics can explain, in part, interindividual variability in methadone metabolism and clearance. Thus, both constitutive variability due to CYP2B6 genetics, and CYP2B6-mediated drug interactions, can alter methadone disposition, clinical effect, and drug safety. Methadone is not a substrate for major influx or efflux transporters. © 2017, The American College of Clinical Pharmacology

Author Keywords
CYP2B6;  CYP3A4;  EDDP;  methadone;  P-glycoprotein

Document Type: Article
Source: Scopus


Weidler, B.J., Abrams, R.A.
Simple actions influence pop-out search
(2017) Visual Cognition, pp. 1-14. Article in Press. 

DOI: 10.1080/13506285.2017.1289996

Department of Psychological and Brain Sciences, Washington University, St. Louis, USA

Recent research has revealed that a simple action (pressing a computer key) produced in response to a visual object prioritizes features of that object in subsequent visual search. The effects of simple action, however, have only been studied with search displays that required serial search. Here we explored whether simple actions have an effect when the target in visual search is always a salient singleton. Participants viewed a coloured shape at the beginning of each trial, and sometimes they acted (pressed the space bar) in response to it. In the subsequent search task, after acting (but not after viewing), the previously-seen colour affected search performance even though the target was always a salient singleton and the colour was uninformative. The results reveal that prior action can interact with bottom-up salience during search. Implications for our understanding of both visual search and repetition priming are discussed. © 2017 Informa UK Limited, trading as Taylor & Francis Group

Author Keywords
action and perception;  Action effect;  repetition priming;  visual search

Document Type: Article in Press
Source: Scopus


Glowinski, A.L., Rosen, M.S.
Prevention targets for child and adolescent depression
(2017) JAMA Psychiatry, 74 (2), pp. 160-161. 

DOI: 10.1001/jamapsychiatry.2016.3160

Division of Child and Adolescent Psychiatry, Department of Psychiatry, Washington University, School of Medicine in St. Louis, 4444 Forrest Pkwy, St. Louis, MO, United States

Document Type: Note
Source: Scopus


Cavazos-Rehg, P.A., Krauss, M.J., Sowles, S.J., Connolly, S., Rosas, C., Bharadwaj, M., Grucza, R., Bierut, L.J.
An analysis of depression, self-harm, and suicidal ideation content on Tumblr
(2017) Crisis, 38 (1), pp. 44-52. 

DOI: 10.1027/0227-5910/a000409

Department of Psychiatry, Washington University, School of Medicine, St. Louis, MO, United States

Background: Social networking about depression can be indicative of self-reported depression and/or can normalize risk behaviors such as self-harm and suicidal ideation. Aim: To gain a better understanding of the depression, self-harm, and suicidal content that is being shared on Tumblr. Method: From April 16 to May 10, 2014, 17 popular depression-related Tumblr accounts were monitored for new posts and engagement with other Tumblr users. A total of 3,360 posts were randomly selected from all historical posts from these accounts and coded based on themes ascertained by the research team. Results: The 17 Tumblr accounts posted a median number of 185 posts (range = 0-2,954). Content was engaged with (i.e., re-blogged or liked) a median number of 1,677,362 times (range = 0-122,186,504). Of the 3,360 randomly selected posts, 2,739 (82%) were related to depression, suicide, or self-harm. Common themes were self-loathing (412, 15%), loneliness/feeling unloved (405, 15%), self-harm (407, 15%), and suicide (372, 14%). Conclusion: This study takes an important first step at better understanding the displayed depression-related references on Tumblr. The findings signal a need for suicide prevention efforts to intervene on Tumblr and use this platform in a strategic way, given the depression and suicidal content that was readily observed on Tumblr. © 2016 Hogrefe Publishing.

Author Keywords
Adolescent;  Depression;  Self-injurious behavior;  Social media;  Suicidal ideation

Document Type: Article
Source: Scopus


Firszt, J.B., Reeder, R.M., Holden, L.K.
Unilateral Hearing Loss: Understanding Speech Recognition and Localization Variability - Implications for Cochlear Implant Candidacy
(2017) Ear and Hearing, 38 (2), pp. 159-173. 

DOI: 10.1097/AUD.0000000000000380

Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO, United States

Objectives: At a minimum, unilateral hearing loss (UHL) impairs sound localization ability and understanding speech in noisy environments, particularly if the loss is severe to profound. Accompanying the numerous negative consequences of UHL is considerable unexplained individual variability in the magnitude of its effects. Identification of covariables that affect outcome and contribute to variability in UHLs could augment counseling, treatment options, and rehabilitation. Cochlear implantation as a treatment for UHL is on the rise yet little is known about factors that could impact performance or whether there is a group at risk for poor cochlear implant outcomes when hearing is near-normal in one ear. The overall goal of our research is to investigate the range and source of variability in speech recognition in noise and localization among individuals with severe to profound UHL and thereby help determine factors relevant to decisions regarding cochlear implantation in this population. Design: The present study evaluated adults with severe to profound UHL and adults with bilateral normal hearing. Measures included adaptive sentence understanding in diffuse restaurant noise, localization, roving-source speech recognition (words from 1 of 15 speakers in a 140° arc), and an adaptive speech-reception threshold psychoacoustic task with varied noise types and noise-source locations. There were three age-sex-matched groups: UHL (severe to profound hearing loss in one ear and normal hearing in the contralateral ear), normal hearing listening bilaterally, and normal hearing listening unilaterally. Results: Although the normal-hearing-bilateral group scored significantly better and had less performance variability than UHLs on all measures, some UHL participants scored within the range of the normal-hearing-bilateral group on all measures. The normal-hearing participants listening unilaterally had better monosyllabic word understanding than UHLs for words presented on the blocked/deaf side but not the open/hearing side. In contrast, UHLs localized better than the normal-hearing unilateral listeners for stimuli on the open/hearing side but not the blocked/deaf side. This suggests that UHLs had learned strategies for improved localization on the side of the intact ear. The UHL and unilateral normal-hearing participant groups were not significantly different for speech in noise measures. UHL participants with childhood rather than recent hearing loss onset localized significantly better; however, these two groups did not differ for speech recognition in noise. Age at onset in UHL adults appears to affect localization ability differently than understanding speech in noise. Hearing thresholds were significantly correlated with speech recognition for UHL participants but not the other two groups. Conclusions: Auditory abilities of UHLs varied widely and could be explained only in part by hearing threshold levels. Age at onset and length of hearing loss influenced performance on some, but not all measures. Results support the need for a revised and diverse set of clinical measures, including sound localization, understanding speech in varied environments, and careful consideration of functional abilities as individuals with severe to profound UHL are being considered potential cochlear implant candidates. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

Author Keywords
Cochlear Implant;  Localization;  Speech recognition;  Unilateral hearing loss

Document Type: Conference Paper
Source: Scopus


Jun, G.R.a b , Chung, J.b , Mez, J.c , Barber, R.d , Beecham, G.W.e , Bennett, D.A.f , Buxbaum, J.D.g h i , Byrd, G.S.j , Carrasquillo, M.M.k , Crane, P.K.l , Cruchaga, C.m n , De Jager, P.o p , Ertekin-Taner, N.k , Evans, D.q , Fallin, M.D.r , Foroud, T.M.s , Friedland, R.P.t , Goate, A.M.g , Graff-Radford, N.R.k , Hendrie, H.u v , Hall, K.S.v w , Hamilton-Nelson, K.L.e , Inzelberg, R.x , Kamboh, M.I.y , Kauwe, J.S.K.z , Kukull, W.A.aa ab , Kunkle, B.W.e , Kuwano, , Larson, E.B.p ad , Logue, M.W.b f ae , Manly, ag , Martin, E.R.e , Montine, T.J.ah , Mukherjee, S.l , Naj, , Reiman, E.M.aj ak al am , Reitz, ao ap , Sherva, R.b , St. George-Hyslop, ar , Thornton, T.l , Younkin, S.G.k , Vardarajan, ag an , Wang, L.-S.aj , Wendlund, , Winslow, , Haines, , Mayeux, ag an ao ap , Pericak-Vance, M.A.e , Schellenberg, G.aj , Lunetta, , Farrer, L.A.b c au av aw 
Transethnic genome-wide scan identifies novel Alzheimer's disease loci
(2017) Alzheimer's and Dementia, . Article in Press. 

DOI: 10.1016/j.jalz.2016.12.012

a Neurogenetics and Integrated Genomics, Andover Innovative Medicines Institute, Eisai Inc, Andover, MA, USA
b Department of Medicine (Biomedical Genetics), Boston University Schools of Medicine, Boston, MA, USA
c Department of Neurology, Boston University Schools of Medicine, Boston, MA, USA
d Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX, USA
e The John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA
f Department of Neurological Sciences and Rush Alzheimer's Disease Center, Chicago, IL, USA
g Department of Neuroscience, Mount Sinai School of Medicine, New York, NY, USA
h Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, USA
i Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY, USA
j Department of Biology, North Carolina A and T State University, Greensboro, NC, USA
k Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA
l Department of Medicine, University of Washington, Seattle, WA, USA
m Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University School of Medicine, St Louis, MO, USA
n Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA
o Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Department of Neurology and Psychiatry, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
p Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA
q Rush Institute for Healthy Aging, Department of Internal Medicine, Rush University Medical Center, Chicago, IL, USA
r Department of Mental Health, Johns Hopkins University School of Medicine, Baltimore, MD, USA
s Department of Medical and Molecular Genetics, Indiana University, Indianapolis, IN, USA
t Department of Neurology, University of Louisville, Louisville, KY, USA
u Department of Psychiatry, Indiana University, Indianapolis, IN, USA
v Regenstrief Institute, Inc, Indianapolis, IN, USA
w Department of Medicine, Indiana University, Indianapolis, IN, USA
x Department of Neurology and Neurosurgery, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
y University of Pittsburgh Alzheimer's Disease Research Center and Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA
z Department of Biology, Brigham Young University, Provo, UT, USA
aa Department of Epidemiology, University of Washington, Seattle, WA, USA
ab National Alzheimer's Coordinating Center, University of Washington, Seattle, WA, USA
ac Department of Molecular Genetics, Brain Research Institute, Niigata University, Niigata, Japan
ad Group Health, Group Health Research Institute, Seattle, WA, USA
ae National Center for PTSD, Behavioral Science Division, Boston VA Healthcare System, Boston, MA, USA
af The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, USA
ag The Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA
ah Department of Pathology, Stanford University, Stanford, CA, USA
ai Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
aj Arizona Alzheimer's Consortium, Phoenix, AZ, USA
ak Department of Psychiatry, University of Arizona, Phoenix, AZ, USA
al Banner Alzheimer's Institute, Phoenix, AZ, USA
am Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA
an The Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA
ao The Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY, USA
ap The Department of Epidemiology, College of Physicians and Surgeons, Columbia University, New York, NY, USA
aq Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Canada
ar Cambridge Institute for Medical Research and Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
as PharmaTherapeutics Clinical Research, Pfizer Worldwide Research and Development, Cambridge, MA, USA
at Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA
au Department of Biostatistics, Boston University Schools of Public Health, Boston, MA, USA
av Department of Ophthalmology, Boston University Schools of Medicine, Boston, MA, USA
aw Department of Epidemiology, Boston University Schools of Public Health, Boston, MA, USA

Introduction: Genetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood. Methods: We conducted a transethnic genome-wide association study (GWAS) for late-onset AD in Stage 1 sample including whites of European Ancestry, African-Americans, Japanese, and Israeli-Arabs assembled by the Alzheimer's Disease Genetics Consortium. Suggestive results from Stage 1 from novel loci were followed up using summarized results in the International Genomics Alzheimer's Project GWAS dataset. Results: Genome-wide significant (GWS) associations in single-nucleotide polymorphism (SNP)-based tests (P &lt; 5 × 10-8) were identified for SNPs in PFDN1/HBEGF, USP6NL/ECHDC3, and BZRAP1-AS1 and for the interaction of the (apolipoprotein E) APOE e(open)4 allele with NFIC SNP. We also obtained GWS evidence (P &lt; 2.7 × 10-6) for gene-based association in the total sample with a novel locus, TPBG (P = 1.8 × 10-6). Discussion: Our findings highlight the value of transethnic studies for identifying novel AD susceptibility loci. © 2017 The Authors.

Author Keywords
Alzheimer's disease;  APOE interaction;  Genome-wide association;  Transethnic

Document Type: Article in Press
Source: Scopus


Bogdan, R.a , Salmeron, B.J.c , Carey, C.E.a , Agrawal, A.b , Calhoun, V.D.d e f , Garavan, H.g , Hariri, A.R.h , Heinz, A.i , Hill, M.N.j , Holmes, A.k , Kalin, N.H.m n o , Goldman, D.l 
Imaging Genetics and Genomics in Psychiatry: A Critical Review of Progress and Potential
(2017) Biological Psychiatry, . Article in Press. 

DOI: 10.1016/j.biopsych.2016.12.030

a BRAIN Lab, Department of Psychological and Brain Sciences, St. Louis, Missouri
b Department of Psychiatry, Washington University in St. Louis, St. Louis, Missouri
c Neuroimaging Research Branch, Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland
d Mind Research Network and Lovelace Biomedical and Environmental Research Institute, University of New Mexico, Albuquerque, New Mexico
e Departments of Psychiatry and Neuroscience, University of New Mexico, Albuquerque, New Mexico
f Electronic and Computer Engineering, University of New Mexico, Albuquerque, New Mexico
g Department of Psychiatry, University of Vermont, Burlington, Vermont
h Laboratory of NeuroGenetics, Department of Psychology and Neuroscience, Duke University, Durham, North Carolina
i Department of Child and Adolescent Psychiatry, Psychosomatics, and Psychotherapy, Charité-Universitätsmedizin Berlin, Berlin, Germany
j Hotchkiss Brain Institute, Departments of Cell Biology and Anatomy and Psychiatry, University of Calgary, Calgary, Alberta, Canada
k Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland
l Laboratory of Neurogenetics, Intramural Research Program, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland
m Department of Psychiatry, University of Wisconsin, Madison, Wisconsin
n Neuroscience Training Program (NHK, RK, PHR, DPMT, MEE), University of Wisconsin, Madison, Wisconsin
o Wisconsin National Primate Research Center (NHK, MEE), Madison, Wisconsin

Imaging genetics and genomics research has begun to provide insight into the molecular and genetic architecture of neural phenotypes and the neural mechanisms through which genetic risk for psychopathology may emerge. As it approaches its third decade, imaging genetics is confronted by many challenges, including the proliferation of studies using small sample sizes and diverse designs, limited replication, problems with harmonization of neural phenotypes for meta-analysis, unclear mechanisms, and evidence that effect sizes may be more modest than originally posited, with increasing evidence of polygenicity. These concerns have encouraged the field to grow in many new directions, including the development of consortia and large-scale data collection projects and the use of novel methods (e.g., polygenic approaches, machine learning) that enhance the quality of imaging genetic studies but also introduce new challenges. We critically review progress in imaging genetics and offer suggestions and highlight potential pitfalls of novel approaches. Ultimately, the strength of imaging genetics and genomics lies in their translational and integrative potential with other research approaches (e.g., nonhuman animal models, psychiatric genetics, pharmacologic challenge) to elucidate brain-based pathways that give rise to the vast individual differences in behavior as well as risk for psychopathology. © 2017 Society of Biological Psychiatry.

Author Keywords
Candidate;  Genetics;  Genomics;  Imaging;  MRI;  Neurogenetics;  Polygenic

Document Type: Article in Press
Source: Scopus