WashU weekly Neuroscience publications

Genomic prediction of alcohol-related morbidity and mortality
(2020) Translational Psychiatry, 10 (1), art. no. 23, . 

Kiiskinen, T.^{a f} , Mars, N.J.^f , Palviainen, T.^f , Koskela, J.^f , Rämö, J.T.^f , Ripatti, P.^f , Ruotsalainen, S.^f , Palotie, A.^{f g h} , Madden, P.A.F.^b , Rose, R.J.^c , Kaprio, J.^{d f} , Salomaa, V.^a , Mäkelä, P.^a , Havulinna, A.S.^{a f} , Ripatti, S.^{d e f} , FinnGen, GSCAN Consortium^{f g h}

^a Finnish Institute for Health and Welfare (THL), Helsinki, Finland
^b Department of Psychiatry, Washington University School of Medicine in St.Louis, St.Louis, MO, United States
^c Department of Psychological and Brain Sciences, Indiana University Bloomington, Bloomington, IN, United States
^d Department of Public Health, Clinicum, Faculty of Medicine, University of Helsinki, Helsinki, Finland
^e The Broad Institute of MIT and Harvard, Cambridge, MA, United States
^f Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland
^g Analytic and Translational Genetics Unit, Department of Medicine, Department of Neurology and Department of Psychiatry Massachusetts General Hospital, Boston, MA, United States
^h The Stanley Center for Psychiatric Research and Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, Boston, MA, United States

Abstract
While polygenic risk scores (PRS) have been shown to predict many diseases and risk factors, the potential of genomic prediction in harm caused by alcohol use has not yet been extensively studied. Here, we built a novel polygenic risk score of 1.1 million variants for alcohol consumption and studied its predictive capacity in 96,499 participants from the FinnGen study and 39,695 participants from prospective cohorts with detailed baseline data and up to 25 years of follow-up time. A 1 SD increase in the PRS was associated with 11.2 g (=0.93 drinks) higher weekly alcohol consumption (CI = 9.85–12.58 g, p = 2.3 × 10–58). The PRS was associated with alcohol-related morbidity (4785 incident events) and the risk estimate between the highest and lowest quintiles of the PRS was 1.83 (95% CI = 1.66–2.01, p = 1.6 × 10–36). When adjusted for self-reported alcohol consumption, education, marital status, and gamma-glutamyl transferase blood levels in 28,639 participants with comprehensive baseline data from prospective cohorts, the risk estimate between the highest and lowest quintiles of the PRS was 1.58 (CI = 1.26–1.99, p = 8.2 × 10–5). The PRS was also associated with all-cause mortality with a risk estimate of 1.33 between the highest and lowest quintiles (CI = 1.20–1.47, p = 4.5 × 10–8) in the adjusted model. In conclusion, the PRS for alcohol consumption independently associates for both alcohol-related morbidity and all-cause mortality. Together, these findings underline the importance of heritable factors in alcohol-related health burden while highlighting how measured genetic risk for an important behavioral risk factor can be used to predict related health outcomes. © 2019, The Author(s).

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Medication-assisted therapies for opioid use disorders in patients with chronic pain
(2020) Journal of the Neurological Sciences, 411, art. no. 116728, . 

Oesterle, T.S.^a , Kolla, B.P.^a , Rummans, T.A.^a , Gold, M.S.^b

^a Mayo Clinic – Rochester, Department of Psychiatry & Psychology, 200 First Street SW, Rochester, MN 55905, United States
^b Washington University in St. Louis, School of Medicine, St Louis, MO, United States

Abstract
Opioids have been used to treat pain and invoke pleasure for centuries. Modern scientific advancements have led to more potent, synthetic opioids. While certainly more effective in treating pain, they can also be much more addictive. Over the years the scientific community has developed a clearer understanding of the role opioid receptors play in causing and treating opioid use disorders (OUD) and we now know that OUD can develop in individuals taking opioids for “legitimate” pain. Current guidelines suggest that all prescribers (especially those prescribing opioids) be capable treating OUD. Pharmacological advances have led to a wide array of safe and effective treatment options to address OUDs. This paper will discuss the history of opioid development, what is known about the transition from analgesic uses to addiction and modern evidenced based treatment strategies to address OUDs. © 2020 Elsevier B.V.

Document Type: Review
Publication Stage: Final
Source: Scopus

Molecular neurological correlates of endorphinergic/dopaminergic mechanisms in reward circuitry linked to endorphinergic deficiency syndrome (EDS)
(2020) Journal of the Neurological Sciences, 411, art. no. 116733, . 

Blum, K.^a , Baron, D.^a , McLaughlin, T.^b , Gold, M.S.^c

^a Graduate School of Biomedical Sciences, Western University Health Sciences, Pomona, CA, United States
^b Center for Psychiatric Medicine, Lawrence, MA, United States
^c Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States

Abstract
The consensus of the current literature strongly supports the concept that brain neurotransmitters, and second messengers involved in the net release of dopamine in the mesolimbic region, especially the Nucleus Accumbens (NAc), is directly linked to motivation, anti-stress, incentive salience (wanting), and well-being. The role of dopamine in terms of alcohol withdrawal symptomology, cocaine craving behavior, dopamine –condensation products (TIQs), and more recently, the genetic aspects of drug-seeking and pro-dopamine regulation, provide compelling evidence of the relevant molecular neurological correlates of dopaminergic /endorphinergic mechanisms in reward circuitry due to genetic polymorphisms and epigenetic insults. In the face of an Americans opioid epidemic, the clinical consensus is to treat Opioid Use Disorder (OUD) with life-long opioid substitution therapy. However, the authors suggest a paradigm shift involving novel modalities like targeting the endorphinergic system linked to dopamine release at the NAc, in terms of the induction of required “dopamine homeostasis.” Utilizing the known genetic – environmental interaction theorem P = G +E, the authors provide a clear rationale for the adoption of genetic risk testing coupled with endorphinergic/dopamine regulation to address dysfunction across the brain reward circuitry. The goal of altering resting-state, functional connectivity may require a gentle “neurotransmitter fix” vis enkephalinase inhibition to overcome or combat – self-induction of acute dopamine release via psychoactive substance misuse resulting in chronic dopamine down-regulation. As subsets of reward deficiency, we are poised to provide novel, genetically guided therapy for endorphinergic, opioidergic, and dopaminergic deficiencies and related syndromes, utilizing “Precision Addiction Management. © 2020

Author Keywords
Brain Reward Cascade (BRC);  Dopamine deficiency syndrome;  Dopamine release and homeostasis;  Endorphinergic deficiency syndrome;  Endorphinergic mechanisms;  Genetic testing of addiction liability;  Neurotransmission;  Opioid deficiency syndrome;  Opioid Use Disorder (OUD);  Precision Addiction Management (PAM);  Reward Deficiency Syndrome (RDS)

Document Type: Review
Publication Stage: Final
Source: Scopus

TRPM3_miR-204: a complex locus for eye development and disease
(2020) Human Genomics, 14 (1), p. 7. 

Shiels, A.

Ophthalmology and Visual Sciences, Washington University School of Medicine, 660 S. Euclid Ave., Box 8096, St. Louis, MO, 63110, USA

Abstract
First discovered in a light-sensitive retinal mutant of Drosophila, the transient receptor potential (TRP) superfamily of non-selective cation channels serve as polymodal cellular sensors that participate in diverse physiological processes across the animal kingdom including the perception of light, temperature, pressure, and pain. TRPM3 belongs to the melastatin sub-family of TRP channels and has been shown to function as a spontaneous calcium channel, with permeability to other cations influenced by alternative splicing and/or non-canonical channel activity. Activators of TRPM3 channels include the neurosteroid pregnenolone sulfate, calmodulin, phosphoinositides, and heat, whereas inhibitors include certain drugs, plant-derived metabolites, and G-protein subunits. Activation of TRPM3 channels at the cell membrane elicits a signal transduction cascade of mitogen-activated kinases and stimulus response transcription factors. The mammalian TRPM3 gene hosts a non-coding microRNA gene specifying miR-204 that serves as both a tumor suppressor and a negative regulator of post-transcriptional gene expression during eye development in vertebrates. Ocular co-expression of TRPM3 and miR-204 is upregulated by the paired box 6 transcription factor (PAX6) and mutations in all three corresponding genes underlie inherited forms of eye disease in humans including early-onset cataract, retinal dystrophy, and coloboma. This review outlines the genomic and functional complexity of the TRPM3_miR-204 locus in mammalian eye development and disease.

Author Keywords
Eye development;  Eye disease;  MicroRNA;  TRP channel

Document Type: Review
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Reconfigurable nanophotonic silicon probes for sub-millisecond deep-brain optical stimulation
(2020) Nature Biomedical Engineering, . 

Mohanty, A.^{a b} , Li, Q.^{c d} , Tadayon, M.A.^a , Roberts, S.P.^a , Bhatt, G.R.^a , Shim, E.^a , Ji, X.^{a b} , Cardenas, J.^{a e} , Miller, S.A.^a , Kepecs, A.^{c d f} , Lipson, M.^a

^a Department of Electrical Engineering, Columbia University, New York, NY, United States
^b School of Electrical and Computer Engineering, Cornell University, Ithaca, NY, United States
^c Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, NY, United States
^d Department of Neuroscience, Washington University in St. Louis, St. Louis, MO, United States
^e Institute of Optics, University of Rochester, Rochester, NY, United States
^f Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States

Abstract
The use of nanophotonics to rapidly and precisely reconfigure light beams for the optical stimulation of neurons in vivo has remained elusive. Here we report the design and fabrication of an implantable silicon-based probe that can switch and route multiple optical beams to stimulate identified sets of neurons across cortical layers and simultaneously record the produced spike patterns. Each switch in the device consists of a silicon nitride waveguide structure that can be rapidly (<20 μs) reconfigured by electrically tuning the phase of light. By using an eight-beam probe, we show in anaesthetized mice that small groups of single neurons can be independently stimulated to produce multineuron spike patterns at sub-millisecond precision. We also show that a probe integrating co-fabricated electrical recording sites can simultaneously optically stimulate and electrically measure deep-brain neural activity. The technology is scalable, and it allows for beam focusing and steering and for structured illumination via beam shaping. The high-bandwidth optical-stimulation capacity of the device might facilitate the probing of the spatiotemporal neural codes underlying behaviour. © 2020, The Author(s), under exclusive licence to Springer Nature Limited.

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Shared genetic risk between eating disorder- and substance-use-related phenotypes: Evidence from genome-wide association studies
(2020) Addiction Biology, art. no. e12880, . 

Munn-Chernoff, M.A.^a , Johnson, E.C.^b , Chou, Y.-L.^b , Coleman, J.R.I.^{c d} , Thornton, L.M.^a , Walters, R.K.^{e f} , Yilmaz, Z.^{a g} , Baker, J.H.^a , Hübel, C.^{c h} , Gordon, S.ⁱ , Medland, S.E.ⁱ , Watson, H.J.^{a j k} , Gaspar, H.A.^{c d} , Bryois, J.^h , Hinney, A.^l , Leppä, V.M.^h , Mattheisen, M.^{m n o p} , Ripke, S.^{e f q} , Yao, S.^h , Giusti-Rodríguez, P.^g , Hanscombe, K.B.^r , Adan, R.A.H.^{s t u} , Alfredsson, L.^v , Ando, T.^w , Andreassen, O.A.^x , Berrettini, W.H.^y , Boehm, I.^z , Boni, C.^aa , Boraska Perica, V.^{ab ac} , Buehren, K.^ad , Burghardt, R.^ae , Cassina, M.^af , Cichon, S.^{ag ah ai} , Clementi, M.^af , Cone, R.D.^aj , Courtet, P.^ak , Crow, S.^al , Crowley, J.J.^{g n} , Danner, U.N.^am , Davis, O.S.P.^{an ao} , de Zwaan, M.^ap , Dedoussis, G.^aq , Degortes, D.^ar , DeSocio, J.E.^as , Dick, D.M.^{at au av} , Dikeos, D.^aw , Dina, C.^ax , Dmitrzak-Weglarz, M.^ay , Docampo, E.^{az ba bb} , Duncan, L.E.^bc , Egberts, K.^bd , Ehrlich, S.^z , Escaramís, G.^{az ba bb} , Esko, T.^{be bf} , Estivill, X.^{az ba bb bg} , Farmer, A.^c , Favaro, A.^ar , Fernández-Aranda, F.^{bh bi} , Fichter, M.M.^{bj bk} , Fischer, K.^be , Föcker, M.^bl , Foretova, L.^bm , Forstner, A.J.^{ah bn bo bp} , Forzan, M.^af , Franklin, C.S.^ab , Gallinger, S.^bq , Giegling, I.^br , Giuranna, J.^l , Gonidakis, F.^bs , Gorwood, P.^{bt bu} , Gratacos Mayora, M.^{az ba bb} , Guillaume, S.^ak , Guo, Y.^bv , Hakonarson, H.^{bv bw} , Hatzikotoulas, K.^{ab bx} , Hauser, J.^by , Hebebrand, J.^l , Helder, S.G.^{c bz} , Herms, S.^{ag ah} , Herpertz-Dahlmann, B.^ad , Herzog, W.^ca , Huckins, L.M.^{ab cb} , Hudson, J.I.^cc , Imgart, H.^cd , Inoko, H.^ce , Janout, V.^cf , Jiménez-Murcia, S.^{bh bi} , Julià, A.^cg , Kalsi, G.^c , Kaminská, D.^ch , Karhunen, L.^ci , Karwautz, A.^cj , Kas, M.J.H.^{s ck} , Kennedy, J.L.^{cl cm cn} , Keski-Rahkonen, A.^co , Kiezebrink, K.^cp , Kim, Y.-R.^cq , Klump, K.L.^cr , Knudsen, G.P.S.^cs , La Via, M.C.^a , Le Hellard, S.^{ct cu cv} , Levitan, R.D.^cm , Li, D.^bv , Lilenfeld, L.^cw , Lin, B.D.^s , Lissowska, J.^cx , Luykx, J.^s , Magistretti, P.J.^{cy cz} , Maj, M.^da , Mannik, K.^{be db} , Marsal, S.^cg , Marshall, C.R.^dc , Mattingsdal, M.^dd , McDevitt, S.^{de df} , McGuffin, P.^c , Metspalu, A.^{be dg} , Meulenbelt, I.^dh , Micali, N.^{di dj} , Mitchell, K.^{dk dl} , Monteleone, A.M.^da , Monteleone, P.^dm , Nacmias, B.^dn , Navratilova, M.^bm , Ntalla, I.^aq , O’Toole, J.K.^do , Ophoff, R.A.^{dp dq} , Padyukov, L.^dr , Palotie, A.^{bf ds dt} , Pantel, J.^aa , Papezova, H.^ch , Pinto, D.^cb , Rabionet, R.^{du dv dw} , Raevuori, A.^co , Ramoz, N.^aa , Reichborn-Kjennerud, T.^{cs dx} , Ricca, V.^dy , Ripatti, S.^dz , Ritschel, F.^{z ea} , Roberts, M.^c , Rotondo, A.^eb , Rujescu, D.^br , Rybakowski, F.^ec , Santonastaso, P.^ed , Scherag, A.^ee , Scherer, S.W.^{ef eg} , Schmidt, U.^eh , Schork, N.J.^ei , Schosser, A.^ej , Seitz, J.^ad , Slachtova, L.^ek , Slagboom, P.E.^el , Slof-Op’t Landt, M.C.T.^{em en} , Slopien, A.^eo , Sorbi, S.^{dn ep} , Świątkowska, B.^eq , Szatkiewicz, J.P.^g , Tachmazidou, I.^ab , Tenconi, E.^ar , Tortorella, A.^{er es} , Tozzi, F.^et , Treasure, J.^eh , Tsitsika, A.^eu , Tyszkiewicz-Nwafor, M.^eo , Tziouvas, K.^ev , van Elburg, A.A.^{t ew} , van Furth, E.F.^{em en} , Wagner, G.^cj , Walton, E.^z , Widen, E.^ds , Zeggini, E.^{ab bx} , Zerwas, S.^a , Zipfel, S.^ex , Bergen, A.W.^{ey ez} , Boden, J.M.^fa , Brandt, H.^fb , Crawford, S.^fb , Halmi, K.A.^fc , Horwood, L.J.^fa , Johnson, C.^fd , Kaplan, A.S.^{cl cm cn} , Kaye, W.H.^fe , Mitchell, J.^ff , Olsen, C.M.^fg , Pearson, J.F.^fh , Pedersen, N.L.^h , Strober, M.^{fi fj} , Werge, T.^fk , Whiteman, D.C.^fg , Woodside, D.B.^{cm cn fl fm} , Grove, J.^{m fn fo fp} , Henders, A.K.^fq , Larsen, J.T.^{fn fr fs} , Parker, R.ⁱ , Petersen, L.V.^{fn fr fs} , Jordan, J.^{ft fu} , Kennedy, M.A.^fv , Birgegård, A.^{h n o} , Lichtenstein, P.^h , Norring, C.^{n o} , Landén, M.^{h fw} , Mortensen, P.B.^{fn fr fs} , Polimanti, R.^{fx fy} , McClintick, J.N.^fz , Adkins, A.E.^{at au} , Aliev, F.^{at ga} , Bacanu, S.-A.^{gb gc gd} , Batzler, A.^ge , Bertelsen, S.^gf , Biernacka, J.M.^{gg gh} , Bigdeli, T.B.^gi , Chen, L.-S.^b , Clarke, T.-K.^gj , Degenhardt, F.^gk , Docherty, A.R.^gl , Edwards, A.C.^{gc gd} , Foo, J.C.^gm , Fox, L.^b , Frank, J.^gm , Hack, L.M.^bc , Hartmann, A.M.^br , Hartz, S.M.^b , Heilmann-Heimbach, S.^gk , Hodgkinson, C.^gn , Hoffmann, P.^{bo go gp} , Hottenga, J.-J.^gq , Konte, B.^br , Lahti, J.^gr , Lahti-Pulkkinen, M.^gs , Lai, D.^gt , Ligthart, L.^gq , Loukola, A.^ds , Maher, B.S.^gu , Mbarek, H.^gq , McIntosh, A.M.^gv , McQueen, M.B.^gw , Meyers, J.L.^gx , Milaneschi, Y.^gy , Palviainen, T.^ds , Peterson, R.E.^{gc gd} , Ryu, E.^gh , Saccone, N.L.^hb , Salvatore, J.E.^{at gc gd} , Sanchez-Roige, S.^fe , Schwandt, M.^gz , Sherva, R.^ha , Streit, F.^gm , Strohmaier, J.^gm , Thomas, N.^{at au} , Wang, J.-C.^gf , Webb, B.T.^{gb gc gd} , Wedow, R.^{e f hb hc} , Wetherill, L.^gt , Wills, A.G.^hd , Zhou, H.^{fx fy} , Boardman, J.D.^{he hf} , Chen, D.^f , Choi, D.-S.^hg , Copeland, W.E.^hh , Culverhouse, R.C.^hi , Dahmen, N.^hj , Degenhardt, L.^hk , Domingue, B.W.^hl , Frye, M.A.^gh , Gäbel, W.^hm , Hayward, C.^hn , Ising, M.^ho , Keyes, M.^hp , Kiefer, F.^hq , Koller, G.^hr , Kramer, J.^hs , Kuperman, S.^ht , Lucae, S.^ho , Lynskey, M.T.^ht , Maier, W.^hu , Mann, K.^hq , Männistö, S.^hv , Müller-Myhsok, B.^hw , Murray, A.D.^hx , Nurnberger, J.I.^{gu hy} , Preuss, U.^{hz ia} , Räikkönen, K.^gs , Reynolds, M.D.^ib , Ridinger, M.^ic , Scherbaum, N.^id , Schuckit, M.A.^fe , Soyka, M.^{ie if} , Treutlein, J.^gm , Witt, S.H.^gm , Wodarz, N.^ig , Zill, P.^ih , Adkins, D.E.^{gl ii} , Boomsma, D.I.^gq , Bierut, L.J.^b , Brown, S.A.^{fe ij} , Bucholz, K.K.^b , Costello, E.J.^ik , de Wit, H.^il , Diazgranados, N.^im , Eriksson, J.G.^{in io} , Farrer, L.A.^{hb ip iq ir is} , Foroud, T.M.^gt , Gillespie, N.A.^{gc gd} , Goate, A.M.^gf , Goldman, D.^{gn it} , Grucza, R.A.^b , Hancock, D.B.^iu , Harris, K.M.^{iv iw} , Hesselbrock, V.^ix , Hewitt, J.K.^iy , Hopfer, C.J.^iz , Iacono, W.G.^hq , Johnson, E.O.^{iv ja} , Karpyak, V.M.^gg , Kendler, K.S.^{gc gd} , Kranzler, H.R.^{jb jc} , Krauter, K.^jd , Lind, P.A.ⁱ , McGue, M.^hq , MacKillop, J.^{je jf} , Madden, P.A.F.^b , Maes, H.H.^gc , Magnusson, P.K.E.^h , Nelson, E.C.^b , Nöthen, M.M.^gk , Palmer, A.A.^{fe jg} , Penninx, B.W.J.H.^jh , Porjesz, B.^gx , Rice, J.P.^b , Rietschel, M.^gm , Riley, B.P.^{gb gc gd} , Rose, R.J.^ji , Shen, P.-H.^gn , Silberg, J.^{gc gd} , Stallings, M.C.^iz , Tarter, R.E.^ic , Vanyukov, M.M.^ic , Vrieze, S.^hq , Wall, T.L.^fe , Whitfield, J.B.ⁱ , Zhao, H.^jj , Neale, B.M.^{e f} , Wade, T.D.^jk , Heath, A.C.^b , Montgomery, G.W.^{i fq jl} , Martin, N.G.ⁱ , Sullivan, P.F.^{a g h} , Kaprio, J.^{co ds} , Breen, G.^{c d} , Gelernter, J.^{fx fy jm jn} , Edenberg, H.J.^{fz gt} , Bulik, C.M.^{a h jn} , Agrawal, A.^b

^a Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
^b Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, United States
^c Social, Genetic and Developmental Psychiatry (SGDP) Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom
^d National Institute for Health Research Biomedical Research Centre, King’s College London and South London and Maudsley National Health Service Trust, London, United Kingdom
^e Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
^f Stanley Center for Psychiatric Research, Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA, United States
^g Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
^h Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
ⁱ QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
^j School of Psychology, Curtin University, Perth, WA, Australia
^k School of Paediatrics and Child Health, University of Western Australia, Perth, WA, Australia
^l Department of Child and Adolescent Psychiatry, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
^m Department of Biomedicine, Aarhus University, Aarhus, Denmark
ⁿ Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
^o Center for Psychiatry Research, Stockholm Health Care Services, Stockholm City Council, Stockholm, Sweden
^p Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Germany
^q Department of Psychiatry and Psychotherapy, Charité – Universitätsmedizin, Berlin, Germany
^r Department of Medical and Molecular Genetics, King’s College London, Guy’s Hospital, London, United Kingdom
^s Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, Netherlands
^t Center for Eating Disorders Rintveld, Altrecht Mental Health Institute, Zeist, Netherlands
^u Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
^v Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
^w Department of Behavioral Medicine, National Institute of Mental Health, National Center of Neurology and Psychiatry, Kodaira, Japan
^x Division of Mental Health and Addiction, NORMENT Centre, University of Oslo, Oslo University Hospital, Oslo, Norway
^y Department of Psychiatry, Center for Neurobiology and Behavior, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
^z Division of Psychological and Social Medicine and Developmental Neurosciences, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
^aa Centre of Psychiatry and Neuroscience, INSERM U894, Paris, France
^ab Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, United Kingdom
^ac Department of Medical Biology, School of Medicine, University of Split, Split, Croatia
^ad Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, RWTH Aachen University, Aachen, Germany
^ae Klinikum Frankfurt/Oder, Frankfurt, Germany
^af Clinical Genetics Unit, Department of Woman and Child Health, University of Padova, Italy
^ag Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland
^ah Department of Biomedicine, University of Basel, Basel, Switzerland
^ai Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Germany
^aj Department of Molecular and Integrative Physiology, Life Sciences Institute, University of Michigan, Ann Arbor, MI, United States
^ak Department of Emergency Psychiatry and Post-Acute Care, CHRU Montpellier, University of Montpellier, Montpellier, France
^al Department of Psychiatry, University of Minnesota, Minneapolis, MN, United States
^am Altrecht Eating Disorders Rintveld, Altrecht Mental Health Institute, Zeist, Netherlands
^an MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom
^ao School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom
^ap Department of Psychosomatic Medicine and Psychotherapy, Hannover Medical School, Hannover, Germany
^aq Department of Nutrition and Dietetics, Harokopio University, Athens, Greece
^ar Department of Neurosciences, University of Padova, Padova, Italy
^as College of Nursing, Seattle University, Seattle, WA, United States
^at Department of Psychology, Virginia Commonwealth University, Richmond, VA, United States
^au College Behavioral and Emotional Health Institute, Virginia Commonwealth University, Richmond, VA, United States
^av Department of Human & Molecular Genetics, Virginia Commonwealth University, Richmond, VA, United States
^aw Department of Psychiatry, Athens University Medical School, Athens University, Athens, Greece
^ax l’institut du thorax, INSERM, CNRS, Univ Nantes, Nantes, France
^ay Department of Psychiatric Genetics, Poznan University of Medical Sciences, Poznan, Poland
^az Barcelona Institute of Science and Technology, Barcelona, Spain
^ba Universitat Pompeu Fabra, Barcelona, Spain
^bb Centro de Investigación Biomédica en Red en Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain
^bc Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, United States
^bd Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Centre for Mental Health, University Hospital of Würzburg, Würzburg, Germany
^be Estonian Genome Center, University of Tartu, Tartu, Estonia
^bf Program in Medical and Population Genetics, Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA, United States
^bg Genomics and Disease, Bioinformatics and Genomics Programme, Centre for Genomic Regulation, Barcelona, Spain
^bh Department of Psychiatry, University Hospital of Bellvitge –IDIBELL and CIBERobn, Barcelona, Spain
^bi Department of Clinical Sciences, School of Medicine, University of Barcelona, Barcelona, Spain
^bj Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University, Munich, Germany
^bk Schön Klinik Roseneck affiliated with the Medical Faculty of the University of Munich, Munich, Germany
^bl Department of Child and Adolescent Psychiatry, University of Münster, Münster, Germany
^bm Department of Cancer, Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic
^bn Centre for Human Genetics, University of Marburg, Marburg, Germany
^bo Institute of Human Genetics, School of Medicine & University Hospital Bonn, University of Bonn, Bonn, Germany
^bp Department of Psychiatry (UPK), University of Basel, Basel, Switzerland
^bq Department of Surgery, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
^br Department of Psychiatry, Psychotherapy and Psychosomatics, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany
^bs 1st Psychiatric Department, National and Kapodistrian University of Athens, Medical School, Eginition Hospital, Athens, Greece
^bt Institute of Psychiatry and Neuroscience of Paris, INSERM U1266, Paris, France
^bu CMME (GHU Paris Psychiatrie et Neurosciences), Paris Descartes University, Paris, France
^bv Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
^bw Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
^bx Helmholtz Zentrum München – German Research Centre for Environmental Health, Institute of Translational Genomics, Neuherberg, Germany
^by Department of Adult Psychiatry, Poznan University of Medical Sciences, Poznan, Poland
^bz Zorg op Orde, Delft, Netherlands
^ca Department of General Internal Medicine and Psychosomatics, Heidelberg University Hospital, Heidelberg University, Heidelberg, Germany
^cb Department of Psychiatry, and Genetics and Genomics Sciences, Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^cc Biological Psychiatry Laboratory, McLean Hospital/Harvard Medical School, Boston, MA, United States
^cd Eating Disorders Unit, Parklandklinik, Bad Wildungen, Germany
^ce Department of Molecular Life Science, Division of Basic Medical Science and Molecular Medicine, School of Medicine, Tokai University, Isehara, Japan
^cf Faculty of Health Sciences, Palacky University, Olomouc, Czech Republic
^cg Rheumatology Research Group, Vall d’Hebron Research Institute, Barcelona, Spain
^ch Department of Psychiatry, First Faculty of Medicine, Charles University, Prague, Czech Republic
^ci Department of Clinical Nutrition, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
^cj Eating Disorders Unit, Department of Child and Adolescent Psychiatry, Medical University of Vienna, Vienna, Austria
^ck Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen, Netherlands
^cl Centre for Addiction and Mental Health, Toronto, ON, Canada
^cm Institute of Medical Science, University of Toronto, Toronto, ON, Canada
^cn Department of Psychiatry, University of Toronto, Toronto, ON, Canada
^co Department of Public Health, University of Helsinki, Helsinki, Finland
^cp Institute of Applied Health Sciences, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, United Kingdom
^cq Department of Psychiatry, Seoul Paik Hospital, Inje University, Seoul, South Korea
^cr Department of Psychology, Michigan State University, East Lansing, MI, United States
^cs Department of Mental Disorders, Norwegian Institute of Public Health, Oslo, Norway
^ct Department of Clinical Science, Norwegian Centre for Mental Disorders Research (NORMENT), University of Bergen, Bergen, Norway
^cu Dr. Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway
^cv Department of Clinical Medicine, Laboratory Building, Haukeland University Hospital, Bergen, Norway
^cw The Chicago School of Professional Psychology, Washington DC Campus, Washington, District of Columbia, United States
^cx Department of Cancer Epidemiology and Prevention, M Skłodowska-Curie Cancer Center – Oncology Center, Warsaw, Poland
^cy BESE Division, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia
^cz Department of Psychiatry, University of Lausanne-University Hospital of Lausanne (UNIL-CHUV), Lausanne, Switzerland
^da Department of Psychiatry, University of Campania “Luigi Vanvitelli”, Naples, Italy
^db Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
^dc Department of Paediatric Laboratory Medicine, Division of Genome Diagnostics, The Hospital for Sick Children, Toronto, ON, Canada
^dd NORMENT KG Jebsen Centre, Division of Mental Health and Addiction, University of Oslo, Oslo University Hospital, Oslo, Norway
^de Department of Psychiatry, University College Cork, Cork, Ireland
^df Eist Linn Adolescent Unit, Bessborough, Health Service Executive South, Cork, Ireland
^dg Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia
^dh Molecular Epidemiology Section (Department of Biomedical Datasciences), Leiden University Medical Centre, Leiden, Netherlands
^di Department of Psychiatry, Faculty of Medicine, University of Geneva, Geneva, Switzerland
^dj Division of Child and Adolescent Psychiatry, Geneva University Hospital, Geneva, Switzerland
^dk National Center for PTSD, VA Boston Healthcare System, Boston, MA, United States
^dl Department of Psychiatry, Boston University School of Medicine, Boston, MA, United States
^dm Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Salerno, Italy
^dn Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy
^do Kartini Clinic, Portland, OR, United States
^dp Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA, United States
^dq Department of Psychiatry, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands
^dr Department of Medicine, Center for Molecular Medicine, Division of Rheumatology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
^ds Institute for Molecular Medicine FIMM, HiLIFE, University of Helsinki, Helsinki, Finland
^dt Center for Human Genome Research, Massachusetts General Hospital, Boston, MA, United States
^du Saint Joan de Déu Research Institute, Saint Joan de Déu Barcelona Children’s Hospital, Barcelona, Spain
^dv Institute of Biomedicine (IBUB), University of Barcelona, Barcelona, Spain
^dw Department of Genetics, Microbiology and Statistics, University of Barcelona, Barcelona, Spain
^dx Institute of Clinical Medicine, University of Oslo, Oslo, Norway
^dy Department of Health Science, University of Florence, Florence, Italy
^dz Department of Biometry, University of Helsinki, Helsinki, Finland
^ea Department of Child and Adolescent Psychiatry, Faculty of Medicine, Eating Disorders Research and Treatment Center, Technische Universität Dresden, Dresden, Germany
^eb Department of Psychiatry, Neurobiology, Pharmacology, and Biotechnologies, University of Pisa, Pisa, Italy
^ec Department of Psychiatry, Poznan University of Medical Sciences, Poznan, Poland
^ed Department of Neurosciences, Padua Neuroscience Center, University of Padova, Padova, Italy
^ee Institute of Medical Statistics, Computer and Data Sciences, Jena University Hospital, Jena, Germany
^ef Department of Genetics and Genomic Biology, The Hospital for Sick Children, Toronto, ON, Canada
^eg McLaughlin Centre, University of Toronto, Toronto, ON, Canada
^eh Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom
^ei J. Craig Venter Institute (JCVI), La Jolla, CA, United States
^ej Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria
^ek Department of Pediatrics and Center of Applied Genomics, First Faculty of Medicine, Charles University, Prague, Czech Republic
^el Molecular Epidemiology Section (Department of Medical Statistics), Leiden University Medical Centre, Leiden, Netherlands
^em Center for Eating Disorders Ursula, Rivierduinen, Leiden, Netherlands
^en Department of Psychiatry, Leiden University Medical Centre, Leiden, Netherlands
^eo Department of Child and Adolescent Psychiatry, Poznan University of Medical Sciences, Poznan, Poland
^ep IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy
^eq Department of Environmental Epidemiology, Nofer Institute of Occupational Medicine, Lodz, Poland
^er Department of Psychiatry, University of Naples SUN, Naples, Italy
^es Department of Psychiatry, University of Perugia, Perugia, Italy
^et Brain Sciences Department, Stremble Ventures, Limassol, Cyprus
^eu Adolescent Health Unit, Second Department of Pediatrics, “P. & A. Kyriakou” Children’s Hospital, University of Athens, Athens, Greece
^ev Pediatric Intensive Care Unit, “P. & A. Kyriakou” Children’s Hospital, University of Athens, Athens, Greece
^ew Faculty of Social and Behavioral Sciences, Utrecht University, Utrecht, Netherlands
^ex Department of Internal Medicine VI, Psychosomatic Medicine and Psychotherapy, University Medical Hospital Tuebingen, Tuebingen, Germany
^ey BioRealm, LLC, Walnut, CA, United States
^ez Oregon Research Institute, Eugene, OR, United States
^fa Christchurch Health and Development Study, University of Otago, Christchurch, New Zealand
^fb The Center for Eating Disorders at Sheppard Pratt, Baltimore, MD, United States
^fc Department of Psychiatry, Weill Cornell Medical College, New York, NY, United States
^fd Eating Recovery Center, Denver, CO, United States
^fe Department of Psychiatry, University of California San Diego, La Jolla, CA, United States
^ff Department of Psychiatry and Behavioral Science, University of North Dakota School of Medicine and Health Sciences, Fargo, ND, United States
^fg Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
^fh Biostatistics and Computational Biology Unit, University of Otago, Christchurch, New Zealand
^fi Department of Psychiatry and Biobehavioral Science, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, California, Los Angeles, United States
^fj David Geffen School of Medicine, University of California Los Angeles, California, Los Angeles, United States
^fk Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
^fl Centre for Mental Health, University Health Network, Toronto, ON, Canada
^fm Program for Eating Disorders, University Health Network, Toronto, ON, Canada
^fn The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus, Denmark
^fo Centre for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark
^fp Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark
^fq Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia
^fr National Centre for Register-Based Research, Aarhus BSS, Aarhus University, Aarhus, Denmark
^fs Centre for Integrated Register-based Research (CIRRAU), Aarhus University, Aarhus, Denmark
^ft Department of Psychological Medicine, University of Otago, Christchurch, New Zealand
^fu Canterbury District Health Board, Christchurch, New Zealand
^fv Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand
^fw Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
^fx Department of Psychiatry, Division of Human Genetics, Yale School of Medicine, New Haven, CT, United States
^fy Veterans Affairs Connecticut Healthcare System, West Haven, CT, United States
^fz Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, United States
^ga Faculty of Business, Karabuk University, Karabuk, Turkey
^gb Virginia Commonwealth University Alcohol Research Center, Virginia Commonwealth University, Richmond, VA, United States
^gc Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, United States
^gd Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, United States
^ge Psychiatric Genomics and Pharmacogenomics Program, Mayo Clinic, Rochester, MN, United States
^gf Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^gg Department of Health Sciences Research, Mayo Clinic, Rochester, MN, United States
^gh Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, United States
^gi Department of Psychiatry and Behavioral Sciences, State University of New York Downstate Medical Center, Brooklyn, NY, United States
^gj Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom
^gk Institute of Human Genetics, University of Bonn School of Medicine & University Hospital Bonn, Bonn, Germany
^gl Department of Psychiatry, University of Utah, Salt Lake City, UT, United States
^gm Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
^gn Laboratory of Neurogenetics, NIH/NIAAA, Bethesda, MD, United States
^go Human Genomics Research Group, Department of Biomedicine, University of Basel, Basel, Switzerland
^gp Institute of Medical Genetics and Pathology, University Hospital Basel, University Hospital Basel, Basel, Switzerland
^gq Department of Biological Psychology, Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
^gr Turku Institute for Advanced Studies, University of Turku, Turku, Finland
^gs Department of Psychology and Logopedics, University of Helsinki, Helsinki, Finland
^gt Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
^gu Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States
^gv Division of Psychiatry, Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom
^gw Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, United States
^gx Department of Psychiatry and Behavioral Sciences, Henri Begleiter Neurodynamics Laboratory, SUNY Downstate Medical Center, Brooklyn, NY, United States
^gy Department of Psychiatry, Amsterdam Public Health Research Institute, VU University Medical Center/GGz inGeest, Amsterdam, Netherlands
^gz Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, United States
^ha Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Cambridge, MA, United States
^hb Department of Sociology, Harvard University, Cambridge, MA, United States
^hc Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, United States
^hd Institute of Behavioral Science, University of Colorado, Boulder, CO, United States
^he Department of Sociology, University of Colorado, Boulder, CO, United States
^hf Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, United States
^hg Department of Psychiatry, University of Vermont Medical Center, Burlington, VT, United States
^hh Department of Medicine, Division of Biostatistics, Washington University School of Medicine, Saint Louis, MO, United States
^hi Department of Psychiatry, University of Mainz, Mainz, Germany
^hj National Drug and Alcohol Research Centre, University of New South Wales, Sydney, NSW, Australia
^hk Stanford University Graduate School of Education, Stanford University, Stanford, CA, United States
^hl Department of Psychiatry and Psychotherapy, University of Düsseldorf, Duesseldorf, Germany
^hm MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
^hn Max-Planck-Institute of Psychiatry, Munich, Germany
^ho Department of Psychology, University of Minnesota, Minneapolis, MN, United States
^hp Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
^hq Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Munich, Germany
^hr Department of Psychiatry, University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, IA, United States
^hs Addictions Department, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, United Kingdom
^ht Department of Psychiatry, University of Bonn, Bonn, Germany
^hu Department of Public Health Solutions, National Institute for Health and Welfare, Helsinki, Finland
^hv Department of Statistical Genetics, Max-Planck-Institute of Psychiatry, München, Germany
^hw Aberdeen Biomedical Imaging Centre, School of Medicine, Medical Sciences & Nutrition, University of Aberdeen, Foresterhill, Aberdeen, United Kingdom
^hx Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, United States
^hy Department of Psychiatry, Psychotherapy and Psychosomatics, Martin-Luther-University Halle-Wittenberg, Herborn, Germany
^hz Department of Psychiatry and Psychotherapy, Vitos Hospital Herborn, Herborn, Germany
^ia School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, United States
^ib Department of Psychiatry and Psychotherapy, University of Regensburg Psychiatric Health Care Aargau, Regensburg, Germany
^ic Department of Psychiatry and Psychotherapy and Department of Addictive Behaviour and Addiction Medicine, Medical Faculty, LVR-Hospital Essen, University of Duisburg-Essen, Essen, Germany
^id Medical Park Chiemseeblick in Bernau-Felden, Ludwig-Maximilians-University, Bernau am Chiemsee, Germany
^ie Psychiatric Hospital, Ludwig-Maximilians-University, Bernau am Chiemsee, Germany
^if Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany
^ig Department of Psychiatry, Psychiatric Hospital, Ludwig-Maximilians-University, Munich, Germany
^ih Department of Sociology, University of Utah, Salt Lake City, UT, United States
ⁱⁱ Department of Psychology, University of California San Diego, San Diego, CA, United States
^ij Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, United States
^ik Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, United States
^il NIAAA Intramural Research Program, Bethesda, MD, United States
^im Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland
ⁱⁿ National Institute for Health and Welfare, Helsinki, Finland
^io Department of Neurology, Boston University School of Medicine, Boston, MA, United States
^ip Department of Ophthalmology, Boston University School of Medicine, Boston, MA, United States
^iq Department of Epidemiology, School of Public Health, Boston University, Boston, MA, United States
^ir Department of Biostatistics, School of Public Health, Boston University, Boston, MA, United States
^is Office of the Clinical Director, NIH/NIAAA, Besthesda, MD, United States
^it Center for Omics Discovery and Epidemiology, Behavioral Health Research Division, RTI International, Research Triangle Park, NC, United States
^iu Department of Sociology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
^iv Carolina Population Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
^iw Department of Psychiatry, University of Connecticut School of Medicine, Farmington, CT, United States
^ix Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO, United States
^iy Department of Psychiatry, University of Colorado Denver, Aurora, CO, United States
^iz Fellow Program, RTI International, Research Triangle Park, NC, United States
^ja Center for Studies of Addiction, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
^jb VISN 4 MIRECC, Crescenz VAMC, Philadelphia, PA, United States
^jc Department of Molecular, Cellular, and Developmental Biology, University of Colorado Boulder, Boulder, CO, United States
^jd Peter Boris Centre for Addictions Research, McMaster University/St. Joseph’s Healthcare Hamilton, Hamilton, ON, Canada
^je Michael G. DeGroote Centre for Medicinal Cannabis Research, McMaster University/St. Joseph’s Healthcare Hamilton, Hamilton, ON, Canada
^jf Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, United States
^jg Department of Psychiatry, Amsterdam UMC, VU University and GGZinGeest, Amsterdam, Netherlands
^jh Department of Psychological & Brain Sciences, Indiana University Bloomington, Bloomington, IN, United States
^ji Department of Biostatistics, Yale School of Public Health, Yale University, New Haven, CT, United States
^jj School of Psychology, Flinders University, Adelaide, SA, Australia
^jk Queensland Brain Institute, University of Queensland, Brisbane, QLD, Australia
^jl Department of Genetics, Yale School of Medicine, New Haven, CT, United States
^jm Department of Neuroscience, Yale School of Medicine, New Haven, CT, United States
^jn Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States

Abstract
Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [rg], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from ~2400 to ~537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (rg = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (rg = 0.23; q &lt; 0.0001), and cannabis initiation and AN with binge eating (rg = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (rgs = −0.19 to −0.23; qs &lt; 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-specific relationships among these behaviors. © 2020 Society for the Study of Addiction

Author Keywords
eating disorders;  genetic correlation;  substance use

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Density and Dichotomous Family History Measures of Alcohol Use Disorder as Predictors of Behavioral and Neural Phenotypes: A Comparative Study Across Gender and Race/Ethnicity
(2020) Alcoholism: Clinical and Experimental Research, . 

Pandey, G.^a , Seay, M.J.^b , Meyers, J.L.^a , Chorlian, D.B.^a , Pandey, A.K.^a , Kamarajan, C.^a , Ehrenberg, M.^a , Pitti, D.^a , Kinreich, S.^a , Subbie-Saenz de Viteri, S.^a , Acion, L.^c , Anokhin, A.^d , Bauer, L.^e , Chan, G.^e , Edenberg, H.^f , Hesselbrock, V.^e , Kuperman, S.^g , McCutcheon, V.V.^d , Bucholz, K.K.^d , Schuckit, M.^h , Porjesz, B.^a

^a Department of Psychiatry and Behavioral Sciences, Downstate Medical Center, State University of New York, Brooklyn, NY, United States
^b Department of Psychology, University of California, Los Angeles, CA, United States
^c Iowa Consortium for Substance Abuse Research and Evaluation, University of Iowa, Iowa City, IA, United States
^d Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^e Department of Psychiatry, University of Connecticut School of Medicine, Farmington, CT, United States
^f Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, United States
^g Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, United States
^h Department of Psychiatry, University of California San Diego, La Jolla, CA, United States

Abstract
Background: Family history (FH) is an important risk factor for the development of alcohol use disorder (AUD). A variety of dichotomous and density measures of FH have been used to predict alcohol outcomes; yet, a systematic comparison of these FH measures is lacking. We compared 4 density and 4 commonly used dichotomous FH measures and examined variations by gender and race/ethnicity in their associations with age of onset of regular drinking, parietal P3 amplitude to visual target, and likelihood of developing AUD. Methods: Data from the Collaborative Study on the Genetics of Alcoholism (COGA) were utilized to compute the density and dichotomous measures. Only subjects and their family members with DSM-5 AUD diagnostic information obtained through direct interviews using the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) were included in the study. Area under receiver operating characteristic curves were used to compare the diagnostic accuracy of FH measures at classifying DSM-5 AUD diagnosis. Logistic and linear regression models were used to examine associations of FH measures with alcohol outcomes. Results: Density measures had greater diagnostic accuracy at classifying AUD diagnosis, whereas dichotomous measures presented diagnostic accuracy closer to random chance. Both dichotomous and density measures were significantly associated with likelihood of AUD, early onset of regular drinking, and low parietal P3 amplitude, but density measures presented consistently more robust associations. Further, variations in these associations were observed such that among males (vs. females) and Whites (vs. Blacks), associations of alcohol outcomes with density (vs. dichotomous) measures were greater in magnitude. Conclusions: Density (vs. dichotomous) measures seem to present more robust associations with alcohol outcomes. However, associations of dichotomous and density FH measures with different alcohol outcomes (behavioral vs. neural) varied across gender and race/ethnicity. These findings have great applicability for alcohol research examining FH of AUD. © 2020 by the Research Society on Alcoholism

Author Keywords
Alcohol Use Disorder;  Endophenotype;  Family History;  P300;  Risk and Development

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Neural stem cell therapy of foetal onset hydrocephalus using the HTx rat as experimental model
(2020) Cell and Tissue Research, . 

Henzi, R.^{a b} , Vío, K.^a , Jara, C.^a , Johanson, C.E.^c , McAllister, J.P.^d , Rodríguez, E.M.^a , Guerra, M.^a

^a Instituto de Anatomía, Histología y Patología, Facultad de Medicina, Universidad Austral de Chile, Valdivia, Chile
^b Centro de Investigaciones Biomédicas, Facultad de Medicina, Universidad de los Andes, Santiago, Chile
^c Department of Neurosurgery, Alpert Medical School at Brown University, Providence, RI, United States
^d Department of Neurosurgery Division of Pediatric Neurosurgery, Washington University and the Saint Louis Children’s Hospital, St. Louis, MO, United States

Abstract
Foetal onset hydrocephalus is a disease starting early in embryonic life; in many cases it results from a cell junction pathology of neural stem (NSC) and neural progenitor (NPC) cells forming the ventricular zone (VZ) and sub-ventricular zone (SVZ) of the developing brain. This pathology results in disassembling of VZ and loss of NSC/NPC, a phenomenon known as VZ disruption. At the cerebral aqueduct, VZ disruption triggers hydrocephalus while in the telencephalon, it results in abnormal neurogenesis. This may explain why derivative surgery does not cure hydrocephalus. NSC grafting appears as a therapeutic opportunity. The present investigation was designed to find out whether this is a likely possibility. HTx rats develop hereditary hydrocephalus; 30–40% of newborns are hydrocephalic (hyHTx) while their littermates are not (nHTx). NSC/NPC from the VZ/SVZ of nHTx rats were cultured into neurospheres that were then grafted into a lateral ventricle of 1-, 2- or 7-day-old hyHTx. Once in the cerebrospinal fluid, neurospheres disassembled and the freed NSC homed at the areas of VZ disruption. A population of homed cells generated new multiciliated ependyma at the sites where the ependyma was missing due to the inherited pathology. Another population of NSC homed at the disrupted VZ differentiated into βIII-tubulin+ spherical cells likely corresponding to neuroblasts that progressed into the parenchyma. The final fate of these cells could not be established due to the protocol used to label the grafted cells. The functional outcomes of NSC grafting in hydrocephalus remain open. The present study establishes an experimental paradigm of NSC/NPC therapy of foetal onset hydrocephalus, at the etiologic level that needs to be further explored with more analytical methodologies. © 2020, Springer-Verlag GmbH Germany, part of Springer Nature.

Author Keywords
Congenital hydrocephalus;  Ependymogenesis;  Homing;  Neural stem cells;  Neurospheres;  Repair;  Transplantation;  Ventricular zone disruption

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Complex interactions underlie racial disparity in the risk of developing Alzheimer’s disease dementia
(2020) Alzheimer’s and Dementia, . 

Xiong, C.^{a b} , Luo, J.^{a c d} , Coble, D.^{a b} , Agboola, F.^{a b} , Kukull, W.^{e f} , Morris, J.C.^{b g h}

^a Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States
^b Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
^c Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, MO, United States
^d Siteman Cancer Center Biostatistics Core, Washington University School of Medicine, St. Louis, MO, United States
^e Department of Epidemiology, University of Washington, Seattle, WA, United States
^f National Alzheimer’s Coordinating Center, University of Washington, Seattle, WA, United States
^g Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^h Departments of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Introduction: We aim to determine racial disparities and their modifying factors in risk for Alzheimer’s disease (AD) dementia among cognitively normal individuals 65 years or older. Methods: Longitudinal data from the National Alzheimer’s Coordinating Center Uniform Data Set on 1229 African Americans (AAs) and 6679 whites were analyzed for the risk of AD using competing risk models with death as a competing event. Results: Major AD risk factors modified racial differences which, when statistically significant, occurred only with older age among APOE ε4 negative individuals, but also with younger age among APOE ε4 positive individuals. The racial differences favored AAs among individuals with body mass index (BMI) < 30, but whites among individuals with a high BMI (≥ 30), and were additionally modified by sex, education, hypertension, and smoking status. Conclusions: The presence, direction, and relative magnitude of racial disparity for AD represent an interactive function of major AD and cerebrovascular risk factors. © 2020 the Alzheimer’s Association

Author Keywords
competing risk survival model;  interactions;  racial disparity;  risk of Alzheimer’s disease

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Skeletal Muscle Regeneration in Advanced Diabetic Peripheral Neuropathy
(2020) Foot and Ankle International, . 

Bohnert, K.L.^a , Hastings, M.K.^{a b} , Sinacore, D.R.^c , Johnson, J.E.^b , Klein, S.E.^b , McCormick, J.J.^b , Gontarz, P.^d , Meyer, G.A.^{a b e}

^a Program in Physical Therapy, Washington University, St. Louis, MO, United States
^b Department of Orthopaedic Surgery, Washington University, St. Louis, MO, United States
^c Department of Physical Therapy, High Point University, High Point, NC, United States
^d Department of Developmental Biology, Washington University, St. Louis, MO, United States
^e Departments of Neurology and Biomedical Engineering, Washington University, St. Louis, MO, United States

Abstract
Background: Decreased lean muscle mass in the lower extremity in diabetic peripheral neuropathy (DPN) is thought to contribute to altered joint loading, immobility, and disability. However, the mechanism behind this loss is unknown and could derive from a reduction in size of myofibers (atrophy), destruction of myofibers (degeneration), or both. Degenerative changes require participation of muscle stem (satellite) cells to regenerate lost myofibers and restore lean mass. Determining the degenerative state and residual regenerative capacity of DPN muscle will inform the utility of regeneration-targeted therapeutic strategies. Methods: Biopsies were acquired from 2 muscles in 12 individuals with and without diabetic neuropathy undergoing below-knee amputation surgery. Biopsies were subdivided for histological analysis, transcriptional profiling, and satellite cell isolation and culture. Results: Histological analysis revealed evidence of ongoing degeneration and regeneration in DPN muscles. Transcriptional profiling supports these findings, indicating significant upregulation of regeneration-related pathways. However, regeneration appeared to be limited in samples exhibiting the most severe structural pathology as only extremely small, immature regenerated myofibers were found. Immunostaining for satellite cells revealed a significant decrease in their relative frequency only in the subset with severe pathology. Similarly, a reduction in fusion in cultured satellite cells in this group suggests impairment in regenerative capacity in severe DPN pathology. Conclusion: DPN muscle exhibited features of degeneration with attempted regeneration. In the most severely pathological muscle samples, regeneration appeared to be stymied and our data suggest that this may be partly due to intrinsic dysfunction of the satellite cell pool in addition to extrinsic structural pathology (eg, nerve damage). Clinical Relevance: Restoration of DPN muscle function for improved mobility and physical activity is a goal of surgical and rehabilitation clinicians. Identifying myofiber degeneration and compromised regeneration as contributors to dysfunction suggests that adjuvant cell-based therapies may improve clinical outcomes. © The Author(s) 2020.

Author Keywords
degeneration;  diabetes;  satellite cells;  transcriptional analysis

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Concern of photosensitive seizures evoked by 3D video displays or virtual reality headsets in children: Current perspective
(2020) Eye and Brain, 12, pp. 45-48. 

Tychsen, L.^{a b c} , Thio, L.L.^{b c d}

^a Department of Ophthalmology and Visual Sciences, St. Louis Children’s Hospital, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
^b Department of Pediatrics, St. Louis Children’s Hospital, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
^c Department of Neuroscience, St. Louis Children’s Hospital, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
^d Department of Neurology, St. Louis Children’s Hospital, Washington University in St. Louis School of Medicine, St. Louis, MO, United States

Abstract
This review assesses the risk of a photic-induced seizure in a child during viewing of 3D (binocular 3 dimensional, stereoscopic) movies or games, either on standard video displays or when wearing a virtual reality (VR) headset. Studies published by pediatric epilepsy experts emphasize the low risk of 3D viewing even for children with known photosensitive epilepsy (PSE). The low incidence of PSE is noteworthy because the number of hours devoted to 2D or 3D screen viewing and/or VR headset use by children worldwide has increased markedly over the last decade. The medical literature does not support the notion that VR headset use poses a risk for PSE. © 2020 Tychsen and Thio.

Author Keywords
Children;  Epilepsy;  Stereoscopic;  Virtual reality

Document Type: Review
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Using practice effects for targeted trials or sub-group analysis in Alzheimer’s disease: How practice effects predict change over time
(2020) PLoS ONE, 15 (2), art. no. e0228064, . 

Wang, G.^a , Kennedy, R.E.^b , Goldberg, T.E.^c , Fowler, M.E.^d , Cutter, G.R.^e , Schneider, L.S.^f

^a Division of Biostatistics, Washington University in St. Louis, St. Louis, MO, United States
^b Comprehensive Center of Aging Health, University of Alabama at Birmingham, Birmingham, AL, United States
^c Department of Psychiatry, Columbia University, New York, NY, United States
^d Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, United States
^e Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, United States
^f Department of Psychiatry and The Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States

Abstract
Objective To describe the presence of practice effects in persons with Alzheimer disease (AD) or mild cognitive impairment (MCI) and to evaluate how practice effects affect cognitive progression and the outcome of clinical trials. Methods Using data from a meta-database consisting of 18 studies including participants from the Alzheimer disease Cooperative Study (ADCS) and the Alzheimer Disease Neuroimaging Initiative (ADNI) with ADAS-Cog11 as the primary outcome, we defined practice effects based on the improvement in the first two ADAS-Cog11 scores and then estimated the presence of practice effects and compared the cognitive progression between participants with and without practice effects. The robustness of practice effects was investigated using CDR SB, an outcome independent the definition itself. Furthermore, we evaluated how practice effects can affect sample size estimation. Results The overall percent of practice effects for AD participants was 39.0% and 53.3% for MCI participants. For AD studies, the mean change from baseline to 2 years was 12.8 points for the non-practice effects group vs 7.4 for the practice effects group; whereas for MCI studies, it was 4.1 for non-practice effects group vs 0.2 for the practice effects group. AD participants without practice effects progressed 0.9 points faster than those with practice effects over a period of 2 years in CDR-SB; whereas for MCI participants, the difference is 0.7 points. The sample sizes can be different by over 35% when estimated based on participants with/without practice effects. Conclusion Practice effects were prevalent and robust in persons with AD or MCI and affected the cognitive progression and sample size estimation. Planning of future AD or MCI clinical trials should account for practice effects to avoid underpower or considers target trials or stratification analysis based on practice effects. © 2020 Wang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Document Type: Article
Publication Stage: Final
Source: Scopus