Genome-wide association study identifies 30 Loci Associated with Bipolar Disorder

This paper is dedicated to the memory of Psychiatric Genomics Consortium (PGC) founding member and Bipolar disorder working group co-chair Pamela Sklar. We thank the participants who donated their time, experiences and DNA to this research, and to the clinical and scientific teams that worked with them. We are deeply indebted to the investigators who comprise the PGC. The views expressed are those of the authors and not necessarily those of any funding or regulatory body. Analyses were carried out on the NL Genetic Cluster Computer (http://www.geneticcluster.org ) hosted by SURFsara, and the Mount Sinai high performance computing cluster (http://hpc.mssm.edu).Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P<1x10-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (GWS, p < 5x10-8) in the discovery GWAS were not GWS in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis 30 loci were GWS including 20 novel loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene-sets including regulation of insulin secretion and endocannabinoid signaling. BDI is strongly genetically correlated with schizophrenia, driven by psychosis, whereas BDII is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential new biological mechanisms for BD.This work was funded in part by the Brain and Behavior Research Foundation, Stanley Medical Research Institute, University of Michigan, Pritzker Neuropsychiatric Disorders Research Fund L.L.C., Marriot Foundation and the Mayo Clinic Center for Individualized Medicine, the NIMH Intramural Research Program; Canadian Institutes of Health Research; the UK Maudsley NHS Foundation Trust, NIHR, NRS, MRC, Wellcome Trust; European Research Council; German Ministry for Education and Research, German Research Foundation IZKF of Münster, Deutsche Forschungsgemeinschaft, ImmunoSensation, the Dr. Lisa-Oehler Foundation, University of Bonn; the Swiss National Science Foundation; French Foundation FondaMental and ANR; Spanish Ministerio de Economía, CIBERSAM, Industria y Competitividad, European Regional Development Fund (ERDF), Generalitat de Catalunya, EU Horizon 2020 Research and Innovation Programme; BBMRI-NL; South-East Norway Regional Health Authority and Mrs. Throne-Holst; Swedish Research Council, Stockholm County Council, Söderström Foundation; Lundbeck Foundation, Aarhus University; Australia NHMRC, NSW Ministry of Health, Janette M O'Neil and Betty C Lynch

Improving Genetic Prediction by Leveraging Genetic Correlations Among Human Diseases and Traits

Genomic prediction has the potential to contribute to precision medicine. However, to date, the utility of such predictors is limited due to low accuracy for most traits. Here theory and simulation study are used to demonstrate that widespread pleiotropy among phenotypes can be utilised to improve genomic risk prediction. We show how a genetic predictor can be created as a weighted index that combines published genome-wide association study (GWAS) summary statistics across many different traits. We apply this framework to predict risk of schizophrenia and bipolar disorder in the Psychiatric Genomics consortium data, finding substantial heterogeneity in prediction accuracy increases across cohorts. For six additional phenotypes in the UK Biobank data, we find increases in prediction accuracy ranging from 0.7 for height to 47 for type 2 diabetes, when using a multi-trait predictor that combines published summary statistics from multiple traits, as compared to a predictor based only on one trait. © 2018 The Author(s)

Energy dependence of ϕ meson production at forward rapidity in pp collisions at the LHC

The production of $\phi$ mesons has been studied in pp collisions at LHC energies with the ALICE detector via the dimuon decay channel in the rapidity region $2.5< y < 4$. Measurements of the differential cross section $\mathrm{d}^2\sigma /\mathrm{d}y \mathrm{d}p_{\mathrm {T}}$ are presented as a function of the transverse momentum ($p_{\mathrm {T}}$) at the center-of-mass energies $\sqrt{s}=5.02$, 8 and 13 TeV and compared with the ALICE results at midrapidity. The differential cross sections at $\sqrt{s}=5.02$ and 13 TeV are also studied in several rapidity intervals as a function of $p_{\mathrm {T}}$, and as a function of rapidity in three $p_{\mathrm {T}}$ intervals. A hardening of the $p_{\mathrm {T}}$-differential cross section with the collision energy is observed, while, for a given energy, $p_{\mathrm {T}}$ spectra soften with increasing rapidity and, conversely, rapidity distributions get slightly narrower at increasing $p_{\mathrm {T}}$. The new results, complementing the published measurements at $\sqrt{s}=2.76$ and 7 TeV, allow one to establish the energy dependence of $\phi$ meson production and to compare the measured cross sections with phenomenological models. None of the considered models manages to describe the evolution of the cross section with $p_{\mathrm {T}}$ and rapidity at all the energies.publishedVersio

Multiplicity dependence of inclusive J/psi production at midrapidity in pp collisions at root s=13 TeV

Measurements of the inclusive J/psi yield as a function of charged-particle pseudorapidity density dN(ch)/d eta in pp collisions at root s = 13 TeV with ALICE at the LHC are reported. The J/psi meson yield is measured at midrapidity (vertical bar y vertical bar <0.9) in the dielectron channel, for events selected based on the charged-particle multiplicity at midrapidity (vertical bar eta vertical bar <1) and at forward rapidity (-3.7 <eta <-1.7 and 2.8 <eta <5.1); both observables are normalized to their corresponding averages in minimum bias events. The increase of the normalized J/psi yield with normalized dN(ch)/d eta is significantly stronger than linear and dependent on the transverse momentum. The data are compared to theoretical predictions, which describe the observed trends well, albeit not always quantitatively. (C) 2020 European Organization for Nuclear Research. Published by Elsevier B.V.Peer reviewe

ϒ production in p–Pb collisions at √sNN=8.16 TeV

ϒ production in p–Pb interactions is studied at the centre-of-mass energy per nucleon–nucleon collision √sNN = 8.16 TeV with the ALICE detector at the CERN LHC. The measurement is performed reconstructing bottomonium resonances via their dimuon decay channel, in the centre-of-mass rapidity intervals 2.03 < ycms < 3.53 and −4.46 < ycms < −2.96, down to zero transverse momentum. In this work, results on the ϒ(1S) production cross section as a function of rapidity and transverse momentum are presented. The corresponding nuclear modification factor shows a suppression of the ϒ(1S) yields with respect to pp collisions, both at forward and backward rapidity. This suppression is stronger in the low transverse momentum region and shows no significant dependence on the centrality of the interactions. Furthermore, the ϒ(2S) nuclear modification factor is evaluated, suggesting a suppression similar to that of the ϒ(1S). A first measurement of the ϒ(3S) has also been performed. Finally, results are compared with previous ALICE measurements in p–Pb collisions at √sNN = 5.02 TeV and with theoretical calculations.publishedVersio

(Anti-)deuteron production in pp collisions at 1as=13TeV

The study of (anti-)deuteron production in pp collisions has proven to be a powerful tool to investigate the formation mechanism of loosely bound states in high-energy hadronic collisions. In this paper the production of (anti-)deuterons is studied as a function of the charged particle multiplicity in inelastic pp collisions at s=13 TeV using the ALICE experiment. Thanks to the large number of accumulated minimum bias events, it has been possible to measure (anti-)deuteron production in pp collisions up to the same charged particle multiplicity (d Nch/ d \u3b7 3c 26) as measured in p\u2013Pb collisions at similar centre-of-mass energies. Within the uncertainties, the deuteron yield in pp collisions resembles the one in p\u2013Pb interactions, suggesting a common formation mechanism behind the production of light nuclei in hadronic interactions. In this context the measurements are compared with the expectations of coalescence and statistical hadronisation models (SHM)

Multiplicity dependence of (anti-)deuteron production in pp collisions at root s=7 TeV

none1019siIn this letter, the production of deuterons and anti-deuterons in pp collisions at root s = 7 TeV is studied as a function of the charged-particle multiplicity density at mid-rapidity with the ALICE detector at the LHC. Production yields are measured at mid-rapidity in five multiplicity classes and as a function of the deuteron transverse momentum (p(T)). The measurements are discussed in the context of hadron-coalescence models. The coalescence parameter B-2, extracted from the measured spectra of (anti-)deuteronsand primary (anti-)protons, exhibits no significant p(T)-dependence for p(T) < 3 GeV/c, in agreement with the expectations of a simple coalescence picture. At fixed transverse momentum per nucleon, the B-2 parameter is found to decrease smoothly from low multiplicity pp to Pb-Pb collisions, in qualitative agreement with more elaborate coalescence models. The measured mean transverse momentum of (anti-)deuterons in pp is not reproduced by the Blast-Wave model calculations that simultaneously describe pion, kaon and proton spectra, in contrast to central Pb-Pb collisions. The ratio between the p(T)-integrated yield of deuterons to protons, d/p, is found to increase with the charged-particle multiplicity, as observed in inelastic pp collisions at different centre-of-mass energies. The d/p ratios are reported in a wide range, from the lowest to the highest multiplicity values measured in pp collisions at the LHC. (C) 2019 The Author(s). Published by Elsevier B.VnoneAcharya, S.; Acosta, F. T.; Adamova, D.; Adhya, S. P.; Adler, A.; Adolfsson, J.; Aggarwal, M. M.; Rinella, G. Aglieri; Agnello, M.; Ahammed, Z.; Ahmad, S.; Ahn, S. U.; Aiola, S.; Akindinov, A.; Al-Turany, M.; Alam, S. N.; Albuquerque, D. S. D.; Aleksandrov, D.; Alessandro, B.; Alfanda, H. M.; Alfaro Molina, R.; Ali, B.; Ali, Y.; Alici, A.; Alkin, A.; Alme, J.; Alt, T.; Altenkamper, L.; Altsybeev, I; Anaam, M. N.; Andrei, C.; Andreou, D.; Andrews, H. A.; Andronic, A.; Angeletti, M.; Anguelov, V; Anson, C.; Anticic, T.; Antinori, F.; Antonioli, P.; Anwar, R.; Apadula, N.; Aphecetche, L.; Appelshaeuser, H.; Arcelli, S.; Arnaldi, R.; Arratia, M.; Arsene, I. C.; Arslandok, M.; Augustinus, A.; Averbeck, R.; Azmi, M. D.; Badala, A.; Baek, Y. W.; Bagnasco, S.; Bailhache, R.; Bala, R.; Baldisseri, A.; Ball, M.; Baral, R. C.; Barbera, R.; Barioglio, L.; Barnafoldi, G. G.; Barnby, L. S.; Barret, V; Bartalini, P.; Barth, K.; Bartsch, E.; Bastid, N.; Basu, S.; Batigne, G.; Batyunya, B.; Batzing, P. C.; Bauri, D.; Bazo Alba, J. L.; Bearden, I. G.; Bedda, C.; Behera, N. K.; Belikov, I; Bellini, F.; Bello Martinez, H.; Bellwied, R.; Beltran, L. G. E.; Belyaev, V; Bencedi, G.; Beole, S.; Bercuci, A.; Berdnikov, Y.; Berenyi, D.; Bertens, R. A.; Berzano, D.; Betev, L.; Bhasin, A.; Bhat, I. R.; Bhatt, H.; Bhattacharjee, B.; Bianchi, A.; Bianchi, L.; Bianchi, N.; Bielcik, J.; Bielcikova, J.; Bilandzic, A.; Biro, G.; Biswas, R.; Biswas, S.; Blair, J. T.; Blau, D.; Blume, C.; Boca, G.; Bock, F.; Bogdanov, A.; Boldizsar, L.; Bolozdynya, A.; Bombara, M.; Bonomi, G.; Bonora, M.; Borel, H.; Borissov, A.; Borri, M.; Botta, E.; Bourjau, C.; Bratrud, L.; Braun-Munzinger, P.; Bregant, M.; Broker, T. A.; Broz, M.; Brucken, E. J.; Bruna, E.; Bruno, G. E.; Buckland, M. D.; Budnikov, D.; Buesching, H.; Bufalino, S.; Buhler, P.; Buncic, P.; Busch, O.; Buthelezi, Z.; Butt, J. B.; Buxton, J. T.; Caffarri, D.; Caines, H.; Caliva, A.; Calvo Villar, E.; Camacho, R. S.; Camerini, P.; Capon, A. A.; Carnesecchi, F.; Castellanos, J. Castillo; Castro, A. J.; Casula, E. A. R.; Sanchez, C. Ceballos; Chakraborty, P.; Chandra, S.; Chang, B.; Chang, W.; Chapeland, S.; Chartier, M.; Chattopadhyay, S.; Chauvin, A.; Cheshkov, C.; Cheynis, B.; Barroso, V. Chibante; Chinellato, D. D.; Cho, S.; Chochula, P.; Chowdhury, T.; Christakoglou, P.; Christensen, C. H.; Christiansen, P.; Chujo, T.; Cicalo, C.; Cifarelli, L.; Cindolo, F.; Cleymans, J.; Colamaria, F.; Colella, D.; Collu, A.; Colocci, M.; Concas, M.; Balbastre, G. Conesa; del Valle, Z. Conesa; Contin, G.; Contreras, J. G.; Cormier, T. M.; Morales, Y. Corrales; Cortese, P.; Cosentino, M. R.; Costa, F.; Costanza, S.; Crkovska, J.; Crochet, P.; Cuautle, E.; Cunqueiro, L.; Dabrowski, D.; Dahms, T.; Dainese, A.; Damas, F. P. A.; Dani, S.; Danisch, M. C.; Danu, A.; Das, D.; Das, I; Das, S.; Dash, A.; Dash, S.; Dashi, A.; De, S.; De Caro, A.; de Cataldo, G.; de Conti, C.; de Cuveland, J.; De Falco, A.; De Gruttola, D.; De Marco, N.; De Pasquale, S.; De Souza, R. D.; Degenhardt, H. F.; Deisting, A.; Deloff, A.; Delsanto, S.; Dhankher, P.; Di Bari, D.; Di Mauro, A.; Diaz, R. A.; Dietel, T.; Dillenseger, P.; Ding, Y.; Divia, R.; Djuvsland, O.; Dobrin, A.; Domenicis Gimenez, D.; Doenigus, B.; Dordic, O.; Dubey, A. K.; Dubla, A.; Dudi, S.; Duggal, A. K.; Dukhishyam, M.; Dupieux, P.; Ehlers, R. J.; Elia, D.; Engel, H.; Epple, E.; Erazmus, B.; Erhardt, F.; Erokhin, A.; Ersdal, M. R.; Espagnon, B.; Eulisse, G.; Eum, J.; Evans, D.; Evdokimov, S.; Fabbietti, L.; Faggin, M.; Faivre, J.; Fantoni, A.; Fasel, M.; Feldkamp, L.; Feliciello, A.; Feofilov, G.; Fernandez Tellez, A.; Ferrero, A.; Ferretti, A.; Festanti, A.; Feuillard, V. J. G.; Figiel, J.; Filchagin, S.; Finogeev, D.; Fionda, F. M.; Fiorenza, G.; Flor, F.; Floris, M.; Foertsch, S.; Foka, P.; Fokin, S.; Fragiacomo, E.; Francisco, A.; Frankenfeld, U.; Fronze, G. G.; Fuchs, U.; Furget, C.; Furs, A.; Girard, M. Fusco; Gaardhoje, J. J.; Gagliardi, M.; Gago, A. M.; Gajdosova, K.; Galvan, C. D.; Ganoti, P.; Garabatos, C.; Garcia-Solis, E.; Garg, K.; Gargiulo, C.; Garner, K.; Gasik, P.; Gauger, E. F.; Gay Ducati, M. B.; Germain, M.; Ghosh, J.; Ghosh, P.; Ghosh, S. K.; Gianotti, P.; Giubellino, P.; Giubilato, P.; Glaessel, P.; Gomez Coral, D. M.; Ramirez, A. Gomez; Gonzalez, V; Gonzalez-Zamora, P.; Gorbunov, S.; Gorlich, L.; Gotovac, S.; Grabski, V; Graczykowski, L. K.; Graham, K. L.; Greiner, L.; Grelli, A.; Grigoras, C.; Grigoriev, V; Grigoryan, A.; Grigoryan, S.; Gronefeld, J. M.; Grosa, F.; Grosse-Oetringhaus, J. F.; Grosso, R.; Guernane, R.; Guerzoni, B.; Guittiere, M.; Gulbrandsen, K.; Gunji, T.; Gupta, A.; Gupta, R.; Guzman, I. B.; Haake, R.; Habib, M. K.; Hadjidakis, C.; Hamagaki, H.; Hamar, G.; Hamid, M.; Hamon, J. C.; Hannigan, R.; Haque, M. R.; Harlenderova, A.; Harris, J. W.; Harton, A.; Hassan, H.; Hatzifotiadou, D.; Hauer, P.; Hayashi, S.; Heckel, S. T.; Hellbaer, E.; Helstrup, H.; Herghelegiu, A.; Hernandez, E. G.; Herrera Corral, G.; Herrmann, F.; Hetland, K. F.; Hilden, T. E.; Hillemanns, H.; Hills, C.; Hippolyte, B.; Hohlweger, B.; Horak, D.; Hornung, S.; Hosokawa, R.; Hota, J.; Hristov, P.; Huang, C.; Hughes, C.; Huhn, P.; Humanic, T. J.; Hushnud, H.; Husova, L. A.; Hussain, N.; Hussain, T.; Hutter, D.; Hwang, D. S.; Iddon, J. P.; Ilkaev, R.; Inaba, M.; Ippolitov, M.; Islam, M. S.; Ivanov, M.; Ivanov, V; Izucheev, V; Jacak, B.; Jacazio, N.; Jacobs, P. M.; Jadhav, M. B.; Jadlovska, S.; Jadlovsky, J.; Jaelani, S.; Jahnke, C.; Jakubowska, M. J.; Janik, M. A.; Jercic, M.; Jevons, O.; Bustamante, R. T. Jimenez; Jin, M.; Jones, P. G.; Jusko, A.; Kalinak, P.; Kalweit, A.; Kang, J. H.; Kaplin, V; Kar, S.; Uysal, A. Karasu; Karavichev, O.; Karavicheva, T.; Karczmarczyk, P.; Karpechev, E.; Kebschull, U.; Keidel, R.; Keil, M.; Ketzer, B.; Khabanova, Z.; Khan, A. M.; Khan, S.; Khan, S. A.; Khanzadeev, A.; Kharlov, Y.; Khatun, A.; Khuntia, A.; Kielbowicz, M. M.; Kileng, B.; Kim, B.; Kim, D.; Kim, D. J.; Kim, E. J.; Kim, H.; Kim, J. S.; Kim, J.; Kim, M.; Kim, S.; Kim, T.; Kindra, K.; Kirsch, S.; Kisel, I; Kiselev, S.; Kisiel, A.; Klay, J. L.; Klein, C.; Klein, J.; Klein, S.; Klein-Boesing, C.; Klewin, S.; Kluge, A.; Knichel, M. L.; Knospe, A. G.; Kobdaj, C.; Kofarago, M.; Koehler, M. K.; Kollegger, T.; Kondratyeva, N.; Kondratyuk, E.; Konopka, P. J.; Konyushikhin, M.; Koska, L.; Kovalenko, O.; Kovalenko, V; Kowalski, M.; Kralik, I; Kravcakova, A.; Kreis, L.; Krivda, M.; Krizek, F.; Krueger, M.; Kryshen, E.; Krzewicki, M.; Kubera, A. M.; Kucera, V; Kuhn, C.; Kuijer, P. G.; Kumar, L.; Kumar, S.; Kundu, S.; Kurashvili, P.; Kurepin, A.; Kurepin, A. B.; Kushpil, S.; Kvapil, J.; Kweon, M. J.; Kwon, Y.; La Pointe, S. L.; La Rocca, P.; Lai, Y. S.; Langoy, R.; Lapidus, K.; Lardeux, A.; Larionov, P.; Laudi, E.; Lavicka, R.; Lazareva, T.; Lea, R.; Leardini, L.; Lee, S.; Lehas, F.; Lehner, S.; Lehrbach, J.; Lemmon, R. C.; Leon Monzon, I; Levai, P.; Li, X.; Li, X. L.; Lien, J.; Lietava, R.; Lim, B.; Lindal, S.; Lindenstruth, V; Lindsay, S. W.; Lippmann, C.; Lisa, M. A.; Litichevskyi, V; Liu, A.; Ljunggren, H. M.; Llope, W. J.; Lodato, D. F.; Loginov, V; Loizides, C.; Loncar, P.; Lopez, X.; Lopez Torres, E.; Luettig, P.; Luhder, J. R.; Lunardon, M.; Luparello, G.; Lupi, M.; Maevskaya, A.; Mager, M.; Mahmood, S. M.; Mahmoud, T.; Maire, A.; Majka, R. D.; Malaev, M.; Malik, Q. W.; Malinina, L.; Mal'Kevich, D.; Malzacher, P.; Mamonov, A.; Manko, V; Manso, F.; Manzari, V; Mao, Y.; Marchisone, M.; Mares, J.; Margagliotti, G., V; Margotti, A.; Margutti, J.; Marin, A.; Markert, C.; Marquard, M.; Martin, N. A.; Martinengo, P.; Martinez, J. L.; Martinez, M., I; Garcia, G. Martinez; Pedreira, M. Martinez; Masciocchi, S.; Masera, M.; Masoni, A.; Massacrier, L.; Masson, E.; Mastroserio, A.; Mathis, A. M.; Matuoka, P. F. T.; Matyja, A.; Mayer, C.; Mazzilli, M.; Mazzoni, M. A.; Meddi, F.; Melikyan, Y.; Menchaca-Rocha, A.; Meninno, E.; Meres, M.; Mhlanga, S.; Miake, Y.; Micheletti, L.; Mieskolainen, M. M.; Mihaylov, D. L.; Mikhaylov, K.; Mischke, A.; Mishra, A. N.; Miskowiec, D.; Mitra, J.; Mitu, C. M.; Mohammadi, N.; Mohanty, A. P.; Mohanty, B.; Khan, M. Mohisin; Mondal, M. M.; Mordasini, C.; De Godoy, D. A. Moreira; Moreno, L. A. P.; Moretto, S.; Morreale, A.; Morsch, A.; Mrnjavac, T.; Muccifora, V; Mudnic, E.; Muehlheim, D.; Muhuri, S.; Mukherjee, M.; Mulligan, J. D.; Munhoz, M. G.; Muenning, K.; Munzer, R. H.; Murakami, H.; Murray, S.; Musa, L.; Musinsky, J.; Myers, C. J.; Myrcha, J. W.; Naik, B.; Nair, R.; Nandi, B. K.; Nania, R.; Nappi, E.; Naru, M. U.; Nassirpour, A. F.; Natal da Luz, H.; Nattrass, C.; Navarro, S. R.; Nayak, K.; Nayak, R.; Nayak, T. K.; Nazarenko, S.; De Oliveira, R. A. Negrao; Nellen, L.; Nesbo, S., V; Neskovic, G.; Ng, F.; Nielsen, B. S.; Nikolaev, S.; Nikulin, S.; Nikulin, V; Noferini, F.; Nomokonov, P.; Nooren, G.; Noris, J. C. C.; Norman, J.; Nyanin, A.; Nystrand, J.; Ogino, M.; Ohlson, A.; Oleniacz, J.; Oliveira Da Silva, A. C.; Oliver, M. H.; Onderwaater, J.; Oppedisano, C.; Orava, R.; Ortiz Velasquez, A.; Oskarsson, A.; Otwinowski, J.; Oyama, K.; Pachmayer, Y.; Pacik, V; Pagano, D.; Paic, G.; Palni, P.; Pan, J.; Pandey, A. K.; Panebianco, S.; Papikyan, V; Pareek, P.; Park, J.; Parkkila, J. E.; Parmar, S.; Passfeld, A.; Pathak, S. P.; Patra, R. N.; Paul, B.; Pei, H.; Peitzmann, T.; Peng, X.; Pereira, L. G.; Da Costa, H. Pereira; Peresunko, D.; Perez, G. M.; Lezama, E. Perez; Peskov, V; Pestov, Y.; Petracek, V; Petrovici, M.; Pezzi, R. P.; Piano, S.; Pikna, M.; Pillot, P.; Pimentel, L. O. D. L.; Pinazza, O.; Pinsky, L.; Pisano, S.; Piyarathna, D. B.; Ploskon, M.; Planinic, M.; Pliquett, F.; Pluta, J.; Pochybova, S.; Podesta-Lerma, P. L. M.; Poghosyan, M. G.; Polichtchouk, B.; Poljak, N.; Poonsawat, W.; Pop, A.; Poppenborg, H.; Porteboeuf-Houssais, S.; Pozdniakov, V; Prasad, S. K.; Preghenella, R.; Prino, F.; Pruneau, C. A.; Pshenichnov, I; Puccio, M.; Punin, V; Puranapanda, K.; Putschke, J.; Quishpe, R. E.; Ragoni, S.; Raha, S.; Rajput, S.; Rak, J.; Rakotozafindrabe, A.; Ramello, L.; Rami, F.; Raniwala, R.; Raniwala, S.; Rasanen, S. S.; Rascanu, B. T.; Rath, R.; Ratza, V; Ravasenga, I; Read, K. F.; Redlich, K.; Rehman, A.; Reichelt, P.; Reidt, F.; Ren, X.; Renfordt, R.; Reshetin, A.; Revol, J-P; Reygers, K.; Riabov, V; Richert, T.; Richter, M.; Riedler, P.; Riegler, W.; Riggi, F.; Ristea, C.; Rode, S. P.; Rodriguez Cahuantzi, M.; Roed, K.; Rogalev, R.; Rogochaya, E.; Rohr, D.; Rohrich, D.; Rokita, P. S.; Ronchetti, F.; Rosas, E. D.; Roslon, K.; Rosnet, P.; Rossi, A.; Rotondi, A.; Roukoutakis, F.; Roy, A.; Roy, P.; Rueda, O., V; Rui, R.; Rumyantsev, B.; Rustamov, A.; Ryabinkin, E.; Ryabov, Y.; Rybicki, A.; Saarinen, S.; Sadhu, S.; Sadovsky, S.; Safarik, K.; Saha, S. K.; Sahoo, B.; Sahoo, P.; Sahoo, R.; Sahoo, S.; Sahu, P. 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Short telomere length is associated with impaired cognitive performance in European ancestry cohorts

The association between telomere length (TL) dynamics on cognitive performance over the life-course is not well understood. This study meta-analyses observational and causal associations between TL and six cognitive traits, with stratifications on APOE genotype, in a Mendelian Randomization (MR) framework. Twelve European cohorts (N = 17 052; mean age = 59.2 ± 8.8 years) provided results for associations between qPCR-measured TL (T/S-ratio scale) and general cognitive function, mini-mental state exam (MMSE), processing speed by digit symbol substitution test (DSST), visuospatial functioning, memory and executive functioning (STROOP). In addition, a genetic risk score (GRS) for TL including seven known genetic variants for TL was calculated, and used in associations with cognitive traits as outcomes in all cohorts. Observational analyses showed that longer telomeres were associated with better scores on DSST (β = 0.051 per s.d.-increase of TL; 95% confidence interval (CI): 0.024, 0.077; P = 0.0002), and MMSE (β = 0.025; 95% CI: 0.002, 0.047; P = 0.03), and faster STROOP (β =-0.053; 95% CI:-0.087,-0.018; P = 0.003). Effects for DSST were stronger in APOE ϵ4 non-carriers (β = 0.081; 95% CI: 0.045, 0.117; P = 1.0 × 10-5), whereas carriers performed better in STROOP (β =-0.074; 95% CI:-0.140,-0.009; P = 0.03). Causal associations were found for STROOP only (β =-0.598 per s.d.-increase of TL; 95% CI:-1.125,-0.072; P = 0.026), with a larger effect in ϵ4-carriers (β =-0.699; 95% CI:-1.330,-0.069; P = 0.03). Two-sample replication analyses using CHARGE summary statistics showed causal effects between TL and general cognitive function and DSST, but not with STROOP. In conclusion, we suggest causal effects from longer TL on better cognitive performance, where APOE ϵ4-carriers might be at differential risk