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1. Social and non-social autism symptoms and trait domains are genetically dissociable

Author

Freddy Cliquet, Varun Warrier, Roberto Toro, Hyejung Won, Richard Delorme, Thomas Bourgeron, Anders D. Børglum, Janita Bralten, Claire S. Leblond, Geert Poelmans, Jakob Grove, Ward De Witte, Bhismadev Chakrabarti, David A. Hinds, Simon Baron-Cohen, Toro, Roberto [0000-0002-6671-858X], Cliquet, Freddy [0000-0002-9989-0685], Chakrabarti, Bhismadev [0000-0002-6649-7895], Børglum, Anders D. [0000-0001-8627-7219], Grove, Jakob [0000-0003-2284-5744], Hinds, David A. [0000-0002-4911-803X], Apollo - University of Cambridge Repository, University of Cambridge [UK] (CAM), Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), Child and Adolescent Psychiatry Department [AP- HP Hôpital Robert Debré], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Radboud University Medical Center [Nijmegen], Radboud University [Nijmegen], University of Reading (UOR), The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus University [Aarhus], 23andMe Inc., V.W. was funded by St. John’s College, Cambridge, and the Cambridge Commonwealth Trust. This study was funded by grants to SBC from the Medical Research Council, the Wellcome Trust, the Autism Research Trust, the Templeton World Charity Foundation, and to T.B. from the Institut Pasteur, the CNRS, the INSERM, The Fondamental Foundation, the APHP, the BioPsy Labex and the University Paris Diderot. The research was conducted in association with the National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care East of England at Cambridgeshire and Peterborough NHS Foundation Trust. We also received support from the NIHR Cambridge Biomedical Research Centre. We acknowledge with gratitude the generous support of Drs Dennis and Mireille Gillings in strengthening the collaboration between S.B.-C. and T.B., and between Cambridge University and the Institut Pasteur. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Data obtained from 23andMe was supported by the National Human Genome Research Institute of the National Institutes of Health (grant number R44HG006981). The UK Medical Research Council and Wellcome (grant ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. GWAS data were generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. This publication is the work of the authors who will serve as guarantors for the content of this paper. The iPSYCH (The Lundbeck Foundation Initiative for Integrative Psychiatric Research) team acknowledges funding from The Lundbeck Foundation (grant nos. R102-A9118 and R155-2014-1724), the Stanley Medical Research Institute, the European Research Council (project no.: 294838), the Novo Nordisk Foundation for supporting the Danish National Biobank resource, and grants from Aarhus and Copenhagen Universities and University Hospitals, including support to the iSEQ Center, the GenomeDK HPC facility, and the CIRRAU Center. The project leading to this application has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement no. 777394. The JU receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA and AUTISM SPEAKS, Autistica, SFARI. We thank the iPSCH-Broad Autism Group and the EU-AIMS LEAP group for sharing data. A full list of the authors and affiliations in the iPSYCH-Broad autism group and the EU-AIMS LEAP group is provided in the Supplementary Information., The 23andMe Research Team : Michelle Agee, Babak Alipanahi, Adam Auton, Robert K. Bell, Katarzyna Bryc, Sarah L. Elson, Pierre Fontanillas, Nicholas A. Furlotte, Karen E. Huber, Aaron Kleinman, Nadia K. Litterman, Jennifer C. McCreight, Matthew H. McIntyre, Joanna L. Mountain, Carrie A.M. Northover, Steven J. Pitts, J. Fah Sathirapongsasuti, Olga V. Sazonova, Janie F. Shelton, Suyash Shringarpure, Chao Tian, Joyce Y. Tung, Vladimir Vacic & Catherine H. Wilson, European Project: 294838,EC:FP7:ERC,ERC-2011-ADG_20110310,EIMS(2012), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), and Radboud university [Nijmegen]

Subjects
Male, DIAGNOSTIC OBSERVATION SCHEDULE, LD SCORE REGRESSION, 45/43, Medicine (miscellaneous), Genome-wide association study, Genome-wide association studies, Developmental psychology, FUNCTIONING AUTISM, Cohort Studies, 0302 clinical medicine, Heritability of autism, MESH: Cohort Studies, lcsh:QH301-705.5, GENERAL-POPULATION, 631/208/366/1373, 0303 health sciences, MESH: Genetic Predisposition to Disease, article, Autism spectrum disorders, MESH: Reproducibility of Results, Phenotype, Autistic traits, 631/208/727/2000, Trait, Female, General Agricultural and Biological Sciences, Psychology, MESH: Social Behavior, EMPATHY QUOTIENT, MESH: Autistic Disorder, 631/208/205/2138, Genetic predisposition to disease, MESH: Phenotype, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, PSYCHOMETRIC ANALYSIS, All institutes and research themes of the Radboud University Medical Center, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], mental disorders, medicine, Humans, REPETITIVE BEHAVIOR, Autistic Disorder, GENOME-WIDE ASSOCIATION, Social Behavior, Association (psychology), 030304 developmental biology, SYSTEMATIZING QUOTIENT, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], MESH: Humans, Reproducibility of Results, SPECTRUM QUOTIENT AQ, medicine.disease, MESH: Male, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, lcsh:Biology (General), MESH: Genome-Wide Association Study, Autism, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], MESH: Female, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

The core diagnostic criteria for autism comprise two symptom domains – social and communication difficulties, and unusually repetitive and restricted behaviour, interests and activities. There is some evidence to suggest that these two domains are dissociable, though this hypothesis has not yet been tested using molecular genetics. We test this using a genome-wide association study (N = 51,564) of a non-social trait related to autism, systemising, defined as the drive to analyse and build systems. We demonstrate that systemising is heritable and genetically correlated with autism. In contrast, we do not identify significant genetic correlations between social autistic traits and systemising. Supporting this, polygenic scores for systemising are significantly and positively associated with restricted and repetitive behaviour but not with social difficulties in autistic individuals. These findings strongly suggest that the two core domains of autism are genetically dissociable, and point at how to fractionate the genetics of autism., Varun Warrier et al. report a genome-wide association study of systemising, a non-social trait associated with autism. They find 3 loci associated with systemising and show that this trait has no significant genetic correlations to social phenotypic measures, demonstrating that the social and non-social aspects of autism are genetically distinct.

Published
2019
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2. Human candidate gene polymorphisms and risk of severe malaria in children in Kilifi, Kenya: a case-control association study

Author

Ndila, Carolyne M, Uyoga, Sophie, Macharia, Alexander W, Nyutu, Gideon, Peshu, Norbert, Ojal, John, Shebe, Mohammed, Awuondo, Kennedy O, Mturi, Neema, Tsofa, Benjamin, Sepúlveda, Nuno, Clark, Taane G, Band, Gavin, Clarke, Geraldine, Rowlands, Kate, Hubbart, Christina, Jeffreys, Anna, Kariuki, Silvia, Marsh, Kevin, Mackinnon, Margaret, Maitland, Kathryn, Kwiatkowski, Dominic P, Rockett, Kirk A, Williams, Thomas N, Abathina, Amadou, Abubakar, Ismaela, Achidi, Eric, Agbenyega, Tsiri, Aiyegbo, Mohammed, Akoto, Alex, Allen, Angela, Allen, Stephen, Amenga-Etego, Lucas, Amodu, Folakemi, Amodu, Olukemi, Anchang-Kimbi, Judith, Ansah, Nana, Ansah, Patrick, Ansong, Daniel, Antwi, Sampson, Anyorigiya, Thomas, Apinjoh, Tobias, Asafo-Agyei, Emmanuel, Asoala, Victor, Atuguba, Frank, Auburn, Sarah, Bah, Abdou, Bamba, Kariatou, Bancone, Germana, Barnwell, David, Barry, Abdoulaye, Bauni, Evasius, Besingi, Richard, Bojang, Kalifa, Bougouma, Edith, Bull, Susan, Busby, George, Camara, Abdoulie, Camara, Landing, Campino, Susana, Carter, Richard, Carucci, Dan, Casals-Pascual, Climent, Ceesay, Ndey, Ceesay, Pa, Chau, Tran, Chuong, Ly, Clark, Taane, Cole-Ceesay, Ramou, Conway, David, Cook, Katharine, Cook, Olivia, Cornelius, Victoria, Corran, Patrick, Correa, Simon, Cox, Sharon, Craik, Rachel, Danso, Bakary, Davis, Timothy, Day, Nicholas, Deloukas, Panos, Dembele, Awa, Devries, Jantina, Dewasurendra, Rajika, Diakite, Mahamadou, Diarra, Elizabeth, Dibba, Yaya, Diss, Andrea, Djimdé, Abdoulaye, Dolo, Amagana, Doumbo, Ogobara, Doyle, Alan, Drakeley, Chris, Drury, Eleanor, Duffy, Patrick, Dunstan, Sarah, Ebonyi, Augustine, Elhassan, Ahmed, Elhassan, Ibrahim, Elzein, Abier, Enimil, Anthony, Esangbedo, Pamela, Evans, Jennifer, Evans, Julie, Farrar, Jeremy, Fernando, Deepika, Fitzpatrick, Kathryn, Fullah, Janet, Garcia, Jacob, Ghansah, Anita, Gottleib, Michael, Green, Angie, Hart, Lee, Hennsman, Meike, Hien, Tran, Hieu, Nguyen, Hilton, Eliza, Hodgson, Abraham, Horstmann, Rolf, Hughes, Catherine, Hussein, Ayman, Hutton, Robert, Ibrahim, Muntaser, Ishengoma, Deus, Jaiteh, Jula, Jallow, Mariatou, Jallow, Muminatou, Jammeh, Kebba, Jasseh, Momodou, Jobarteh, Amie, Johnson, Kimberly, Joseph, Sarah, Jyothi, Dushyanth, Kachala, David, Kamuya, Dorcas, Kanyi, Haddy, Karunajeewa, Harin, Karunaweera, Nadira, Keita, Momodou, Kerasidou, Angeliki, Khan, Aja, Kivinen, Katja, Kokwaro, Gilbert, Konate, Amadou, Konate, Salimata, Koram, Kwadwo, Kwiatkowski, Dominic, Laman, Moses, Si, Le, Leffler, Ellen, Lemnge, Martha, Lin, Enmoore, Alioune, Ly, Macharia, Alexander, Macinnis, Bronwyn, Mai, Nguyen, Makani, Julie, Malangone, Cinzia, Mangano, Valentina, Manjurano, Alphaxard, Manneh, Lamin, Manning, Laurens, Manske, Magnus, Marsh, Vicki, Maslen, Gareth, Maxwell, Caroline, Mbunwe, Eric, Mccreight, Marilyn, Mead, Daniel, Mendy, Alieu, Mendy, Anthony, Mensah, Nathan, Michon, Pascal, Miles, Alistair, Miotto, Olivo, Modiano, David, Mohamed, Hiba, Molloy, Sile, Molyneux, Malcolm, Molyneux, Sassy, Moore, Mike, Moyes, Catherine, Mtei, Frank, Mtove, George, Mueller, Ivo, Mugri, Regina, Munthali, Annie, Mutabingwa, Theonest, Nadjm, Behzad, Ndi, Andre, Ndila, Carolyne, Newton, Charles, Niangaly, Amadou, Njie, Haddy, Njie, Jalimory, Njie, Madi, Njie, Malick, Njie, Sophie, Njiragoma, Labes, Nkrumah, Francis, Ntunthama, Neema, Nyika, Aceme, Nyirongo, Vysaul, O'Brien, John, Obu, Herbert, Oduro, Abraham, Ofori, Alex, Olaniyan, Subulade, Olaosebikan, Rasaq, Oluoch, Tom, Omotade, Olayemi, Oni, Olajumoke, Onykwelu, Emmanuel, Opi, Daniel, Orimadegun, Adebola, O'Riordan, Sean, Ouedraogo, Issa, Oyola, Samuel, Parker, Michael, Pearson, Richard, Pensulo, Paul, Phiri, Ajib, Phu, Nguyen, Pinder, Margaret, Pirinen, Matti, Plowe, Chris, Potter, Claire, Poudiougou, Belco, Puijalon, Odile, Quyen, Nguyen, Ragoussis, Ioannis, Ragoussis, Jiannis, Rasheed, Oba, Reeder, John, Reyburn, Hugh, Riley, Eleanor, Risley, Paul, Rockett, Kirk, Rodford, Joanne, Rogers, Jane, Rogers, William, Ruano-Rubio, Valentín, Sabally-Ceesay, Kumba, Sadiq, Abubacar, Saidy-Khan, Momodou, Saine, Horeja, Sakuntabhai, Anavaj, Sall, Abdourahmane, Sambian, David, Sambou, Idrissa, Sanjoaquin, Miguel, Shah, Shivang, Shelton, Jennifer, Siba, Peter, Silva, Nilupa, Simmons, Cameron, Simpore, Jaques, Singhasivanon, Pratap, Sinh, Dinh, Sirima, Sodiomon, Sirugo, Giorgio, Sisay-Joof, Fatoumatta, Sissoko, Sibiry, Small, Kerrin, Somaskantharajah, Elilan, Spencer, Chris, Stalker, Jim, Stevens, Marryat, Suriyaphol, Prapat, Sylverken, Justice, Taal, Bintou, Tall, Adama, Taylor, Terrie, Teo, Yik, Thai, Cao, Thera, Mahamadou, Titanji, Vincent, Toure, Ousmane, Troye-Blomberg, Marita, Usen, Stanley, Vanderwal, Aaron, Wangai, Hannah, Watson, Renee, Williams, Thomas, Wilson, Michael, Wrigley, Rebecca, Yafi, Clarisse, Yamoah, Lawrence, The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford, London School of Hygiene and Tropical Medicine (LSHTM), The Wellcome Trust Sanger Institute [Cambridge], St Mary's Hospital, Imperial College, TNW and MM are funded through awards from the Wellcome Trust (grants 091758 and 202800 [to TNW] and grant 088634 [to MM]) and DPK and TGC receive support from the Medical Research Council (grant G19/9 [to DPK] and grants MR/K000551/1, MR/M01360X/1, MR/N010469/1, and MC_PC_15103 [to TGC]). The research leading to these results received funding from the European Community's Seventh Framework Programme (FP7/2007-2013, under grant agreement 242095) and from the Medical Research Council (grant G0600718). MalariaGEN is supported by the Wellcome Trust (WT077383/Z/05/Z) and by the Foundation for the National Institutes of Health (grant 566) as part of the Bill & Melinda Gates' Grand Challenges in Global Health Initiative. The Resource Centre for Genomic Epidemiology of Malaria is supported by the Wellcome Trust (grant 090770/Z/09/Z). Support was also provided by the Medical Research Council (grant G0600718). The Wellcome Trust also provides core awards to the Wellcome Trust Centre for Human Genetics (grant 090532/Z/09/Z) and to the Wellcome Trust Sanger Institute (grant 098051). This work forms part of a larger collaboration with the MalariaGEN Consortium, whose members are listed at http://www.malariagen.net/projects/host/consortium-members. This paper is published with permission from the Director of the Kenya Medical Research Institute (KEMRI)., MalariaGEN Consortium (Anavaj Sakuntabhai), and European Project: 242095,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,EVIMALAR(2009)

Subjects
Case-Control Studies, Child, Child, Preschool, Female, Gene Frequency, Genetic Predisposition to Disease, Humans, Kenya, Malaria, Male, Polymorphism, Genetic, Hematology, macromolecular substances, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Article, Genetic, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, parasitic diseases, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Polymorphism, Preschool
Abstract

Summary Background Human genetic factors are important determinants of malaria risk. We investigated associations between multiple candidate polymorphisms—many related to the structure or function of red blood cells—and risk for severe Plasmodium falciparum malaria and its specific phenotypes, including cerebral malaria, severe malaria anaemia, and respiratory distress. Methods We did a case-control study in Kilifi County, Kenya. We recruited as cases children presenting with severe malaria to the high-dependency ward of Kilifi County Hospital. We included as controls infants born in the local community between Aug 1, 2006, and Sept 30, 2010, who were part of a genetics study. We tested for associations between a range of candidate malaria-protective genes and risk for severe malaria and its specific phenotypes. We used a permutation approach to account for multiple comparisons between polymorphisms and severe malaria. We judged p values less than 0·005 significant for the primary analysis of the association between candidate genes and severe malaria. Findings Between June 11, 1995, and June 12, 2008, 2244 children with severe malaria were recruited to the study, and 3949 infants were included as controls. Overall, 263 (12%) of 2244 children with severe malaria died in hospital, including 196 (16%) of 1233 with cerebral malaria. We investigated 121 polymorphisms in 70 candidate severe malaria-associated genes. We found significant associations between risk for severe malaria overall and polymorphisms in 15 genes or locations, of which most were related to red blood cells: ABO, ATP2B4, ARL14, CD40LG, FREM3, INPP4B, G6PD, HBA (both HBA1 and HBA2), HBB, IL10, LPHN2 (also known as ADGRL2), LOC727982, RPS6KL1, CAND1, and GNAS. Combined, these genetic associations accounted for 5·2% of the variance in risk for developing severe malaria among individuals in the general population. We confirmed established associations between severe malaria and sickle-cell trait (odds ratio [OR] 0·15, 95% CI 0·11–0·20; p=2·61 × 10−58), blood group O (0·74, 0·66–0·82; p=6·26 × 10−8), and –α3·7-thalassaemia (0·83, 0·76–0·90; p=2·06 × 10−6). We also found strong associations between overall risk of severe malaria and polymorphisms in both ATP2B4 (OR 0·76, 95% CI 0·63–0·92; p=0·001) and FREM3 (0·64, 0·53–0·79; p=3·18 × 10−14). The association with FREM3 could be accounted for by linkage disequilibrium with a complex structural mutation within the glycophorin gene region (comprising GYPA, GYPB, and GYPE) that encodes for the rare Dantu blood group antigen. Heterozygosity for Dantu was associated with risk for severe malaria (OR 0·57, 95% CI 0·49–0·68; p=3·22 × 10−11), as was homozygosity (0·26, 0·11–0·62; p=0·002). Interpretation Both ATP2B4 and the Dantu blood group antigen are associated with the structure and function of red blood cells. ATP2B4 codes for plasma membrane calcium-transporting ATPase 4 (the major calcium pump on red blood cells) and the glycophorins are ligands for parasites to invade red blood cells. Future work should aim at uncovering the mechanisms by which these polymorphisms can result in severe malaria protection and investigate the implications of these associations for wider health. Funding Wellcome Trust, UK Medical Research Council, European Union, and Foundation for the National Institutes of Health as part of the Bill & Melinda Gates Grand Challenges in Global Health Initiative.

Published
2018

3. Environment, epigenetics and neurodegeneration: Focus on nutrition in Alzheimer's disease

Author

Marco Lucarelli, Andrea Fuso, Vincenzina Nicolia, Department of Surgery, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Department of Cellular Biotechnologies and Haematology, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome]-Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), European Center for Brain Research (CERC)/Santa Lucia Foundation I.R.C.C.S., This paper was supported by funding from the EC 7th Framework Program (FP7/2007–2013) grant no. 278486 'DEVELAGE' and from the Sapienza Università di Roma, Scientific Research Programs 2012 and 2013., European Project: 278486,EC:FP7:HEALTH,FP7-HEALTH-2011-two-stage,DEVELAGE(2012), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti, and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA)

Subjects
Adult, Aging, Nutritional Status, Disease, Biology, Alzheimer's Disease, Biochemistry, Epigenesis, Genetic, Endocrinology, Alzheimer Disease, Mental stress, Genetics, medicine, Humans, Genetic Predisposition to Disease, Epigenetics, Neurodegeneration, Molecular Biology, Organism, DNA methylation, [SDV.MHEP.GEG]Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, Age Factors, food and beverages, Neurodegenerative Diseases, Cell Biology, Epigenome, medicine.disease, 3. Good health, B vitamins, Vitamin B Complex, Gene-Environment Interaction, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neuroscience, epigenetics, neurodegeneration, Alzheimer's disease
Abstract

International audience; Many different environmental factors (nutrients, pollutants, chemicals, physical activity, lifestyle, physical and mental stress) can modulate epigenetic markers in the developing and adult organism. Epigenetics, in turn, can cause and is associated with several neurodegenerative and aging-dependent human diseases. Alzheimer's disease certainly represents one of the most relevant neurodegenerative disorders due to its incidence and its huge socio-economic impact. Therefore, it is easy to understand why recent literature focuses on the epigenetic modifications associated with Alzheimer's disease and other neurodegenerative disorders. One of the most intriguing and, at the same time, worrying evidence is that even "mild" environmental factors (such as behavioral or physical stress) as well as the under-threshold exposure to pollutants and chemicals, can be effective. Finally, even mild nutrients disequilibria can result in long-lasting and functional alterations of many epigenetic markers, although they don't have an immediate acute effect. Therefore, we will probably have to re-define the current risk threshold for many factors, molecules and stresses. Among the many different environmental factors affecting the epigenome, nutrition represents one of the most investigated fields; the reasons are probably that each person interacts with nutrients and that, in turn, nutrients can modulate at molecular level the epigenetic biochemical pathways. The role that nutrition can exert in modulating epigenetic modifications in Alzheimer's disease will be discussed with particular emphasis on the role of B vitamins and DNA methylation.

Published
2015