Benjamin I Perry1, Hannah J Jones2, Tom G Richardson3, Stan Zammit4, Nicholas J Wareham5, Glyn Lewis6, Peter B Jones7, Golam M Khandaker7. 1. Department of Psychiatry, University of Cambridge School of Clinical Medicine, Cambridge, England, UK; Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, England, UK. Electronic address: bip20@medschl.cam.ac.uk. 2. Centre for Academic Mental Health, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, England, UK; NIHR Biomedical Research Centre, University Hospitals Bristol NHS Foundation Trust and University of Bristol, Bristol, UK. 3. MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, England, UK. 4. Centre for Academic Mental Health, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, England, UK; NIHR Biomedical Research Centre, University Hospitals Bristol NHS Foundation Trust and University of Bristol, Bristol, UK; MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, Wales, UK. 5. MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, England, UK. 6. Division of Psychiatry, University College London, London, England, UK. 7. Department of Psychiatry, University of Cambridge School of Clinical Medicine, Cambridge, England, UK; Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, England, UK.
Abstract
BACKGROUND: Psychosis and type 2 diabetes mellitus (T2DM) are commonly comorbid and may share pathophysiologic mechanisms. To investigate shared genetic variation and inflammation as potential common mechanisms, we tested: (i) associations between genetic predisposition for T2DM and psychotic experiences and psychotic disorder in young adults; (ii) the association between genetic predisposition for schizophrenia and insulin resistance (IR), a precursor of T2DM; and (iii) whether these associations are mediated by childhood inflammation. METHODS: Psychotic experiences (PEs), psychotic disorder and IR were assessed at age 18. Polygenic risk scores (PRS) for T2DM and schizophrenia were derived based on large genome-wide association studies. Associations between PRS and psychotic/IR outcomes were assessed using regression analysis based on 3768 ALSPAC birth cohort participants with complete data. Inflammatory markers C-reactive protein (CRP) and interleukin 6 (IL-6) measured at age 9 were used in regression and mediation analyses. RESULTS: Genetic predisposition for T2DM was associated with PEs (adjusted OR = 1.21; 95% CI, 1.01-1.45) and psychotic disorder (adjusted OR = 1.51; 95% CI, 1.04-2.03) at age 18 in a linear dose-response fashion. Genetic predisposition for schizophrenia was weakly associated with IR (adjusted OR = 1.10; 95% C·I, 0.99-1.22) at age 18. The association between genetic risk for T2DM and PEs was partly mediated by childhood CRP (p = .040). CONCLUSIONS: Comorbidity between psychosis and T2DM may be partly underpinned by shared genes and inflammation. A summation of minor genetic variation representing lifetime risk for T2DM at conception may predispose individuals to psychosis in adulthood by influencing physiologic changes, such as low-grade inflammation, detectable as early as childhood.
BACKGROUND: Psychosis and type 2 diabetes mellitus (T2DM) are commonly comorbid and may share pathophysiologic mechanisms. To investigate shared genetic variation and inflammation as potential common mechanisms, we tested: (i) associations between genetic predisposition for T2DM and psychotic experiences and psychotic disorder in young adults; (ii) the association between genetic predisposition for schizophrenia and insulin resistance (IR), a precursor of T2DM; and (iii) whether these associations are mediated by childhood inflammation. METHODS: Psychotic experiences (PEs), psychotic disorder and IR were assessed at age 18. Polygenic risk scores (PRS) for T2DM and schizophrenia were derived based on large genome-wide association studies. Associations between PRS and psychotic/IR outcomes were assessed using regression analysis based on 3768 ALSPAC birth cohort participants with complete data. Inflammatory markers C-reactive protein (CRP) and interleukin 6 (IL-6) measured at age 9 were used in regression and mediation analyses. RESULTS: Genetic predisposition for T2DM was associated with PEs (adjusted OR = 1.21; 95% CI, 1.01-1.45) and psychotic disorder (adjusted OR = 1.51; 95% CI, 1.04-2.03) at age 18 in a linear dose-response fashion. Genetic predisposition for schizophrenia was weakly associated with IR (adjusted OR = 1.10; 95% C·I, 0.99-1.22) at age 18. The association between genetic risk for T2DM and PEs was partly mediated by childhood CRP (p = .040). CONCLUSIONS: Comorbidity between psychosis and T2DM may be partly underpinned by shared genes and inflammation. A summation of minor genetic variation representing lifetime risk for T2DM at conception may predispose individuals to psychosis in adulthood by influencing physiologic changes, such as low-grade inflammation, detectable as early as childhood.
Authors: Anubha Mahajan; Min Jin Go; Weihua Zhang; Jennifer E Below; Kyle J Gaulton; Teresa Ferreira; Momoko Horikoshi; Andrew D Johnson; Maggie C Y Ng; Inga Prokopenko; Danish Saleheen; Xu Wang; Eleftheria Zeggini; Goncalo R Abecasis; Linda S Adair; Peter Almgren; Mustafa Atalay; Tin Aung; Damiano Baldassarre; Beverley Balkau; Yuqian Bao; Anthony H Barnett; Ines Barroso; Abdul Basit; Latonya F Been; John Beilby; Graeme I Bell; Rafn Benediktsson; Richard N Bergman; Bernhard O Boehm; Eric Boerwinkle; Lori L Bonnycastle; Noël Burtt; Qiuyin Cai; Harry Campbell; Jason Carey; Stephane Cauchi; Mark Caulfield; Juliana C N Chan; Li-Ching Chang; Tien-Jyun Chang; Yi-Cheng Chang; Guillaume Charpentier; Chien-Hsiun Chen; Han Chen; Yuan-Tsong Chen; Kee-Seng Chia; Manickam Chidambaram; Peter S Chines; Nam H Cho; Young Min Cho; Lee-Ming Chuang; Francis S Collins; Marylin C Cornelis; David J Couper; Andrew T Crenshaw; Rob M van Dam; John Danesh; Debashish Das; Ulf de Faire; George Dedoussis; Panos Deloukas; Antigone S Dimas; Christian Dina; Alex S Doney; Peter J Donnelly; Mozhgan Dorkhan; Cornelia van Duijn; Josée Dupuis; Sarah Edkins; Paul Elliott; Valur Emilsson; Raimund Erbel; Johan G Eriksson; Jorge Escobedo; Tonu Esko; Elodie Eury; Jose C Florez; Pierre Fontanillas; Nita G Forouhi; Tom Forsen; Caroline Fox; Ross M Fraser; Timothy M Frayling; Philippe Froguel; Philippe Frossard; Yutang Gao; Karl Gertow; Christian Gieger; Bruna Gigante; Harald Grallert; George B Grant; Leif C Grrop; Chrisropher J Groves; Elin Grundberg; Candace Guiducci; Anders Hamsten; Bok-Ghee Han; Kazuo Hara; Neelam Hassanali; Andrew T Hattersley; Caroline Hayward; Asa K Hedman; Christian Herder; Albert Hofman; Oddgeir L Holmen; Kees Hovingh; Astradur B Hreidarsson; Cheng Hu; Frank B Hu; Jennie Hui; Steve E Humphries; Sarah E Hunt; David J Hunter; Kristian Hveem; Zafar I Hydrie; Hiroshi Ikegami; Thomas Illig; Erik Ingelsson; Muhammed Islam; Bo Isomaa; Anne U Jackson; Tazeen Jafar; Alan James; Weiping Jia; Karl-Heinz Jöckel; Anna Jonsson; Jeremy B M Jowett; Takashi Kadowaki; Hyun Min Kang; Stavroula Kanoni; Wen Hong L Kao; Sekar Kathiresan; Norihiro Kato; Prasad Katulanda; Kirkka M Keinanen-Kiukaanniemi; Ann M Kelly; Hassan Khan; Kay-Tee Khaw; Chiea-Chuen Khor; Hyung-Lae Kim; Sangsoo Kim; Young Jin Kim; Leena Kinnunen; Norman Klopp; Augustine Kong; Eeva Korpi-Hyövälti; Sudhir Kowlessur; Peter Kraft; Jasmina Kravic; Malene M Kristensen; S Krithika; Ashish Kumar; Jesus Kumate; Johanna Kuusisto; Soo Heon Kwak; Markku Laakso; Vasiliki Lagou; Timo A Lakka; Claudia Langenberg; Cordelia Langford; Robert Lawrence; Karin Leander; Jen-Mai Lee; Nanette R Lee; Man Li; Xinzhong Li; Yun Li; Junbin Liang; Samuel Liju; Wei-Yen Lim; Lars Lind; Cecilia M Lindgren; Eero Lindholm; Ching-Ti Liu; Jian Jun Liu; Stéphane Lobbens; Jirong Long; Ruth J F Loos; Wei Lu; Jian'an Luan; Valeriya Lyssenko; Ronald C W Ma; Shiro Maeda; Reedik Mägi; Satu Männisto; David R Matthews; James B Meigs; Olle Melander; Andres Metspalu; Julia Meyer; Ghazala Mirza; Evelin Mihailov; Susanne Moebus; Viswanathan Mohan; Karen L Mohlke; Andrew D Morris; Thomas W Mühleisen; Martina Müller-Nurasyid; Bill Musk; Jiro Nakamura; Eitaro Nakashima; Pau Navarro; Peng-Keat Ng; Alexandra C Nica; Peter M Nilsson; Inger Njølstad; Markus M Nöthen; Keizo Ohnaka; Twee Hee Ong; Katharine R Owen; Colin N A Palmer; James S Pankow; Kyong Soo Park; Melissa Parkin; Sonali Pechlivanis; Nancy L Pedersen; Leena Peltonen; John R B Perry; Annette Peters; Janini M Pinidiyapathirage; Carl G Platou; Simon Potter; Jackie F Price; Lu Qi; Venkatesan Radha; Loukianos Rallidis; Asif Rasheed; Wolfgang Rathman; Rainer Rauramaa; Soumya Raychaudhuri; N William Rayner; Simon D Rees; Emil Rehnberg; Samuli Ripatti; Neil Robertson; Michael Roden; Elizabeth J Rossin; Igor Rudan; Denis Rybin; Timo E Saaristo; Veikko Salomaa; Juha Saltevo; Maria Samuel; Dharambir K Sanghera; Jouko Saramies; James Scott; Laura J Scott; Robert A Scott; Ayellet V Segrè; Joban Sehmi; Bengt Sennblad; Nabi Shah; Sonia Shah; A Samad Shera; Xiao Ou Shu; Alan R Shuldiner; Gunnar Sigurđsson; Eric Sijbrands; Angela Silveira; Xueling Sim; Suthesh Sivapalaratnam; Kerrin S Small; Wing Yee So; Alena Stančáková; Kari Stefansson; Gerald Steinbach; Valgerdur Steinthorsdottir; Kathleen Stirrups; Rona J Strawbridge; Heather M Stringham; Qi Sun; Chen Suo; Ann-Christine Syvänen; Ryoichi Takayanagi; Fumihiko Takeuchi; Wan Ting Tay; Tanya M Teslovich; Barbara Thorand; Gudmar Thorleifsson; Unnur Thorsteinsdottir; Emmi Tikkanen; Joseph Trakalo; Elena Tremoli; Mieke D Trip; Fuu Jen Tsai; Tiinamaija Tuomi; Jaakko Tuomilehto; Andre G Uitterlinden; Adan Valladares-Salgado; Sailaja Vedantam; Fabrizio Veglia; Benjamin F Voight; Congrong Wang; Nicholas J Wareham; Roman Wennauer; Ananda R Wickremasinghe; Tom Wilsgaard; James F Wilson; Steven Wiltshire; Wendy Winckler; Tien Yin Wong; Andrew R Wood; Jer-Yuarn Wu; Ying Wu; Ken Yamamoto; Toshimasa Yamauchi; Mingyu Yang; Loic Yengo; Mitsuhiro Yokota; Robin Young; Delilah Zabaneh; Fan Zhang; Rong Zhang; Wei Zheng; Paul Z Zimmet; David Altshuler; Donald W Bowden; Yoon Shin Cho; Nancy J Cox; Miguel Cruz; Craig L Hanis; Jaspal Kooner; Jong-Young Lee; Mark Seielstad; Yik Ying Teo; Michael Boehnke; Esteban J Parra; Jonh C Chambers; E Shyong Tai; Mark I McCarthy; Andrew P Morris Journal: Nat Genet Date: 2014-02-09 Impact factor: 38.330
Authors: Stanley Zammit; Daphne Kounali; Mary Cannon; Anthony S David; David Gunnell; Jon Heron; Peter B Jones; Shôn Lewis; Sarah Sullivan; Dieter Wolke; Glyn Lewis Journal: Am J Psychiatry Date: 2013-07 Impact factor: 18.112
Authors: Brendan Bulik-Sullivan; Hilary K Finucane; Verneri Anttila; Alexander Gusev; Felix R Day; Po-Ru Loh; Laramie Duncan; John R B Perry; Nick Patterson; Elise B Robinson; Mark J Daly; Alkes L Price; Benjamin M Neale Journal: Nat Genet Date: 2015-09-28 Impact factor: 38.330
Authors: Benjamin I Perry; Nicholas Bowker; Stephen Burgess; Nicholas J Wareham; Rachel Upthegrove; Peter B Jones; Claudia Langenberg; Golam M Khandaker Journal: Schizophr Bull Open Date: 2022-01-11