Hannah J Jones1, Evie Stergiakouli2, Katherine E Tansey2, Leon Hubbard3, Jon Heron4, Mary Cannon5, Peter Holmans3, Glyn Lewis6, David E J Linden3, Peter B Jones7, George Davey Smith2, Michael C O'Donovan3, Michael J Owen3, James T Walters3, Stanley Zammit8. 1. Centre for Academic Mental Health, School of Social and Community Medicine, University of Bristol, Bristol, England2Medical Research Council (MRC) Integrative Epidemiology Unit, University of Bristol, Bristol, England. 2. Medical Research Council (MRC) Integrative Epidemiology Unit, University of Bristol, Bristol, England. 3. MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Cardiff, Wales. 4. Centre for Academic Mental Health, School of Social and Community Medicine, University of Bristol, Bristol, England. 5. Department of Psychiatry, Royal College of Surgeons in Ireland, Dublin. 6. Division of Psychiatry, University College London, London, England. 7. Department of Psychiatry, University of Cambridge, Cambridge, England. 8. Centre for Academic Mental Health, School of Social and Community Medicine, University of Bristol, Bristol, England3MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University S.
Abstract
IMPORTANCE: Schizophrenia is a highly heritable, polygenic condition characterized by a relatively diverse phenotype and frequent comorbid conditions, such as anxiety and depression. At present, limited evidence explains how genetic risk for schizophrenia is manifest in the general population. OBJECTIVE: To investigate the extent to which genetic risk for schizophrenia is associated with different phenotypes during adolescence in a population-based birth cohort. DESIGN, SETTING, AND PARTICIPANTS: This cohort study used data from the Avon Longitudinal Study of Parents and Children (ALSPAC). Of 14,062 children in the birth cohort, genetic data were available for 9912 adolescents. Data were collected periodically from September 6, 1990, and collection is ongoing. Data were analyzed from March 4 to August 13, 2015. EXPOSURES: Polygenic risk scores (PRSs) for schizophrenia generated for individuals in the ALSPAC cohort using results of the second Psychiatric Genomics Consortium Schizophrenia genome-wide association study as a training set. MAIN OUTCOMES AND MEASURES: Logistic regression was used to assess associations between the schizophrenia PRS and (1) psychotic experiences (Psychosis-Like Symptom Interview at 12 and 18 years of age), (2) negative symptoms (Community Assessment of Psychic Experiences at 16.5 years of age), (3) depressive disorder (Development and Well-Being Assessment at 15.5 years of age), and (4) anxiety disorder (Development and Well-Being Assessment at 15.5 years of age) in adolescence. RESULTS: Of the 8230 ALSPAC participants whose genetic data passed quality control checks (51.2% male, 48.8% female), 3676 to 5444 participated in assessments from 12 to 18 years of age. The PRSs created using single-nucleotide polymorphisms with a training-set P ≤ .05 threshold were associated with negative symptoms (odds ratio [OR] per SD increase in PRS, 1.21; 95% CI, 1.08-1.36; R(2) = 0.007) and anxiety disorder (OR per SD increase in PRS, 1.17; 95% CI, 1.06- 1.29; R(2) = 0.005). No evidence was found of an association between schizophrenia PRS and psychotic experiences (OR per SD increase in PRS, 1.08; 95% CI, 0.98-1.19; R(2) = 0.001) or depressive disorder (OR per SD increase in PRS, 1.02; 95% CI, 0.91-1.13; R(2) = 0.00005). Results were mostly consistent across different training-set P value thresholds and using different cutoffs and measures of the psychopathological outcomes. CONCLUSIONS AND RELEVANCE: This study demonstrates polygenic overlaps between common genetic polymorphisms associated with schizophrenia and negative symptoms and anxiety disorder but not with psychotic experiences or depression. Because the genetic risk for schizophrenia appears to be manifest as anxiety and negative symptoms during adolescence, a greater focus on these phenotypes rather than on psychotic experiences might be required for prediction of transition in at-risk samples.
IMPORTANCE: Schizophrenia is a highly heritable, polygenic condition characterized by a relatively diverse phenotype and frequent comorbid conditions, such as anxiety and depression. At present, limited evidence explains how genetic risk for schizophrenia is manifest in the general population. OBJECTIVE: To investigate the extent to which genetic risk for schizophrenia is associated with different phenotypes during adolescence in a population-based birth cohort. DESIGN, SETTING, AND PARTICIPANTS: This cohort study used data from the Avon Longitudinal Study of Parents and Children (ALSPAC). Of 14,062 children in the birth cohort, genetic data were available for 9912 adolescents. Data were collected periodically from September 6, 1990, and collection is ongoing. Data were analyzed from March 4 to August 13, 2015. EXPOSURES: Polygenic risk scores (PRSs) for schizophrenia generated for individuals in the ALSPAC cohort using results of the second Psychiatric Genomics Consortium Schizophrenia genome-wide association study as a training set. MAIN OUTCOMES AND MEASURES: Logistic regression was used to assess associations between the schizophrenia PRS and (1) psychotic experiences (Psychosis-Like Symptom Interview at 12 and 18 years of age), (2) negative symptoms (Community Assessment of Psychic Experiences at 16.5 years of age), (3) depressive disorder (Development and Well-Being Assessment at 15.5 years of age), and (4) anxiety disorder (Development and Well-Being Assessment at 15.5 years of age) in adolescence. RESULTS: Of the 8230 ALSPAC participants whose genetic data passed quality control checks (51.2% male, 48.8% female), 3676 to 5444 participated in assessments from 12 to 18 years of age. The PRSs created using single-nucleotide polymorphisms with a training-set P ≤ .05 threshold were associated with negative symptoms (odds ratio [OR] per SD increase in PRS, 1.21; 95% CI, 1.08-1.36; R(2) = 0.007) and anxiety disorder (OR per SD increase in PRS, 1.17; 95% CI, 1.06- 1.29; R(2) = 0.005). No evidence was found of an association between schizophrenia PRS and psychotic experiences (OR per SD increase in PRS, 1.08; 95% CI, 0.98-1.19; R(2) = 0.001) or depressive disorder (OR per SD increase in PRS, 1.02; 95% CI, 0.91-1.13; R(2) = 0.00005). Results were mostly consistent across different training-set P value thresholds and using different cutoffs and measures of the psychopathological outcomes. CONCLUSIONS AND RELEVANCE: This study demonstrates polygenic overlaps between common genetic polymorphisms associated with schizophrenia and negative symptoms and anxiety disorder but not with psychotic experiences or depression. Because the genetic risk for schizophrenia appears to be manifest as anxiety and negative symptoms during adolescence, a greater focus on these phenotypes rather than on psychotic experiences might be required for prediction of transition in at-risk samples.
Authors: Theresa H M Moore; Stanley Zammit; Anne Lingford-Hughes; Thomas R E Barnes; Peter B Jones; Margaret Burke; Glyn Lewis Journal: Lancet Date: 2007-07-28 Impact factor: 79.321
Authors: Andy Boyd; Jean Golding; John Macleod; Debbie A Lawlor; Abigail Fraser; John Henderson; Lynn Molloy; Andy Ness; Susan Ring; George Davey Smith Journal: Int J Epidemiol Date: 2012-04-16 Impact factor: 7.196
Authors: Jeremy Horwood; Giovanni Salvi; Kate Thomas; Larisa Duffy; David Gunnell; Chris Hollis; Glyn Lewis; Paulo Menezes; Andrew Thompson; Dieter Wolke; Stanley Zammit; Glynn Harrison Journal: Br J Psychiatry Date: 2008-09 Impact factor: 9.319
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Caroline M Nievergelt; Ivan Nikolov; Vishwajit Nimgaonkar; Willem A Nolen; Markus M Nöthen; John I Nurnberger; Evaristus A Nwulia; Dale R Nyholt; Colm O'Dushlaine; Robert D Oades; Ann Olincy; Guiomar Oliveira; Line Olsen; Roel A Ophoff; Urban Osby; Michael J Owen; Aarno Palotie; Jeremy R Parr; Andrew D Paterson; Carlos N Pato; Michele T Pato; Brenda W Penninx; Michele L Pergadia; Margaret A Pericak-Vance; Benjamin S Pickard; Jonathan Pimm; Joseph Piven; Danielle Posthuma; James B Potash; Fritz Poustka; Peter Propping; Vinay Puri; Digby J Quested; Emma M Quinn; Josep Antoni Ramos-Quiroga; Henrik B Rasmussen; Soumya Raychaudhuri; Karola Rehnström; Andreas Reif; Marta Ribasés; John P Rice; Marcella Rietschel; Kathryn Roeder; Herbert Roeyers; Lizzy Rossin; Aribert Rothenberger; Guy Rouleau; Douglas Ruderfer; Dan Rujescu; Alan R Sanders; Stephan J Sanders; Susan L Santangelo; Joseph A Sergeant; Russell Schachar; Martin Schalling; Alan F Schatzberg; William A Scheftner; Gerard D Schellenberg; Stephen W Scherer; Nicholas J Schork; Thomas G Schulze; Johannes Schumacher; Markus Schwarz; Edward Scolnick; Laura J Scott; Jianxin Shi; Paul D Shilling; Stanley I Shyn; Jeremy M Silverman; Susan L Slager; Susan L Smalley; Johannes H Smit; Erin N Smith; Edmund J S Sonuga-Barke; David St Clair; Matthew State; Michael Steffens; Hans-Christoph Steinhausen; John S Strauss; Jana Strohmaier; T Scott Stroup; James S Sutcliffe; Peter Szatmari; Szabocls Szelinger; Srinivasa Thirumalai; Robert C Thompson; Alexandre A Todorov; Federica Tozzi; Jens Treutlein; Manfred Uhr; Edwin J C G van den Oord; Gerard Van Grootheest; Jim Van Os; Astrid M Vicente; Veronica J Vieland; John B Vincent; Peter M Visscher; Christopher A Walsh; Thomas H Wassink; Stanley J Watson; Myrna M Weissman; Thomas Werge; Thomas F Wienker; Ellen M Wijsman; Gonneke Willemsen; Nigel Williams; A Jeremy Willsey; Stephanie H Witt; Wei Xu; Allan H Young; Timothy W Yu; Stanley Zammit; Peter P Zandi; Peng Zhang; Frans G Zitman; Sebastian Zöllner; 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