title: Phenotypic Manifestation of Genetic Risk for Schizophrenia During Adolescence in the General Population.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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
  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.affiliation: 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.
authors.forename: Hannah J
authors.initials: HJ
authors.lastname: Jones
authors.affiliation: Medical Research Council (MRC) Integrative Epidemiology Unit, University of Bristol, Bristol, England.
authors.forename: Evie
authors.initials: E
authors.lastname: Stergiakouli
authors.affiliation: Medical Research Council (MRC) Integrative Epidemiology Unit, University of Bristol, Bristol, England.
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Tansey
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Cardiff, Wales.
authors.forename: Leon
authors.initials: L
authors.lastname: Hubbard
authors.affiliation: Centre for Academic Mental Health, School of Social and Community Medicine, University of Bristol, Bristol, England.
authors.forename: Jon
authors.initials: J
authors.lastname: Heron
authors.affiliation: Department of Psychiatry, Royal College of Surgeons in Ireland, Dublin.
authors.forename: Mary
authors.initials: M
authors.lastname: Cannon
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Cardiff, Wales.
authors.forename: Peter
authors.initials: P
authors.lastname: Holmans
authors.affiliation: Division of Psychiatry, University College London, London, England.
authors.forename: Glyn
authors.initials: G
authors.lastname: Lewis
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Cardiff, Wales.
authors.forename: David E J
authors.initials: DE
authors.lastname: Linden
authors.affiliation: Department of Psychiatry, University of Cambridge, Cambridge, England.
authors.forename: Peter B
authors.initials: PB
authors.lastname: Jones
authors.affiliation: Medical Research Council (MRC) Integrative Epidemiology Unit, University of Bristol, Bristol, England.
authors.forename: George
authors.initials: G
authors.lastname: Davey Smith
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Cardiff, Wales.
authors.forename: Michael C
authors.initials: MC
authors.lastname: O'Donovan
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Cardiff, Wales.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Owen
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Cardiff, Wales.
authors.forename: James T
authors.initials: JT
authors.lastname: Walters
authors.affiliation: 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.
authors.forename: Stanley
authors.initials: S
authors.lastname: Zammit
mesh_terms: D000293:Adolescent; D000294:Adolescent Behavior; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D018570:Risk Assessment; D012307:Risk Factors; D012559:Schizophrenia / Q000235:genetics*
references.citation: Soc Psychiatry Psychiatr Epidemiol. 2014 Feb;49(2):169-82
references.pmid: 24435092
references.citation: Nat Genet. 2013 Sep;45(9):984-94
references.pmid: 23933821
references.citation: Arch Gen Psychiatry. 1992 Jan;49(1):37-46
references.pmid: 1728250
references.citation: World J Biol Psychiatry. 2014 Apr;15(3):200-8
references.pmid: 22404658
references.citation: Int J Epidemiol. 2013 Feb;42(1):111-27
references.pmid: 22507743
references.citation: Schizophr Bull. 2009 Mar;35(2):383-402
references.pmid: 19011234
references.citation: Eur Psychiatry. 2002 Mar;17(1):9-16
references.pmid: 11918987
references.citation: Schizophr Res. 2011 Nov;132(2-3):220-7
references.pmid: 21764562
references.citation: Schizophr Bull. 2010 May;36(3):472-85
references.pmid: 20453041
references.citation: PLoS One. 2012;7(6):e37852
references.pmid: 22761660
references.citation: J Child Psychol Psychiatry. 2000 Jul;41(5):645-55
references.pmid: 10946756
references.citation: Psychol Med. 2014 Sep;44(12):2557-66
references.pmid: 25055173
references.citation: Behav Genet. 2015 Sep;45(5):493-502
references.pmid: 26049723
references.citation: Nat Genet. 2013 Oct;45(10):1150-9
references.pmid: 23974872
references.citation: Schizophr Bull. 2014 Jan;40(1):28-38
references.pmid: 23960245
references.citation: Schizophr Bull. 2016 May;42(3):832-42
references.pmid: 26678674
references.citation: Am J Psychiatry. 2013 Jul;170(7):742-50
references.pmid: 23639948
references.citation: Lancet. 2007 Jul 28;370(9584):319-28
references.pmid: 17662880
references.citation: Biol Psychiatry. 2013 May 15;73(10):938-43
references.pmid: 23419543
references.citation: PLoS Genet. 2013 Mar;9(3):e1003348
references.pmid: 23555274
references.citation: Schizophr Bull. 2014 Jan;40(1):120-31
references.pmid: 23180756
references.citation: Nature. 2014 Jul 24;511(7510):421-7
references.pmid: 25056061
references.citation: Psychol Med. 2014 Jan;44(1):17-24
references.pmid: 23414600
references.citation: Am J Psychiatry. 1988 Sep;145(9):1077-83
references.pmid: 3414849
references.citation: Am J Epidemiol. 2016 Jun 15;183(12):1149-58
references.pmid: 27188935
references.citation: Soc Psychiatry Psychiatr Epidemiol. 2001 May;36(5):235-43
references.pmid: 11515701
references.citation: Int J Epidemiol. 2013 Feb;42(1):97-110
references.pmid: 22507742
references.citation: Behav Brain Res. 2000 Aug;113(1-2):117-20
references.pmid: 10942038
references.citation: Mol Psychiatry. 2011 Jul;16(7):773-83
references.pmid: 20567237
references.citation: Schizophr Bull. 2008 May;34(3):568-79
references.pmid: 18003630
references.citation: Br J Psychiatry. 2008 Sep;193(3):185-91
references.pmid: 18757973
references.citation: Schizophr Bull. 2014 Nov;40(6):1254-62
references.pmid: 24174267
references.citation: Lancet. 2013 Apr 20;381(9875):1371-1379
references.pmid: 23453885
references.citation: Lancet. 1994 Nov 19;344(8934):1398-402
references.pmid: 7968076
references.citation: Nature. 2009 Aug 6;460(7256):748-52
references.pmid: 19571811
references.citation: Curr Psychiatry Rep. 2013 May;15(5):354
references.pmid: 23532444
references.citation: PLoS One. 2014 Apr 09;9(4):e94398
references.pmid: 24718684
references.citation: Soc Psychiatry Psychiatr Epidemiol. 2011 Jun;46(6):521-32
references.pmid: 20376427
references.citation: Am J Hum Genet. 2007 Sep;81(3):559-75
references.pmid: 17701901
references.citation: JAMA Psychiatry. 2014 Sep;71(9):1049-57
references.pmid: 25075799
references.citation: Br J Psychiatry. 2013 Aug;203(2):107-11
references.pmid: 23703318
references.citation: Am J Psychiatry. 2013 Jul;170(7):734-41
references.pmid: 23599019
references.citation: Psychol Med. 2002 Feb;32(2):347-58
references.pmid: 11866327
references.citation: Am J Psychiatry. 1978 Apr;135(4):420-6
references.pmid: 637135
references.citation: Mol Psychiatry. 2016 Sep;21(9):1188-93
references.pmid: 26303664
references.citation: Am J Psychiatry. 2012 Dec;169(12):1309-17
references.pmid: 23212062