title: Molecular validation of the schizophrenia spectrum.
abstract: BACKGROUND
  Early descriptive work and controlled family and adoption studies support the hypothesis that a range of personality and nonschizophrenic psychotic disorders aggregate in families of schizophrenic probands. Can we validate, using molecular polygene scores from genome-wide association studies (GWAS), this schizophrenia spectrum?
  
  
  METHODS
  The predictive value of polygenic findings reported by the Psychiatric GWAS Consortium (PGC) was applied to 4 groups of relatives from the Irish Study of High-Density Schizophrenia Families (ISHDSF; N = 836) differing on their assignment within the schizophrenia spectrum. Genome-wide single nucleotide polymorphism data for affected and unaffected relatives were used to construct per-individual polygene risk scores based on the PGC stage-I results. We compared mean polygene scores in the ISHDSF with mean scores in ethnically matched population controls (N = 929).
  
  
  RESULTS
  The schizophrenia polygene score differed significantly across diagnostic categories and was highest in those with narrow schizophrenia spectrum, lowest in those with no psychiatric illness, and in-between in those classified in the intermediate, broad, and very broad schizophrenia spectrum. Relatives of all of these groups of affected subjects, including those with no diagnosis, had schizophrenia polygene scores significantly higher than the control sample.
  
  
  CONCLUSIONS
  In the relatives of high-density families, the observed pattern of enrichment of molecular indices of schizophrenia risk suggests an underlying, continuous liability distribution and validates, using aggregate common risk alleles, a genetic basis for the schizophrenia spectrum disorders. In addition, as predicted by genetic theory, nonpsychotic members of multiply-affected schizophrenia families are significantly enriched for replicated, polygenic risk variants compared with the general population.
authors: *To whom correspondence should be addressed; Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics of VCU, Box 980126, Richmond, VA 23298-0126, US; tel: (804)-828-8590, fax: (804)-828-1471, e-mail: kendler@vcu.edu.
authors: T Bernard
authors: TB
authors: Bigdeli
authors: Silviu-Alin
authors: SA
authors: Bacanu
authors: Bradley T
authors: BT
authors: Webb
authors: Dermot
authors: D
authors: Walsh
authors: F Anthony
authors: FA
authors: O'Neill
authors: Ayman H
authors: AH
authors: Fanous
authors: Brien P
authors: BP
authors: Riley
authors: Kenneth S
authors: KS
authors: Kendler
mesh_terms: D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007494:Ireland / Q000453:epidemiology; D020412:Multifactorial Inheritance / Q000235:genetics*; D009660:Northern Ireland / Q000453:epidemiology; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011237:Predictive Value of Tests; D012559:Schizophrenia / Q000145:classification / Q000453:epidemiology / Q000235:genetics*
keywords: GWAS; polygene score; schizophrenia; schizophrenia spectrum
references: Am J Med Genet. 1996 Jul 26;67(4):332-7
references: 8837698
references: Proc Annu Meet Am Psychopathol Assoc. 1975;(63):147-65
references: 1242222
references: Arch Gen Psychiatry. 1993 Oct;50(10):781-8
references: 8215802
references: Schizophr Bull. 1989;15(4):559-71
references: 2623438
references: Am J Psychiatry. 1995 May;152(5):749-54
references: 7726315
references: Am J Hum Genet. 2009 Dec;85(6):847-61
references: 19931040
references: Arch Gen Psychiatry. 1994 Jun;51(6):456-68
references: 8192548
references: Schizophr Bull. 1988;14(2):217-22
references: 3201179
references: Arch Gen Psychiatry. 2001 Jun;58(6):581-8
references: 11386988
references: G3 (Bethesda). 2011 Nov;1(6):457-70
references: 22384356
references: Schizophr Bull. 1985;11(4):538-53
references: 3909377
references: Arch Gen Psychiatry. 1979 Jan;36(1):17-24
references: 760694
references: Am J Med Genet. 1996 Apr 9;67(2):179-90
references: 8723045
references: Nature. 2012 Nov 1;491(7422):56-65
references: 23128226
references: Nat Genet. 2011 Sep 18;43(10):969-76
references: 21926974
references: Arch Gen Psychiatry. 1993 Aug;50(8):645-52
references: 8343035
references: Schizophr Bull. 2013 Nov;39(6):1252-60
references: 23155182
references: PLoS Genet. 2009 Jun;5(6):e1000529
references: 19543373
references: Nature. 2009 Aug 6;460(7256):748-52
references: 19571811
references: Neurosci Lett. 2011 May 20;495(3):216-20
references: 21457757
references: Biol Psychiatry. 2012 Oct 15;72(8):620-8
references: 22883433
references: Am J Hum Genet. 2007 Sep;81(3):559-75
references: 17701901
references: Arch Gen Psychiatry. 1993 Jul;50(7):527-40
references: 8317947
references: Mol Psychiatry. 2010 Jan;15(1):29-37
references: 19844207
references: Arch Gen Psychiatry. 1994 Jun;51(6):442-55
references: 8192547
references: Mol Psychiatry. 2007 Oct;12(10):958-65
references: 17440434
references: Mol Psychiatry. 2011 Apr;16(4):429-41
references: 20368704
references: Am J Hum Genet. 2003 Feb;72(2):498-9
references: 12596795
references: Am J Psychiatry. 1983 Nov;140(11):1437-42
references: 6624988
references: Nat Methods. 2011 Dec 04;9(2):179-81
references: 22138821