Genome-wide association study reveals greater polygenic loading for schizophrenia in cases with a family history of illness

and Schizophrenia Working Group of the Psychiatric Genomics Consortium, Tim B. Bigdeli, Stephan Ripke, Silviu Alin Bacanu, Sang Hong Lee, Naomi R. Wray, Pablo V. Gejman, Hong Lee, Sven Cichon, David St Clair, Aiden Corvin, George Kirov, Andrew Mcquillin, Hugh Gurling, Dan Rujescu, Ole A. Andreassen, Thomas Werge, Douglas H.R. Blackwood, Carlos N. Pato, Michele T. Pato & 4 others Anil K. Malhotra, Michael C. O'Donovan, Kenneth S. Kendler, Ayman H. Fanous

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19 Citations (Scopus)

Abstract

Genome-wide association studies (GWAS) of schizophrenia have yielded more than 100 common susceptibility variants, and strongly support a substantial polygenic contribution of a large number of small allelic effects. It has been hypothesized that familial schizophrenia is largely a consequence of inherited rather than environmental factors. We investigated the extent to which familiality of schizophrenia is associated with enrichment for common risk variants detectable in a large GWAS. We analyzed single nucleotide polymorphism (SNP) data for cases reporting a family history of psychotic illness (N=978), cases reporting no such family history (N=4,503), and unscreened controls (N=8,285) from the Psychiatric Genomics Consortium (PGC1) study of schizophrenia. We used a multinomial logistic regression approach with model-fitting to detect allelic effects specific to either family history subgroup. We also considered a polygenic model, in which we tested whether family history positive subjects carried more schizophrenia risk alleles than family history negative subjects, on average. Several individual SNPs attained suggestive but not genome-wide significant association with either family history subgroup. Comparison of genome-wide polygenic risk scores based on GWAS summary statistics indicated a significant enrichment for SNP effects among family history positive compared to family history negative cases (Nagelkerke's R2=0.0021; P=0.00331; P-value threshold <0.4). Estimates of variability in disease liability attributable to the aggregate effect of genome-wide SNPs were significantly greater for family history positive compared to family history negative cases (0.32 and 0.22, respectively; P=0.031). We found suggestive evidence of allelic effects detectable in large GWAS of schizophrenia that might be specific to particular family history subgroups. However, consideration of a polygenic risk score indicated a significant enrichment among family history positive cases for common allelic effects. Familial illness might, therefore, represent a more heritable form of schizophrenia, as suggested by previous epidemiological studies.

LanguageEnglish
Pages276-289
Number of pages14
JournalAmerican Journal of Medical Genetics, Part B: Neuropsychiatric Genetics
Volume171
Issue number2
DOIs
Publication statusPublished - 1 Mar 2016

Keywords

  • Family history
  • GWAS
  • Polygenic
  • Schizophrenia

ASJC Scopus subject areas

  • Genetics(clinical)
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

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