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

Bigdeli, Tim B., Ripke, Stephan, Bacanu, Silviu-Alin, Lee, Sang Hong, Wray, Naomi R., Gejman, Pablo V., Rietschel, Marcella, Cichon, Sven, St Clair, David, Corvin, Aiden, Kirov, George, Mcquillin, Andrew, Gurling, Hugh, Rujescu, Dan, Andreassen, Ole A., Werge, Thomas, Blackwood, Douglas H.R., Pato, Carlos N., Pato, Michele T., Malhotra, Anil K., O'Donovan, Michael C., Kendler, Kenneth S. and Fanous, Ayman H. (2015) Genome-wide association study reveals greater polygenic loading for schizophrenia in cases with a family history of illness. American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics, 171 2: 276-289. doi:10.1002/ajmg.b.32402


Author Bigdeli, Tim B.
Ripke, Stephan
Bacanu, Silviu-Alin
Lee, Sang Hong
Wray, Naomi R.
Gejman, Pablo V.
Rietschel, Marcella
Cichon, Sven
St Clair, David
Corvin, Aiden
Kirov, George
Mcquillin, Andrew
Gurling, Hugh
Rujescu, Dan
Andreassen, Ole A.
Werge, Thomas
Blackwood, Douglas H.R.
Pato, Carlos N.
Pato, Michele T.
Malhotra, Anil K.
O'Donovan, Michael C.
Kendler, Kenneth S.
Fanous, Ayman H.
Title Genome-wide association study reveals greater polygenic loading for schizophrenia in cases with a family history of illness
Journal name American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics   Check publisher's open access policy
ISSN 1552-485X
1552-4841
Publication date 2015-12-11
Year available 2015
Sub-type Article (original research)
DOI 10.1002/ajmg.b.32402
Open Access Status Not yet assessed
Volume 171
Issue 2
Start page 276
End page 289
Total pages 14
Place of publication Hoboken, NJ, United States
Publisher John Wiley & Sons
Language eng
Subject 2716 Genetics (clinical)
2738 Psychiatry and Mental health
2804 Cellular and Molecular Neuroscience
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.
Keyword Schizophrenia
Polygenic
GWAS
Family history
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID G0901310
G1000708
PDA/02/06/016
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Queensland Brain Institute Publications
Official 2016 Collection
 
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