Genome-Wide Association Study Reveals Greater Polygenic Loading for Schizophrenia in Cases With a Family History of Illness

Title
Genome-Wide Association Study Reveals Greater Polygenic Loading for Schizophrenia in Cases With a Family History of Illness
Publication Date
2016
Author(s)
Bigdeli, Tim B
Ripke, Stephan
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
Bacanu, Silviu-Alin
O'Donovan, Michael C.
Kendler, Kenneth S
Fanous, Ayman H
Lee, Sang Hong
Wray, Naomi R
Gejman, Pablo V
Rietschel, Marcella
Cichon, Sven
St Clair, David
Corvin, Aiden
Type of document
Journal Article
Language
en
Entity Type
Publication
Publisher
John Wiley & Sons, Inc
Place of publication
United States of America
DOI
10.1002/ajmg.b.32402
UNE publication id
une:19005
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; P¼0.00331; 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.
Link
Citation
American Journal of Medical Genetics. Part B: Neuropsychiatric Genetics, 171(2), p. 276-289
ISSN
1552-485X
1552-4841
Start page
276
End page
289

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