TY - JOUR
T1 - The role of polygenic risk score gene-set analysis in the context of the omnigenic model of schizophrenia
AU - The Schizophrenia Working Group of the Psychiatric Genomics Consortium 2,
AU - Rammos, Alexandros
AU - Gonzalez, Lara A.Neira
AU - Weinberger, Daniel R.
AU - Mitchell, Kevin J.
AU - Nicodemus, Kristin K.
N1 - Funding Information:
AR and KKN were supported by the Irish Research Council GOPIG/2013/763 and by the Science Foundation Ireland [11/SIRG/B2183] to KKN, including support for LANG. Funding support for the Genome-Wide Association of Schizophrenia Study was provided by the National Institute of Mental Health (R01 MH67257, R01 MH59588, R01 MH59571, R01 MH59565, R01 MH59587, R01 MH60870, R01 MH59566, R01 MH59586, R01 MH61675, R01 MH60879, R01 MH81800, U01 MH46276, U01 MH46289 U01 MH46318, U01 MH79469, and U01 MH79470) and the genotyping of samples was provided through the Genetic Association Information Network. The datasets used for the analyses described in this manuscript were obtained from the database of Genotypes and Phenotypes (dbGaP) found at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession numbers phs000021/SARC, phs000167/GRU and phs000167/SARC. Samples and associated phenotype data for the Genome-Wide Association of Schizophrenia Study were provided by the Molecular Genetics of Schizophrenia Collaboration (PI: Pablo V. Gejman, Evanston Northwestern Healthcare and Northwestern University, Evanston, IL, USA). The PGC receives core support from NIMH (1U01MH109514-01). Statistical analyses were carried out on the Genetic Cluster Computer (http://www.geneticcluster.org) hosted by SURFsara and financially supported by the Netherlands Scientific Organization (NWO 480-05-003 PI: Posthuma) along with a supplement from the Dutch Brain Foundation and the VU University Amsterdam. Funding for data collection and genotyping was provided by numerous funding organizations internationally. A list is provided in the original PGC manuscript. A list of all members of the Schizophrenia Working Group of the Psychiatric Genomics Consortium 2 can be found in the supplemental information file. The authors declare no competing interests.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/8/1
Y1 - 2019/8/1
N2 - A recent development in the genetic architecture of schizophrenia suggested that an omnigenic model may underlie the risk for this disorder. The aim of our study was to use polygenic profile scoring to quantitatively assess whether a number of experimentally derived sets would contribute to the disorder above and beyond the omnigenic effect. Using the PGC2 secondary analysis schizophrenia case-control cohort (N = 29,125 cases and 34,836 controls), a robust polygenic signal was observed from gene sets based on TCF4, FMR1, upregulation from MIR137 and downregulation from CHD8. Additional analyses revealed a constant floor effect in the amount of variance explained, consistent with the omnigenic model. Thus, we report that putative core gene sets showed a significant effect above and beyond the floor effect that might be linked with the underlying omnigenic background. In addition, we demonstrate a method to quantify the contribution of specific gene sets within the omnigenic context.
AB - A recent development in the genetic architecture of schizophrenia suggested that an omnigenic model may underlie the risk for this disorder. The aim of our study was to use polygenic profile scoring to quantitatively assess whether a number of experimentally derived sets would contribute to the disorder above and beyond the omnigenic effect. Using the PGC2 secondary analysis schizophrenia case-control cohort (N = 29,125 cases and 34,836 controls), a robust polygenic signal was observed from gene sets based on TCF4, FMR1, upregulation from MIR137 and downregulation from CHD8. Additional analyses revealed a constant floor effect in the amount of variance explained, consistent with the omnigenic model. Thus, we report that putative core gene sets showed a significant effect above and beyond the floor effect that might be linked with the underlying omnigenic background. In addition, we demonstrate a method to quantify the contribution of specific gene sets within the omnigenic context.
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U2 - 10.1038/s41386-019-0410-z
DO - 10.1038/s41386-019-0410-z
M3 - Article
C2 - 31078131
AN - SCOPUS:85066106747
SN - 0893-133X
VL - 44
SP - 1562
EP - 1569
JO - Neuropsychopharmacology
JF - Neuropsychopharmacology
IS - 9
ER -