Psychosis Endophenotypes: A Gene-Set-Specific Polygenic Risk Score Analysis.
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Wang Baihan, Irizar Haritz, Thygesen Johan H, Zartaloudi Eirini, Austin-Zimmerman Isabelle, Bhat Anjali, Harju-Seppänen Jasmine, Pain Oliver, Bass Nick, Gkofa Vasiliki, Alizadeh Behrooz Z, van Amelsvoort Therese, Arranz Maria J, Bender Stephan, Cahn Wiepke, Stella Calafato Maria, Crespo-Facorro Benedicto, Di Forti Marta, Genetic Risk and Outcome of Psychosis (GROUP) Study, Giegling Ina, de Haan Lieuwe, Hall Jeremy, Hall Mei-Hua, van Haren Neeltje, Iyegbe Conrad, Kahn René S, Kravariti Eugenia, Lawrie Stephen M, Lin Kuang, Luykx Jurjen J, Mata Ignacio, McDonald Colm, McIntosh Andrew M, Murray Robin M, Psychosis Endophenotypes International Consortium (PEIC), Picchioni Marco, Powell John, Prata Diana P, Rujescu Dan, Rutten Bart P F, Shaikh Madiha, Simons Claudia J P, Toulopoulou Timothea, Weisbrod Matthias, van Winkel Ruud, Kuchenbaecker Karoline, McQuillin Andrew, Bramon Elvira
Аннотация
STUDY DESIGN: We computed polygenic risk scores for schizophrenia and bipolar disorder restricted to brain-related gene sets retrieved from public databases and previous publications. Three hundred and seventy-eight gene-set-specific polygenic risk scores were generated for 4506 participants. Seven endophenotypes were also measured in the sample. Linear mixed-effects models were fitted to test associations between each endophenotype and each gene-set-specific polygenic risk score.
STUDY RESULTS: After correction for multiple testing, we found that a reduced P300 amplitude was associated with a higher schizophrenia polygenic risk score of the forebrain regionalization gene set (mean difference per SD increase in the polygenic risk score: -1.15 µV; 95% CI: -1.70 to -0.59 µV; P = 6 × 10-5). The schizophrenia polygenic risk score of forebrain regionalization also explained more variance of the P300 amplitude (R2 = 0.032) than other polygenic risk scores, including the genome-wide polygenic risk scores.
CONCLUSIONS: Our finding on reduced P300 amplitudes suggests that certain genetic variants alter early brain development thereby increasing schizophrenia risk years later. Gene-set-specific polygenic risk scores are a useful tool to elucidate biological mechanisms of psychosis and endophenotypes, offering leads for experimental validation in cellular and animal models.