Jiqing Li1,2, Fang Tang3,4, Shucheng Si1,2, Bojie Wang1,2, Fuzhong Xue1,2. 1. Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China. 2. Healthcare Big Data Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China. 3. Center for Big Data Research in Health and Medicine, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China. 4. Shandong Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
Abstract
AIMS: Little is known about the genetic basis of clozapine-related neutropaenia. This study aims to explore candidate genes and pathways involved in clozapine-related neutropaenia. METHODS: This study conducted a two-stage integrative analysis of the summary statistics from the genome-wide association study (GWAS, n = 552) of the lowest absolute neutrophil count (ANC) during clozapine treatment and the summary data of the expressed quantitative trait locus (eQTL). First, we use the probabilistic Mendelian randomization (PMR-Egger) to identify genes whose expression is causally related to ANC, and then use Bayesian co-localization analysis to investigate whether there are shared causal variants between them [posterior probability for hypotheses 4 (PP.H4) > 0.80]. Finally, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were conducted to explore the pathways that may be associated with ANC during clozapine treatment. RESULTS: PMR-Egger analysis identified 146 genes that may be causally associated with ANC after Bonferroni correction (P-value < 3.25e-6). Bayesian co-localization analysis identified six further genes whose gene expression shared common variants with ANC, including NT5E (PP.H4 = 0.96), GLDC (PP.H4 = 0.82), NUDT17 (PP.H4 = 0.88), MSH4 (PP.H4 = 0.88), PTER (PP.H4 = 0.89) and SERPINB6 (PP.H4 = 0.83). Enrichment analysis identified 52 GO terms and seven pathways associated with ANC, such as NAD metabolic process, drug catabolic process and glyoxylate and dicarboxylate metabolism. CONCLUSION: This study identified multiple candidate genes and pathways that may be involved in clozapine-related neutropaenia, providing novel clues for the mechanism of clozapine-related neutropaenia.
AIMS: Little is known about the genetic basis of clozapine-related neutropaenia. This study aims to explore candidate genes and pathways involved in clozapine-related neutropaenia. METHODS: This study conducted a two-stage integrative analysis of the summary statistics from the genome-wide association study (GWAS, n = 552) of the lowest absolute neutrophil count (ANC) during clozapine treatment and the summary data of the expressed quantitative trait locus (eQTL). First, we use the probabilistic Mendelian randomization (PMR-Egger) to identify genes whose expression is causally related to ANC, and then use Bayesian co-localization analysis to investigate whether there are shared causal variants between them [posterior probability for hypotheses 4 (PP.H4) > 0.80]. Finally, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were conducted to explore the pathways that may be associated with ANC during clozapine treatment. RESULTS: PMR-Egger analysis identified 146 genes that may be causally associated with ANC after Bonferroni correction (P-value < 3.25e-6). Bayesian co-localization analysis identified six further genes whose gene expression shared common variants with ANC, including NT5E (PP.H4 = 0.96), GLDC (PP.H4 = 0.82), NUDT17 (PP.H4 = 0.88), MSH4 (PP.H4 = 0.88), PTER (PP.H4 = 0.89) and SERPINB6 (PP.H4 = 0.83). Enrichment analysis identified 52 GO terms and seven pathways associated with ANC, such as NAD metabolic process, drug catabolic process and glyoxylate and dicarboxylate metabolism. CONCLUSION: This study identified multiple candidate genes and pathways that may be involved in clozapine-related neutropaenia, providing novel clues for the mechanism of clozapine-related neutropaenia.