Genome-wide common and rare variant analysis provides novel insights into clozapine-associated neutropenia

S E Legge, M L Hamshere, S Ripke, A F Pardinas, J I Goldstein, E Rees, A L Richards, G Leonenko, L F Jorskog, K D Chambert, D A Collier, G Genovese, I Giegling, P Holmans, A Jonasdottir, G Kirov, S A McCarroll, J H MacCabe, K Mantripragada, J L MoranB M Neale, H Stefansson, D Rujescu, M J Daly, P F Sullivan, M J Owen, M C O'Donovan, J T R Walters, Clozapine-Induced Agranulocytosis Consortium

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Abstract

The antipsychotic clozapine is uniquely effective in the management of schizophrenia; however, its use is limited by its potential to induce agranulocytosis. The causes of this, and of its precursor neutropenia, are largely unknown, although genetic factors have an important role. We sought risk alleles for clozapine-associated neutropenia in a sample of 66 cases and 5583 clozapine-treated controls, through a genome-wide association study (GWAS), imputed human leukocyte antigen (HLA) alleles, exome array and copy-number variation (CNV) analyses. We then combined associated variants in a meta-analysis with data from the Clozapine-Induced Agranulocytosis Consortium (up to 163 cases and 7970 controls). In the largest combined sample to date, we identified a novel association with rs149104283 (odds ratio (OR)=4.32, P=1.79 × 10(-8)), intronic to transcripts of SLCO1B3 and SLCO1B7, members of a family of hepatic transporter genes previously implicated in adverse drug reactions including simvastatin-induced myopathy and docetaxel-induced neutropenia. Exome array analysis identified gene-wide associations of uncommon non-synonymous variants within UBAP2 and STARD9. We additionally provide independent replication of a previously identified variant in HLA-DQB1 (OR=15.6, P=0.015, positive predictive value=35.1%). These results implicate biological pathways through which clozapine may act to cause this serious adverse effect.Molecular Psychiatry advance online publication, 12 July 2016; doi:10.1038/mp.2016.97.

Original languageEnglish
Pages (from-to)1502–1508
JournalMolecular Psychiatry
Volume22
Early online date12 Jul 2016
DOIs
Publication statusE-pub ahead of print - 12 Jul 2016

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  • Genome-wide common and rare variant analysis provides novel insights into clozapine-associated neutropenia

    Legge, S. E., Hamshere, M. L., Ripke, S., Pardinas, A. F., Goldstein, J. I., Rees, E., Richards, A. L., Leonenko, G., Jorskog, L. F., Chambert, K. D., Collier, D. A., Genovese, G., Giegling, I., Holmans, P., Jonasdottir, A., Kirov, G., McCarroll, S. A., MacCabe, J. H., Mantripragada, K., Moran, J. L., & 9 othersNeale, B. M., Stefansson, H., Rujescu, D., Daly, M. J., Sullivan, P. F., Owen, M. J., O'Donovan, M. C., Walters, J. T. R. & Clozapine-Induced Agranulocytosis Consortium, Jan 2018, In: Molecular Psychiatry. 23, 1, p. 162-163 2 p.

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