Dr Sophie Legge

Research Associate, Division of Psychological Medicine and Clinical Neurosciences

School of Medicine

: leggese8@cardiff.ac.uk
: +44 (0)29 2068 8837
: 2.30, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ

My research is primarily focused on the contribution of genetic and environmental factors to the development of psychosis and schizophrenia.

I am interested in dissecting the heterogeneity and dimensionality of schizophrenia by identifying biologically valid phenotypic constructs.

I am also interested in pharmacogenetics, specifically in relation to clozapine use and the Duffy-null genetic variant. My PhD (completed in 2016) was focused on identifying predictors of treatment-resistant schizophrenia, and the genetic causes of clozapine-induced neutropenia, a rare adverse effect of the antipsychotic clozapine.

2022

Caseras, X., Legge, S., Bracher-Smith, M., Anney, R., Owen, M., Escott-Price, V. and Kirov, G. 2022. Copy Number Variants increasing risk for schizophrenia: shared and distinct effects on brain morphometry and cognitive performance. Biological Psychiatry: Global Open Science
Woolway, G. et al. 2022. Schizophrenia polygenic risk and experiences of childhood adversity: a systematic review and meta-analysis. Schizophrenia Bulletin 48(5), pp. 967-980. (10.1093/schbul/sbac049)
Creeth, H. D. J. et al. 2022. Ultrarare coding variants and cognitive function in schizophrenia. JAMA Psychiatry 79(10), pp. 963-970. (10.1001/jamapsychiatry.2022.2289)
Kappel, D. B. et al. 2022. Genomic stratification of clozapine prescription patterns using schizophrenia polygenic scores. Biological Psychiatry (10.1016/j.biopsych.2022.07.014)
Jones, R., Upthegrove, R., Price, M. J., Pritchard, M., Chandan, J. S., Legge, S. and MacCabe, J. H. 2022. Duration of prior psychotic illness and clozapine response: a retrospective observational study using electronic health records. Therapeutic Advances in Psychopharmacology 12, pp. 1-12. (10.1177/20451253221103353)
Owen, M. and Legge, S. 2022. The nature of schizophrenia: as broad as it is long. Schizophrenia Research 242, pp. 109-112. (10.1016/j.schres.2021.10.012)
Chambers, T. et al. 2022. Genetic common variants associated with cerebellar volume and their overlap with mental disorders: a study on 33,265 individuals from the UK-Biobank. Molecular Psychiatry 27, pp. 2282-2290. (10.1038/s41380-022-01443-8)
Trubetskoy, V. et al. 2022. Mapping genomic loci prioritises genes and implicates synaptic biology in schizophrenia. Nature 604, pp. 502-508. (10.1038/s41586-022-04434-5)
Okhuijsen-Pfeifer, C. et al. 2022. Genome-wide association analyses of symptom severity among clozapine-treated patients with schizophrenia spectrum disorders. Translational Psychiatry 12, article number: 145. (10.1038/s41398-022-01884-3)
Vassos, E. et al. 2022. Lack of support for the genes by early environment interaction hypothesis in the pathogenesis of schizophrenia. Schizophrenia Bulletin 48(1), pp. 20-26. (10.1093/schbul/sbab052)
Sanders, B. et al. 2022. Transcriptional programs regulating neuronal differentiation are disrupted in DLG2 knockout human embryonic stem cells and enriched for schizophrenia and related disorders risk variants. Nature Communications 13(1), article number: 27. (10.1038/s41467-021-27601-0)
Pardinas, A. et al. 2022. Interaction testing and polygenic risk scoring to estimate the contribution of common genetic variants to treatment resistance in schizophrenia. JAMA Psychiatry 79(3), pp. 260-269. (10.1001/jamapsychiatry.2021.3799)
Creeth, H. D. J. et al. 2022. Ultra-rare coding variants and cognitive function in schizophrenia. JAMA Psychiatry

2021

Legge, S. E., Santoro, M. L., Periyasamy, S., Okewole, A., Arsalan, A. and Kowalec, K. 2021. Genetic architecture of schizophrenia: a review of major advancements. Psychological Medicine 51(13) (10.1017/S0033291720005334)
Dennison, C. et al. 2021. Risk factors, clinical features, and polygenic risk scores in schizophrenia and schizoaffective disorder depressive-type. Schizophrenia Bulletin 47(5), pp. 1375-1384. (10.1093/schbul/sbab036)
Legge, S. et al. 2021. Associations between schizophrenia polygenic liability, symptom dimensions, and cognitive ability in schizophrenia. JAMA Psychiatry 78(10), pp. 1143-1151. (10.1001/jamapsychiatry.2021.1961)
Hubbard, L. et al. 2021. Rare copy number variations are associated with poorer cognition in schizophrenia. Biological Psychiatry 90(1), pp. 28-34. (10.1016/j.biopsych.2020.11.025)
Willcocks, I. et al. 2021. Clozapine metabolism is associated with absolute neutrophil count in individuals with treatment-resistant schizophrenia. Frontiers in Pharmacology 12, article number: 658734. (10.3389/fphar.2021.658734)
Konte, B. et al. 2021. HLA-DQB1 6672G>C (rs113332494) is associated with clozapine-induced neutropenia and agranulocytosis in individuals of European ancestry. Translational Psychiatry 11, article number: 214. (10.1038/s41398-021-01322-w)
Dennison, C. A. et al. 2021. Association of genetic liability for psychiatric disorders with accelerometer-assessed physical activity in the UK Biobank. PLoS ONE 16(3), article number: e0249189. (10.1371/journal.pone.0249189)
Caseras, X. et al. 2021. Effects of genomic copy number variants penetrant for schizophrenia on cortical thickness and surface area in healthy individuals: analysis of the UK Biobank. British Journal of Psychiatry 218(2), pp. 104-111. (10.1192/bjp.2020.139)

2020

Kendall, K. M. et al. 2020. Impact of schizophrenia genetic liability on the association between schizophrenia and physical illness: a data linkage study. BJPsych Open 6(6), article number: e139. (10.1192/bjo.2020.42)
Legge, S. E. et al. 2020. The Duffy-null genotype and risk of infection. Human Molecular Genetics 29(20), pp. 3341-3349. (10.1093/hmg/ddaa208)
Casetta, C. et al. 2020. A retrospective study of intramuscular clozapine prescription for treatment initiation and maintenance in treatment-resistant psychosis. British Journal of Psychiatry 217(3), pp. 506-513. (10.1192/bjp.2020.115)
Grama, S. et al. 2020. Polygenic risk for schizophrenia and subcortical brain anatomy in the UK Biobank cohort. Translational Psychiatry 10, article number: 309. (10.1038/s41398-020-00940-0)
Legge, S. et al. 2020. Clinical indicators of treatment-resistant psychosis. British Journal of Psychiatry 216(5), pp. 259-266. (10.1192/bjp.2019.120)
Richards, A. et al. 2020. The relationship between polygenic risk scores and cognition in schizophrenia. Schizophrenia Bulletin 46(2), pp. -. (10.1093/schbul/sbz061)
Dennison, C. A., Legge, S. E., Pardinas, A. F. and Walters, J. T. 2020. Genome-wide association studies in schizophrenia: Recent advances, challenges and future perspective. Schizophrenia Research 217, pp. 4-12. (10.1016/j.schres.2019.10.048)
Rees, E. et al. 2020. De novo mutations identified by exome sequencing implicate rare missense variants in SLC6A1 in schizophrenia. Nature Neuroscience 23(2), pp. 179-184. (10.1038/s41593-019-0565-2)

2019

Legge, S. E. et al. 2019. Association of genetic liability to psychotic experiences with neuropsychotic disorders and traits. JAMA Psychiatry 76(12), pp. 1256-1265. (10.1001/jamapsychiatry.2019.2508)
Pardinas, A. F. et al. 2019. Pharmacogenomic variants and drug interactions identified through the genetic analysis of clozapine metabolism. American Journal of Psychiatry 176(6), pp. 477-486. (10.1176/appi.ajp.2019.18050589)
Kendall, K. M. et al. 2019. Association of rare copy number variants with risk of depression. JAMA Psychiatry 76(8), pp. 818-825. (10.1001/jamapsychiatry.2019.0566)
Legge, S. E. et al. 2019. A genome-wide association study in individuals of African ancestry reveals the importance of the Duffy-null genotype in the assessment of clozapine-related neutropenia. Molecular Psychiatry 24, pp. 328-337. (10.1038/s41380-018-0335-7)
Legge, S. E. and Walters, J. T. 2019. Genetics of clozapine-associated neutropenia: recent advances, challenges and future perspective. Pharmacogenomics 20(4), pp. 279-290. (10.2217/pgs-2018-0188)

2018

Ruderfer, D. M. et al. 2018. Genomic dissection of bipolar disorder and schizophrenia, including 28 subphenotypes. Cell 173(7), pp. 1705-1715.e16. (10.1016/j.cell.2018.05.046)
Lynham, A. et al. 2018. Examining cognition across the bipolar / schizophrenia diagnostic spectrum. Journal of Psychiatry and Neuroscience 43(3), article number: 170076. (10.1503/jpn.170076)
Pardinas, A. F. et al. 2018. Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection. Nature Genetics 50, pp. 381-389. (10.1038/s41588-018-0059-2)

2017

Legge, S. E. et al. 2017. Genome-wide common and rare variant analysis provides novel insights into clozapine-associated neutropenia. Molecular Psychiatry 22, pp. 1502-1508. (10.1038/mp.2016.97)
Köhler-Forsberg, O., Horsdal, H. T., Legge, S. E., MacCabe, J. H. and Gasse, C. 2017. Predictors of nonhospitalization and functional response in clozapine treatment: a nationwide, population-based cohort study. Journal of Clinical Psychopharmacology 37(2), pp. 148-154. (10.1097/JCP.0000000000000649)
McLaughlin, R. L. et al. 2017. Genetic correlation between amyotrophic lateral sclerosis and schizophrenia. Nature Communications 8, article number: 14774. (10.1038/ncomms14774)
Marshall, C. R. et al. 2017. Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects. Nature Genetics 49, pp. 27-35. (10.1038/ng.3725)

2016

Rees, E. et al. 2016. Analysis of intellectual disability copy number variants for association with schizophrenia. JAMA Psychiatry 73(9), pp. 963-969. (10.1001/jamapsychiatry.2016.1831)
Pardinas, A. et al. 2016. Common schizophrenia alleles are enriched in mutation-intolerant genes and maintained by background selection. [Online]. bioRxiv. (10.1101/068593) Available at: http://dx.doi.org/10.1101/068593
Legge, S. et al. 2016. Reasons for discontinuing clozapine: a cohort study of patients commencing treatment. Schizophrenia Research 174, pp. 113-119. (10.1016/j.schres.2016.05.002)
Thompson, J. V. et al. 2016. Antipsychotic polypharmacy and augmentation strategies prior to clozapine initiation: a historical cohort study of 310 adults with treatment-resistant schizophrenic disorders. Journal of Psychopharmacology 30(5), pp. 436-443. (10.1177/0269881116632376)
Franke, B. et al. 2016. Genetic influences on schizophrenia and subcortical brain volumes: large-scale proof of concept. Nature Neuroscience 19(3), pp. 420-431. (10.1038/nn.4228)

2015

Legge, S. E. 2015. Examining treatment response and adverse effects of clozapine. PhD Thesis, Cardiff University.

2014

Gusev, A. et al. 2014. Partitioning heritability of regulatory and cell-type-specific variants across 11 common diseases. American Journal of Human Genetics 95(5), pp. 535-552. (10.1016/j.ajhg.2014.10.004)
Ripke, S. et al. 2014. Biological insights from 108 schizophrenia-associated genetic loci. Nature 511(7510), pp. 421-427. (10.1038/nature13595)
Rees, E. et al. 2014. CNV analysis in a large schizophrenia sample implicates deletions at 16p12.1 and SLC1A1 and duplications at 1p36.33 and CGNL1. Human Molecular Genetics 23(6), pp. 1669-1676. (10.1093/hmg/ddt540)
Rees, E. et al. 2014. Analysis of copy number variations at 15 schizophrenia-associated loci. British Journal of Psychiatry 204(2), pp. 108-114. (10.1192/bjp.bp.113.131052)

2013

Rees, E. et al. 2013. Evidence that duplications of 22q11.2 protect against schizophrenia. Molecular Psychiatry n/a (10.1038/mp.2013.156)
Kirov, G. et al. 2013. The penetrance of copy number variations for schizophrenia and developmental delay. Biological Psychiatry 75(5), pp. 378-385. (10.1016/j.biopsych.2013.07.022)

2012

Potter, R. et al. 2012. Missed opportunities: mental disorder in children of parents with depression. British Journal of General Practice (BJGP) 62(600), pp. e487-e493. (10.3399/bjgp12X652355)