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ADAMTSL3 As a Candidate Gene for Schizophrenia: Gene Sequencing and Ultra-High Density Association Analysis by Imputation

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ADAMTSL3 As a Candidate Gene for Schizophrenia: Gene Sequencing and Ultra-High Density Association Analysis by Imputation Schizophrenia Research 127 (2011) 28–34 Contents lists available at ScienceDirect Schizophrenia Research journal homepage: www.elsevier.com/locate/schres ADAMTSL3 as a candidate gene for schizophrenia: Gene sequencing and ultra-high density association analysis by imputation David J. Dow a, Julie Huxley-Jones b, Jamie M. Hall a, Clyde Francks b, Peter R. Maycox a, James N.C. Kew a, Israel S. Gloger a, Nalini A.L. Mehta a, Fiona M. Kelly a, Pierandrea Muglia b, Gerome Breen c, Sarah Jugurnauth c, Inti Pederoso c, David St.Clair d, Dan Rujescu e, Michael R. Barnes b,c,⁎ a Molecular Discovery Research, GlaxoSmithKline Pharmaceuticals, New Frontiers Science Park (North), Third Avenue, Harlow, CM19 5AW, UK b Computational Biology and Genetics, Quantitative Sciences, Drug Discovery, GlaxoSmithKline Pharmaceuticals, Gunnels Wood Road, Stevenage, SG1 2NY, UK c Division of Psychological Medicine and Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College, London, UK d Department of Mental Health, University of Aberdeen, Aberdeen, United Kingdom e Division of Molecular and Clinical Neurobiology, Department of Psychiatry, Ludwig-Maximilians-University, Munich, Germany article info abstract Article history: We previously reported an association with a putative functional variant in the ADAMTSL3 gene, just below Received 27 July 2010 genome-wide significance in a genome-wide association study of schizophrenia. As variants impacting the Received in revised form 29 November 2010 function of ADAMTSL3 (a disintegrin-like and metalloprotease domain with thrombospondin type I motifs- Accepted 11 December 2010 like-3) could illuminate a novel disease mechanism and a potentially specific target, we have used Available online 15 January 2011 complementary approaches to further evaluate the association. We imputed genotypes and performed high density association analysis using data from the HapMap and 1000 genomes projects. To review all variants Keywords: Schizophrenia that could potentially cause the association, and to identify additional possible pathogenic rare variants, we ADAMTSL3 sequenced ADAMTSL3 in 92 schizophrenics. A total of 71 ADAMTSL3 variants were identified by sequencing, Extracellular matrix many were also seen in the 1000 genomes data, but 26 were novel. None of the variants identified by re- Imputation sequencing was in strong linkage disequilibrium (LD) with the associated markers. Imputation analysis Association refined association between ADAMTSL3 and schizophrenia, and highlighted additional common variants with Sequencing similar levels of association. We evaluated the functional consequences of all variants identified by sequencing, or showing direct or imputed association. The strongest evidence for function remained with the originally associated variant, rs950169, suggesting that this variant may be causal of the association. Rare variants were also identified with possible functional impact. Our study confirms ADAMTSL3 as a candidate for further investigation in schizophrenia, using the variants identified here. The utility of imputation analysis is demonstrated, and we recommend wider use of this method to re-evaluate the existing canon of suggestive schizophrenia associations. © 2011 Elsevier B.V. All rights reserved. 1. Background cohorts (Brzustowicz, 2007), while a great deal of effort has also been expended on candidate gene association studies, which have also Despite evidence for high heritability, the identification of genes been largely non replicable. The focus is now shifting to well-powered conferring schizophrenia risk has consistently proved problematic. genome-wide association studies (GWAS) (Purcell et al., 2009; Shi Early linkage studies have largely failed to replicate in independent et al., 2009; Stefansson et al., 2009). We previously carried out a GWAS for schizophrenia susceptibility in a cohort of 871 cases and 863 controls (Need et al., 2009). The strongest association was ⁎ Corresponding author. Computational Biology, GlaxoSmithKline Pharmaceuticals, localised to the ADAMTSL3 (a disintegrin-like and metalloprotease Gunnels Wood Road, Stevenage, SG1 2NY, UK. Tel.: +44 1279 622652; fax: +44 1279 domain with thrombospondin type I motifs-like) gene. Three single 622200. E-mail addresses: [email protected] (D.J. Dow), [email protected] nucleotide polymorphisms (SNPs) in complete linkage disequilibri- (J. Huxley-Jones), [email protected] (J.M. Hall), [email protected] (C. Francks), um, rs2135551, rs950169 and rs1911155, were highly significantly [email protected] (P.R. Maycox), [email protected] (I.S. Gloger), associated. The lowest combined p-value across the original and first [email protected] (N.A.L. Mehta), [email protected] (F.M. Kelly), replication study was 1.3×10− 7 (rs2135551, odds ratio: 0.68, case/ [email protected] (P. Muglia), [email protected] (G. Breen), control minor allele freq: 0.23/0.30). However after applying a [email protected] (S. Jugurnauth), [email protected] fi (I. Pederoso), [email protected] (D. St.Clair), [email protected] Bonferroni correction, the genome-wide threshold for 5% signi cance − 7 (D. Rujescu), [email protected] (M.R. Barnes). was 1.6×10 , confirming that the association was suggestive, but 0920-9964/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2010.12.009 D.J. Dow et al. / Schizophrenia Research 127 (2011) 28–34 29 fell short of this threshold (McCarthy et al., 2008). The case for from the foetus to the adult (Supplementary Fig. 1a and b). Although ADAMTSL3 in schizophrenia was subsequently strengthened by in vivo the gene has not been directly investigated in synaptogenesis or and in vitro evidence that the rs950169 minor allele mediated synaptic remodelling, considering the known biology of other alternative splicing, resulting in a truncated PLAC (protease and superfamily members in the neural ECM, we propose that ADAMTSL3 lacunin) domain in the carboxy terminus of the ADAMTSL3 protein. could plausibly be involved in the PNN abnormalities seen in This suggested a direct causal relationship between rs950169 schizophrenia (Pantazopoulos et al., 2010). (combined p=3.14×10− 7, OR: 0.68) and the observed schizophrenia Considering the possible role of ADAMTSL3 in the development and association, a degree of evidence that is rarely obtained in genetic remodelling of the neuronal architecture of the brain, the results of a association studies. Despite the promising functional and biological recent evolutionary study of Neanderthal and modern human rationale, the most strongly associated SNP (rs2135551) failed to genomes may be significant (Green et al., 2010). ADAMTSL3 alleles replicate in three independent populations (although the putative were shown to rank in the top 5% of genes showing evidence of a causal SNP was only tested by LD proxy). The replication populations selective sweep in modern humans. This suggests that the gene may included 394 cases and 524 controls from Italy (p=0.311), 589 fit within the evolutionary hypotheses that have proposed the schizophrenia cases and 11,491 controls from Iceland (p=0.12) and development of schizophrenia and other forms of psychosis as a by- 179 cases and 267 controls of European-American ancestry (p=0.19) product of social brain evolution in Homo sapiens (Burns, 2006). (Need et al., 2009). There are several possible explanations for the In this study we are seeking to address a generic problem in failure to replicate the ADAMTSL3 association in these modest schizophrenia genetics, namely failure to replicate (Mitchell and replication cohorts, however before considering these further; we Porteous, 2010). A true association can fail to replicate for multiple consider it pertinent to explore the biological rationale that might reasons including, insufficient sample size or variability in phenotype support a role for ADAMTSL3 in schizophrenia. definitions across independent samples. Allele frequencies of variants ADAMTSL3 is a member of the ADAMTS superfamily of proteins, may also differ across studies due to sampling error or population encompassing the 19 human ADAMTS metalloproteases and the differences. In one study replication was shown to fail due to seven non-proteolytic ADAMTS-like proteins. The superfamily show interaction between distinct functional polymorphisms and differ- diverse functions in physiological processes such as angiogenesis, ences in allele frequency were also shown to lead to a reversal of haemostasis, and particularly in the extracellular matrix (ECM) allelic effects where a protective allele became a risk factor in (Huxley-Jones et al., 2005).TheADAMTSproteasescontaina replication studies (Greene et al., 2009). This re-enforces the point metalloprotease domain, and an ancillary domain that determines that variants that fail to replicate should be checked for interactions specificity of substrate-binding, as the protease domain alone is with other polymorphisms, particularly when samples are collected unable to process native substrates (Cal et al., 2002). Members of the from groups with distinct ethnic backgrounds or different geographic ADAMTS-like subfamily lack a metalloprotease domain and hence, regions. Mindful of these recommendations, we have further lack proteolytic activity, but they otherwise have a similar structural evaluated the association between ADAMTSL3 and schizophrenia. organization including the ADAMTS ancillary
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