LETTER TO THE EDITOR Failure to Confirm Association Between PIK4CA and Psychosis in 22q11.2 Deletion Syndrome Masashi Ikeda, 1 * Nigel Williams, 1 Hywel J. Williams, 1 Rhodri Smith, 1 Stephen Monks, 2 Michael J. Owen, 1 Kieran C. Murphy, 2 and Michael C. O’Donovan 1 1 MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK 2 The Department of Psychiatry, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin. Ireland Received 16 July 2009; Accepted 23 November 2009 TO THE EDITOR: The 22q11.2 micro-deletion that gives rise to the 22q11.2 deletion syndrome (22q11.2DS) is associated with a substantial increase in the risk of schizophrenia [Murphy et al., 1999]. This has led to the hypothesis that more subtle sequence variation within the deleted region might influence susceptibility to schizophrenia in more general forms of the disorder [Williams et al., 2008a]. Recently, phosphatidyl-inositol-4-kinase-catalytic-a gene (PIK4CA) has emerged as a potential schizophrenia susceptibility gene in the 22q11.2 region [Saito et al., 2003]. The first significant evidence for association between single nucleotide polymorphisms (SNPs) at this locus and schizophrenia emerged in a Dutch population [310 cases, 880 controls; Jungerius et al., 2008]. In that study, three SNPs in PIK4CA (rs2072513, rs165862, rs165793) showed signifi- cant association at a level that survived correction for multiple testing. This finding obtained some support from the genome-wide association study of the International Schizophrenia Consortium (ISC) which reported nominally significant association at one of these SNPs (rs165862, P ¼ 0.0067) in a sample of white individuals of European origin [International Schizophrenia Consortium, 2009] but not in a much smaller sample from a different ethnic background [Kanahara et al., 2009]. Recently, another of the SNPs, rs165793 (which was not exam- ined in the ISC) was shown to be associated (P ¼ 0.006 after correction for multiple testing) with a schizophrenia/schizoaffec- tive disorder in individuals with 22q11.2DS, who were white and resident in Canada [Vorstman et al., 2009]. In that study of individuals with 22q11.2DS [Vorstman et al., 2009], the effect size estimated at the risk allele in rs165793 was substantially greater (OR ¼ 9.47) than observed in the Caucasian population based study (OR ¼ 1.80) [Jungerius et al., 2008]. This suggests the possi- bility of an interaction effect between PIK4CA and 22q11.2DS in which common variation at PIK4CA shows a much higher pene- trance in subjects in whom PIK4CA function is already compro- mised by hemizygosity. If this hypothesis is correct, in contrast to those of most SNP studies where small effect sizes are expected to be the rule, the finding would be of considerable clinical importance for phenotypic prediction in individuals with 22q11.2DS. In the present study, we sought to test the hypothesis of a strong association between PIK4CA and psychosis in people with 22q11.2DS. Our sample contained 83 individuals (27 male, 56 female) with 22q11.2DS who were Caucasian and were recruited from Ireland and the United Kingdom. Of the total sample, 24 individ- uals (10 male, 14 female, aged 31  11 years old) had experienced episodes of psychosis (18 schizophrenia, 1 schizoaffective disorder, 1 Bipolar disorder with psychotic features, 4 atypical psychosis). The mean age at onset for the schizophrenia and schizoaffective disorder patients was 24 years old. Of the subjects with no history of psychosis, 17 were male and 42 were female (mean age 31  11 years). The presence of the hemizygous deletion at 22q11.2 was confirmed in all cases by fluorescence in situ hybridization with the N25 probe (Oncor, Inc., Gaithersburg, MD). The methods of psychiatric assessment are described elsewhere [Murphy et al., Additional supporting information may be found in the online version of this article. Grant sponsor: Medical Research Council (United Kingdom); Grant sponsor: National Institute of Mental Health (United States); Grant Number: 2 P50 MH066392-05A1; Grant sponsor: Uehara Memorial Foundation; Grant sponsor: Great Britain Sasakawa Foundation. *Correspondence to: Masashi Ikeda, MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK. E-mail: ikedam@cardiff.ac.uk Published online 5 January 2010 in Wiley InterScience (www.interscience.wiley.com) DOI 10.1002/ajmg.b.31060 How to Cite this Article: Ikeda M, Williams N, Williams HJ, Smith R, Monks S, Owen MJ, Murphy KC, O’Donovan MC. 2010. Failure to Confirm Association Between PIK4CA and Psychosis in 22q11.2 Deletion Syndrome. Am J Med Genet Part B 153B:980–982. Ó 2010 Wiley-Liss, Inc. 980 Neuropsychiatric Genetics