An improved in silico selection of phenotype affecting polymorphisms in SLC6A4, HTR1A and HTR2A genes Francesco Piva 1 * , Matteo Giulietti 1 , Bernardo Nardi 2 , Cesario Bellantuono 2 and Giovanni Principato 1 1 Department of Biochemistry, Biology and Genetics, Polytechnic University of Marche, Ancona, Italy 2 Psychiatry Unit, Department of Neurosciences, Polytechnic University of Marche, Ancona, Italy Objective Among the experimentally assessed DNA variations in serotonin related genes, some influence physiological expression of personality and mental disorders, others alter the responses to pharmacological and/or psychotherapeutic treatments. Because of the huge number of polymorphisms lying in genes and of the great length of time necessary to perform association studies, a selection of the variations being studied is a necessary and crucial step. Methods In this work we used the most updated and assessed bioinformatic tools to predict the phenotype affecting polymorphisms of the human HTR1A, HTR2A and SLC6A4 serotonin related genes. Moreover, we carried out a literature search to collect information about the recent association studies to compare it versus our prediction data. Results Gene polymorphism analysis indicated the variations that are worth considering in the association studies in the field of psychiatry, psychology and pharmacogenomics. The literature revision allowed to show both the few well and the most not enough investigated polymorphisms. Conclusions Our data can be useful to select polymorphisms for new association studies, especially those not yet investigated that can be related to behaviour, mental disorders and individual treatment response. Copyright # 2010 John Wiley & Sons, Ltd. key words — computational biology; serotonin; SNP; association; RNA splicing INTRODUCTION Single Nucleotide Polymorphisms (SNPs) may confer an individual susceptibility to develop diseases, determine their severity and progression, affect the response to pathogens, toxins, and chemicals, or drugs and other therapies. Thus, SNPs have become of great value for biomedical research in order to attain personalized medicine. In the human genome are present not only variations as single-nucleotide polymorphisms, small insertion–deletion polymorphisms, variable numbers of repetitive sequences but also copy-number variations (CNVs) that involve gains or losses of DNA sequences > 1 kb among phenotypically normal individuals. Even though the role of CNVs is well established as an important pathogenic factors in a range of common diseases including neuropsychiatric illness (Cook and Scherer, 2008; Alaerts and Del-Favero, 2009), such variations have not been included in genetic studies until recently. In the last years many studies have been carried out exploring genetic differences among individuals, concerning normal and pathological behaviour and the response to pharmacological and/or psychotherapeutic treatments. In particular both physiological expression of personality and mental disorders are related to serotonin (5-hydroxy-tryptamine, 5-HT) system. Therefore, there is a growing interest to investigate genes related to phenotypical expression of 5-HT receptors and transpor- ter. HTR1A gene variants have been reported to play a role in mood, anxiety and psychotic disorders (Celada et al ., 2004; Drevets et al ., 2007; Drago et al., 2008). Variants of the HTR2A gene have been associated with many psychiatric disorders such as schizophrenia, mood disorders, attention deficit hyperactivity disorder (ADHD), suicide, anxiety, obsessive-compulsive beha- viour, eating disorders and Alzheimer’s disease (AD) (Celada et al., 2004; Norton and Owen, 2005; Serretti et al., 2007b). The SLC6A4 serotonin transporter gene variants have been associated with many human behaviours, both normal and pathological (Serretti human psychopharmacology Hum. Psychopharmacol Clin Exp 2010; 25: 153–161. Published online in Wiley InterScience (www.interscience.wiley.com) DOI: 10.1002/hup.1100 *Correspondence to: F. Piva, Department of Biochemistry, Biology and Genetics, Polytechnic University of Marche, 60131 Ancona, Italy. Tel.: 390712204641; Fax: 390712204609. E-mail: f.piva@univpm.it Copyright # 2010 John Wiley & Sons, Ltd. Received 2 November 2009 Accepted 20 January 2010