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Prediction of serotonin transporter promoter polymorphism genotypes from single nucleotide polymorphism arrays using machine learning methods

Lu, Ake Tzu-Huia; Bakker, Stevenc; Janson, Estherd; Cichon, Svene,f; Cantor, Rita M.a,b; Ophoff, Roel A.b,d

doi: 10.1097/YPG.0b013e328353ae23
Original Articles

Background: The serotonin transporter gene (SLC6A4) and its promoter (5-HTTLPR) polymorphism have been the focus of a large number of association studies of behavioral traits and psychiatric disorders. However, large-scale genotyping of the polymorphism has been very difficult. We report the development and validation of a 5-HTTLPR genotype prediction model.

Methods: The single nucleotide polymorphisms (SNPs) from the 2000 kb region surrounding 5-HTTLPR were used to construct a prediction model through a newly developed machine learning method, multicategory vertex discriminant analysis with 2147 individuals from the Northern Finnish Birth Cohort genotyped with the Illumina 370K SNP array and manually genotyped for 5-HTTLPR polymorphism. The prediction model was applied to SNP genotypes in a Dutch/German schizophrenia case–control sample of 3318 individuals to test the association of the polymorphism with schizophrenia.

Result: The prediction model of eight SNPs achieved a 92.4% accuracy rate and a 0.98±0.01 area under the receiving operating characteristic. Evidence for an association of the polymorphism with schizophrenia was observed (P=0.05, odds ratio=1.105).

Conclusion: This prediction model provides an effective substitute of manually genotyped 5-HTTLPR alleles, providing a new approach for large scale association studies of this polymorphism.

aDepartment of Human Genetics, David Geffen School of Medicine at UCLA

bCenter for Neurobehavioral Genetics, UCLA, Los Angeles, California, USA

cDepartment of Psychiatry

dDepartment of Medical Genetics, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands

eInstitute of Human Genetics

fDepartment of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany

Correspondence to Rita M. Cantor, PhD, Department of Human Genetics, David Geffen School of Medicine at UCLA, 695 Charles E. Young Dr South, Los Angeles, CA 90095 7088, USA Tel: +1 310 267 2440; fax: +1 310 794-5446; e-mail:

Received April 15, 2011

Accepted December 28, 2011

© 2012 Lippincott Williams & Wilkins, Inc.