Human Molecular Genetics Advance Access originally published online on October 11, 2006
Human Molecular Genetics 2006 15(22):3324-3328; doi:10.1093/hmg/ddl408
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Overrepresentation of rare variants in a specific ethnic group may confuse interpretation of association analyses
1 Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior and 2 Departments of Human Genetics and Statistics, University of California, Los Angeles, CA, USA, 3 Department of Psychiatry, University of California, San Francisco, CA, USA, 4 Hospital Nacional de Niños, San Jose, Costa Rica, 5 Movement Disorders Center in Psychiatry, North Shore University Hospital, Manhasset, NY, USA, 6 Neuropediatric Unit, Shaare Zedek Medical Center, Jerusalem, Israel, 7 Psychiatry and Behavioral Sciences at the Johns Hopkins University School of Medicine, Baltimore, MD, USA, 8 Department of Neurology, Cleveland Clinic Foundation, OH, USA and 9 Department of Neurology, University of Texas Southwestern Medical School, Dallas, TX, USA
* To whom correspondence should be addressed at: UCLA Center for Neurobehavioral Genetics, Gonda Center, Rm. 3506, 695 Charles E. Young Dr S., Box 951761, Los Angeles, CA 90095, USA. Tel: +1 3107949571; Fax: +1 3107949613; Email: nfreimer{at}mednet.ucla.edu
Received July 14, 2006; Accepted October 5, 2006
Rare sequence variants may be important in understanding the biology of common diseases, but clearly establishing their association with disease is often difficult. Association studies of such variants are becoming increasingly common as large-scale sequence analysis of candidate genes has become feasible. A recent report suggested SLITRK1 (Slit and Trk-like 1) as a candidate gene for Tourette Syndrome (TS). The statistical evidence for this suggestion came from association analyses of a rare 3'-UTR variant, var321, which was observed in two patients but not observed in more than 2000 controls. We genotyped 307 Costa Rican and 515 Ashkenazi individuals (TS probands and their parents) and observed var321 in five independent Ashkenazi parents, two of whom did not transmit this variant to their affected child. Furthermore, we identified var321 in one subject from an Ashkenazi control sample. Our findings do not support the previously reported association and suggest that var321 is overrepresented among Ashkenazi Jews compared with other populations of European origin. The results further suggest that overrepresentation of rare variants in a specific ethnic group may complicate the interpretation of association analyses of such variants, highlighting the particular importance of precisely matching case and control populations for association analyses of rare variants.
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