Keen-Kim Dianne, Mathews Carol A, Reus Victor I, Lowe Thomas L, Herrera Luis Diego, Budman Cathy L, Gross-Tsur Varda, Pulver Ann E, Bruun Ruth D, Erenberg Gerald, Naarden Allan, Sabatti Chiara, Freimer Nelson B
Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA.
Hum Mol Genet. 2006 Nov 15;15(22):3324-8. doi: 10.1093/hmg/ddl408. Epub 2006 Oct 11.
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.
罕见序列变异对于理解常见疾病的生物学机制可能很重要，但要明确确定它们与疾病的关联往往很困难。随着对候选基因进行大规模序列分析变得可行，此类变异的关联研究正变得越来越普遍。最近的一份报告提出，SLITRK1（类Slit和Trk 1）是抽动秽语综合征（TS）的一个候选基因。这一建议的统计证据来自对一种罕见的3'-UTR变异体var321的关联分析，该变异体在两名患者中被观察到，但在2000多名对照中未被观察到。我们对307名哥斯达黎加人和515名德系犹太人个体（TS先证者及其父母）进行了基因分型，在五名独立的德系犹太父母中观察到了var321，其中两名父母没有将这种变异遗传给他们受影响的孩子。此外，我们在一份德系犹太人对照样本的一名个体中鉴定出了var321。我们的研究结果不支持先前报道的关联，并表明与其他欧洲裔人群相比，var321在德系犹太人中出现的比例过高。结果还表明，罕见变异在特定种族群体中的比例过高可能会使对此类变异的关联分析的解释变得复杂，这突出了在罕见变异的关联分析中精确匹配病例和对照人群的特别重要性。
