Department of Psychiatry, New York University School of Medicine, New York City, NY, 10016, USA.
Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA, 19129, USA.
Mol Psychiatry. 2022 Feb;27(2):1031-1046. doi: 10.1038/s41380-021-01341-5. Epub 2021 Oct 14.
The human dopamine transporter gene SLC6A3 has been consistently implicated in several neuropsychiatric diseases but the disease mechanism remains elusive. In this risk synthesis, we have concluded that SLC6A3 represents an increasingly recognized risk with a growing number of familial mutants associated with neuropsychiatric and neurological disorders. At least five loci were related to common and severe diseases including alcohol use disorder (high activity variant), attention-deficit/hyperactivity disorder (low activity variant), autism (familial proteins with mutated networking) and movement disorders (both regulatory variants and familial mutations). Association signals depended on genetic markers used as well as ethnicity examined. Strong haplotype selection and gene-wide epistases support multimarker assessment of functional variations and phenotype associations. Inclusion of its promoter region's functional markers such as DNPi (rs67175440) and 5'VNTR (rs70957367) may help delineate condensate-based risk action, testing a locus-pathway-phenotype hypothesis for one gene-multidisease etiology.
人类多巴胺转运体基因 SLC6A3 一直被认为与多种神经精神疾病有关，但疾病机制仍不清楚。在这项风险综合分析中，我们得出结论，SLC6A3 是一个越来越被认可的风险基因，越来越多的家族突变与神经精神和神经退行性疾病有关。至少有五个基因座与常见和严重疾病有关，包括酒精使用障碍（高活性变体）、注意缺陷多动障碍（低活性变体）、自闭症（带有突变网络的家族蛋白）和运动障碍（调节变体和家族突变）。关联信号取决于所使用的遗传标记以及所研究的种族。强烈的单倍型选择和全基因上位性相互作用支持对功能变异和表型关联的多标记评估。包括其启动子区域的功能标记，如 DNPi（rs67175440）和 5'VNTR（rs70957367），可能有助于描绘基于凝聚物的风险作用，测试一个基因-多种疾病病因的基因座-途径-表型假设。
