Glatt C E, DeYoung J A, Delgado S, Service S K, Giacomini K M, Edwards R H, Risch N, Freimer N B
Neurogenetics Laboratory, Program in Human Genetics, University of California San Francisco, San Francisco, California, USA.
Nat Genet. 2001 Apr;27(4):435-8. doi: 10.1038/86948.
Most human sequence variation is in the form of single-nucleotide polymorphisms (SNPs). It has been proposed that coding-region SNPs (cSNPs) be used for direct association studies to determine the genetic basis of complex traits. The success of such studies depends on the frequency of disease-associated alleles, and their distribution in different ethnic populations. If disease-associated alleles are frequent in most populations, then direct genotyping of candidate variants could show robust associations in manageable study samples. This approach is less feasible if the genetic risk from a given candidate gene is due to many infrequent alleles. Previous studies of several genes demonstrated that most variants are relatively infrequent (<0.05). These surveys genotyped small samples (n<75) and thus had limited ability to identify rare alleles. Here we evaluate the prevalence and distribution of such rare alleles by genotyping an ethnically diverse reference sample that is more than six times larger than those used in previous studies (n=450). We screened for variants in the complete coding sequence and intron-exon junctions of two candidate genes for neuropsychiatric phenotypes: SLC6A4, encoding the serotonin transporter; and SLC18A2, encoding the vesicular monoamine transporter. Both genes have unique roles in neuronal transmission, and variants in either gene might be associated with neurobehavioral phenotypes.
大多数人类序列变异以单核苷酸多态性（SNP）的形式存在。有人提出，编码区SNP（cSNP）可用于直接关联研究，以确定复杂性状的遗传基础。此类研究的成功取决于疾病相关等位基因的频率及其在不同种族人群中的分布。如果疾病相关等位基因在大多数人群中频率较高，那么对候选变异进行直接基因分型可能会在可控的研究样本中显示出显著的关联。如果给定候选基因的遗传风险是由许多低频等位基因导致的，那么这种方法就不太可行。此前对多个基因的研究表明，大多数变异相对罕见（<0.05）。这些调查对小样本（n<75）进行了基因分型，因此识别罕见等位基因的能力有限。在这里，我们通过对一个种族多样化的参考样本进行基因分型来评估此类罕见等位基因的流行情况和分布，该样本比之前研究中使用的样本大六倍多（n=450）。我们在两个神经精神表型候选基因的完整编码序列和内含子 - 外显子连接处筛选变异：SLC6A4，编码血清素转运体；以及SLC18A2，编码囊泡单胺转运体。这两个基因在神经元传递中都具有独特作用，任一基因中的变异都可能与神经行为表型相关。
