Thomson G
Department of Integrative Biology, University of California, Berkeley 94720, USA.
Adv Genet. 2001;42:475-86. doi: 10.1016/s0065-2660(01)42037-2.
Genome-wide linkage scans using affected sibpair families are being conducted on many complex diseases, such as type 1 and type 2 diabetes, multiple sclerosis, rheumatoid arthritis, schizophrenia, asthma, cardiovascular diseases, obesity, and alcoholism. Despite extensive efforts by many groups, progress has been exceedingly slow, and only a few genes and some genomic regions involved in complex diseases have been identified. The general picture is one of difficulty in locating disease genes and replication of reported linkages. This results from the fact that complex diseases and traits may result principally from genetic variation that is relatively common in the general population involving a large number of genes, environmental factors, and their interactions. Genome-wide association studies are now feasible through the use of PCR methodologies with pooled DNA samples and microsatellite variation, and more recently single-nucleotide polymorphism (SNP) variation. Issues relating to significance levels in genome-wide linkage and association scans are discussed, and suggestions for dealing with false positive (type I) errors proposed.
目前正在对许多复杂疾病开展全基因组连锁扫描，这些疾病包括1型和2型糖尿病、多发性硬化症、类风湿性关节炎、精神分裂症、哮喘、心血管疾病、肥胖症以及酗酒等，所使用的是患病同胞对家系。尽管许多研究团队付出了巨大努力，进展却极为缓慢，仅识别出了少数与复杂疾病相关的基因和一些基因组区域。总体情况是，定位疾病基因以及重复所报道的连锁关系都存在困难。这是因为复杂疾病和性状可能主要源于一般人群中相对常见的遗传变异，涉及大量基因、环境因素及其相互作用。通过使用针对混合DNA样本和微卫星变异的PCR方法，以及最近针对单核苷酸多态性（SNP）变异的方法，全基因组关联研究现在变得可行。文中讨论了全基因组连锁和关联扫描中的显著性水平相关问题，并提出了处理假阳性（I型）错误的建议。
