Fadista João, Manning Alisa K, Florez Jose C, Groop Leif
Department of Epidemiology Research, Statens Serum Institut, Copenhagen S, Denmark.
Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, Malmo, Sweden.
Eur J Hum Genet. 2016 Aug;24(8):1202-5. doi: 10.1038/ejhg.2015.269. Epub 2016 Jan 6.
Genome-wide association studies (GWAS) have long relied on proposed statistical significance thresholds to be able to differentiate true positives from false positives. Although the genome-wide significance P-value threshold of 5 × 10(-8) has become a standard for common-variant GWAS, it has not been updated to cope with the lower allele frequency spectrum used in many recent array-based GWAS studies and sequencing studies. Using a whole-genome- and -exome-sequencing data set of 2875 individuals of European ancestry from the Genetics of Type 2 Diabetes (GoT2D) project and a whole-exome-sequencing data set of 13 000 individuals from five ancestries from the GoT2D and T2D-GENES (Type 2 Diabetes Genetic Exploration by Next-generation sequencing in multi-Ethnic Samples) projects, we describe guidelines for genome- and exome-wide association P-value thresholds needed to correct for multiple testing, explaining the impact of linkage disequilibrium thresholds for distinguishing independent variants, minor allele frequency and ancestry characteristics. We emphasize the advantage of studying recent genetic isolate populations when performing rare and low-frequency genetic association analyses, as the multiple testing burden is diminished due to higher genetic homogeneity.
全基因组关联研究（GWAS）长期以来一直依赖于设定的统计显著性阈值来区分真阳性和假阳性。尽管全基因组显著性P值阈值5×10⁻⁸已成为常见变异GWAS的标准，但它尚未更新以应对近期许多基于阵列的GWAS研究和测序研究中使用的较低等位基因频率谱。利用来自2型糖尿病遗传学（GoT2D）项目的2875名欧洲血统个体的全基因组和外显子组测序数据集，以及来自GoT2D和T2D-GENES（多民族样本中下一代测序进行2型糖尿病基因探索）项目的五个血统的13000名个体的全外显子组测序数据集，我们描述了用于校正多重检验所需的全基因组和外显子组关联P值阈值的指导原则，解释了连锁不平衡阈值对区分独立变异、次要等位基因频率和血统特征的影响。我们强调在进行罕见和低频遗传关联分析时研究近期遗传隔离人群的优势在于，由于更高的遗传同质性，多重检验负担会减轻。
