Gamazon Eric R, Cox Nancy J, Davis Lea K
Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, IL 60637, USA.
Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, IL 60637, USA.
Am J Hum Genet. 2014 Nov 6;95(5):477-89. doi: 10.1016/j.ajhg.2014.09.009. Epub 2014 Oct 9.
Despite the discovery of copy-number variation (CNV) across the genome nearly 10 years ago, current SNP-based analysis methodologies continue to collapse the homozygous (i.e., A/A), hemizygous (i.e., A/0), and duplicative (i.e., A/A/A) genotype states, treating the genotype variable as irreducible or unaltered by other colocalizing forms of genetic (e.g., structural) variation. Our understanding of common, genome-wide CNVs suggests that the canonical genotype construct might belie the enormous complexity of the genome. Here we present multiple analyses of several phenotypes and provide methods supporting a conceptual shift that embraces the structural dimension of genotype. We comprehensively investigate the impact of the structural dimension of genotype on (1) GWAS methods, (2) interpretation of rare LOF variants, (3) characterization of genomic architecture, and (4) implications for mapping loci involved in complex disease. Taken together, these results argue for the inclusion of a structural dimension and suggest that some portion of the "missing" heritability might be recovered through integration of the structural dimension of SNP effects on complex traits.
尽管近10年前就发现了全基因组的拷贝数变异（CNV），但目前基于单核苷酸多态性（SNP）的分析方法仍将纯合子（即A/A）、半合子（即A/0）和重复（即A/A/A）基因型状态合并处理，将基因型变量视为不可简化或不受其他共定位形式的遗传（如结构）变异影响。我们对常见的全基因组CNV的理解表明，传统的基因型构建可能掩盖了基因组的巨大复杂性。在此，我们展示了对几种表型的多重分析，并提供了支持一种概念转变的方法，这种转变包含了基因型的结构维度。我们全面研究了基因型结构维度对以下方面的影响：（1）全基因组关联研究（GWAS）方法；（2）罕见功能丧失（LOF）变异的解释；（3）基因组结构的表征；（4）对复杂疾病相关基因座定位的影响。综合来看，这些结果支持纳入结构维度，并表明通过整合SNP效应的结构维度对复杂性状的影响，可能会找回部分“缺失”的遗传力。
