the impact of phenocopy on the genetic analysis of complex traits拟表型的影响复杂性状的遗传分析.pdf

The Impact of Phenocopy on the Genetic Analysis of Complex Traits Francesco Lescai1,2*, Claudio Franceschi2,3 ` 1 Division of Research Strategy, University College London, London, United Kingdom, 2 Centre ‘‘L. Galvani’’ for Biocomplexity, Alma Mater Studiorum - Universita di ` Bologna, Bologna, Italy, 3 Department of Experimental Pathology, Alma Mater Studiorum - Universita di Bologna, Bologna Italy Abstract A consistent debate is ongoing on genome-wide association studies (GWAs). A key point is the capability to identify low- penetrance variations across the human genome. Among the phenomena reducing the power of these analyses, phenocopy level (PE) hampers very seriously the investigation of complex diseases, as well known in neurological disorders, cancer, and likely of primary importance in human ageing. PE seems to be the norm, rather than the exception, especially when considering the role of epigenetics and environmental factors towards phenotype. Despite some attempts, no recognized solution has been proposed, particularly to estimate the effects of phenocopies on the study planning or its analysis design. We present a simulation, where we attempt to define more precisely how phenocopy impacts on different analytical methods under different scenarios. With our approach the critical role of phenocopy emerges, and the more the PE level increases the more the initial difficulty in detecting gene-gene interactions is amplified. In particular, our results show that strong main effects are not hampered by the presence of an increasing amoun