The impact of phenocopy on the genetic analysis of complex traits

Abstract

A consistent debate is ongoing on genome-wide association studies (GWAs). A key point is the capability to identify lowpenetrance 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 amount of phenocopy in the study sample, despite progressively reducing the significance of the association, if the study is sufficiently powered. On the opposite, when purely epistatic effects are simulated, the capability of identifying the association depends on several parameters, such as the strength of the interaction between the polymorphic variants, the penetrance of the polymorphism and the alleles (minor or major) which produce the combined effect and their frequency in the population. We conclude that the neglect of the possible presence of phenocopies in complex traits heavily affects the analysis of their genetic data.

Extensive genome-wide autozygosity in the population isolates of Daghestan

“…75 The utility of population isolates with low long-term N e in the mapping and identification of genes is not only limited to the study of rare diseases-isolated populations also provide a useful resource for the identification of susceptibility genes for complex diseases, initial insights into disease pathogenesis and for understanding the biology underlying common diseases and their component traits. 8,[76][77][78][79][80] The study of isolated populations facilitates the discovery of diseaseassociated genes with alleles that have increased in frequency as a result of a strong genetic drift. 78 As such, the genetic isolates of Daghestan may provide the opportunity to identify both common and rare disease-causing variants through association studies.…”

The Importance of Down Syndrome Phenocopies in the Newborns in Tertiary Obstetric Hospital

“…Among the phenomena reducing the power of these analyses, phenocopy level hampers very seriously the investigation of complex diseases, as well known in neurological disorders, cancer, and likely of primary importance in human ageing. Phenocopy level seems to be the norm, rather than the exception, especially when considering the role of epigenetic and environmental factors towards phenotype [38].…”