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bioRxiv · 10.1101/124560

Disease as collider: a new case-only method to discover environmental factors in complex diseases with genetic risk estimation

Balazard, F.·Le Fur, S.·Bougneres, P.·Valleron, A.-J.·the Isis-Diab collaborative group,
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Abstract

BackgroundCase-only design for gene-environment interaction (CODGEI) relies on the rare disease assumption. A negative association due to collider bias appears between gene and environment when this assumption is not respected. Genetic risk estimation can quantify part of the predisposition of an individual to a disease.\n\nMethodsWe introduce Disease As Collider (DAC), a new case-only methodology to discover environmental factors using genetic risk estimation: a negative correlation between genetic risk and environment in cases provides a signature of a genuine environmental risk marker. Simulation of disease occurrence in a source population allows to estimate the statistical power of DAC and the influence of collider bias in CODGEI. We illustrate DAC in 831 type 1 diabetes (T1D) patients. Results: The power of DAC increases with sample size, prevalence and accuracy of genetic risk estimation. For a prevalence of 1% and a realistic genetic risk estimation, power of 80% is reached for a sample size under 3000. Collider bias offers an alternative interpretation to the results of CODGEI in a published study on breast cancer.\n\nConclusionDAC could provide a new line of evidence for discovering which environmental factors play a role in complex diseases or confirming results obtained in case-control studies. We discuss the circumstances needed for DAC to participate in the dissection of environmental determinants of disease. We provide guidance on the use of CODGEI regarding the rare disease assumption.\n\nO_LSTKey messagesC_LSTO_LIA complex disease is a collider between genetic determinants and environmental factors; it is a consequence of both.\nC_LIO_LICollider bias can affect the results of the case-only design for gene-environment interactions when the disease is common.\nC_LIO_LIUsing genetic risk estimation, collider bias can be used to discover or confirm the association between a disease and an environmental factor in a case-only setting.\nC_LIO_LIStatistical power of this approach is small when the disease is rare. Power increases with sample size, prevalence and genetic risk prediction accuracy.\nC_LI

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Balazard, F., Le Fur, S., Bougneres, P., Valleron, A.-J., the Isis-Diab collaborative group,. 2017-04-10. Disease as collider: a new case-only method to discover environmental factors in complex diseases with genetic risk estimation. https://doi.org/10.1101/124560

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