A key component of the site comparison planned for the deep geological disposal of spent fuel and high-level waste (SF/HLW) in Switzerland is the assessment of the evolution of repository-induced perturbations in the repository nearfield associated with thermal effects from heat production due to radioactive decay of radionuclides, as well as gas pressures developing in the backfilled underground structures from the anaerobic corrosion of the steel waste canisters and tunnel support materials. The assessment of such effects is integrated in the site comparison through safety indicators used to evaluate repository performance. In this context, probabilistic assessments need to integrate the uncertainty of the entire ensemble of input parameters, and estimate the propagation to these indicators in a reliable and computationally efficient manner. This paper presents the development of a methodology for an indicator-based assessment of heat- and gas-induced effects in a SF/HLW repository in Opalinus Clay integrating a probabilistic treatment of parametric uncertainty. The workflow is demonstrated using preliminary data, repository configurations and indicators. Complementary simulations are presented to demonstrate the feedback to the optimization of repository design in order to mitigate repository-induced effects that can potentially compromise the safety function of the engineered and natural barriers.