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Bit blanket as it depends on the rim. I'm running 35mm tyres (madness) on my 35mm external Roval front road wheel.
The aero benefit/loss is also only really relevant to the front wheel, so clever little cookies like me would run the best aero/Crr combo up front and the best Crr/comfort combo in the back.
Deep rims? If so then not too wide otherwise you lose a lot of the aero benefit.
Shallow rims, go as wide as your frame will allow and enjoy the comfort!