Substrate has to be connected to gnd, no other choice.
But Deep Nwell would have a p-tub to accomodate the NMOS and that Ptub could be connected to any potential as per design.
You will nedd analog and digital groun separately or some filtring circuitry between analog and digital groun and than you can connect supstrate with grounds.
In deep nwell process, you can put all your circuits in deep nwell and connect this deep nwell to a clean vdd pin. Then you can reject the noise from substrate.