What changed between the few-gene era and the polygene era is that we got sequencers that could read the genomes of an entire experimental cohort at reasonable cost. Likewise, when we have the capability to do single-cell profiling of the epigenetic signature of an array of relevant cell types, for every member of your cohort, there’s decent odds biologists will think it ludicrous that we hoped to get meaningful results out of lone, unannotated, out-of-context genomes.

EDIT: I would specify that I'm not saying that experimental biology "doesn't work" or doesn't get meaningful results before the bigger new technology arrives. I think the Slate Star Codex article overstates the helplessness of single-gene theories, which did explain a bunch of diseases and simple attributes, and had significant medical impacts in understanding things like cancer and chemotherapy effectiveness. It just failed to accomplish a set of other things that people wanted, like explaining intelligence or height. Each new advance (cheap genome sequencing, epigenetic readouts, hugely longitudinal metabolomics, molecule-level microscopy, and the hundred-plus advances in this direction we haven't even conceived of yet) expands the territory of what we can address through molecular biology.

Scientists are often really optimistic about whether topics of interest lie inside or without this territory at a given moment, which I think has to do more with the incentives of grant writing than anything else.