The small effect size but significant differences in DNAm levels at individual CpGs between patients with schizophrenia compared to controls highlights the intrinsic tradeoff between statistical gains in increasing sample size versus the clinical and likely by extension molecular heterogeneity of the clinically ill state. The genetic heterogeneity of schizophrenia is reflected in small odds ratios (<1.1) for individual genomic loci that reach genome-wide significance only because of very large samples. These odds ratios look similar in magnitude to our results for differentially methylated CpGs, suggesting likely epigenetic heterogeneity as well. Unlike genetic sequence, which is largely determined at conception, these epigenetic signals are malleable across the lifespan, and likely the many epiphenomena that differentiate patients from controls may leave their marks on the epigenome, perhaps differently in different subpopulations of patients. These epiphenomena include the influence of medical therapy, chronic illness, nutrition, body weight, alcohol and cannabis use, etc. Untangling which epigenetic marks better relate to the causes versus the consequences of illness will be difficult. Indeed, only a fraction of the illness associated CpGs, 4.6%, showed association to
