In the case of MS, sequential cell-selective enrichment analysis highlighted two cell types: CD3+ T-cells from cord blood, and CD19+/CD20+ B-cells (Fig. SB). While MS has long been thought to be T-cell mediated, a critical role for B-cells has only recently been recognized and has major therapeutic implications (30). It is notable that cord blood CD3+ cells – essentially a naïve population – garner the most highly selective enrichment, particularly in comparison with total adult CD3+ cells or other T-cell subsets, suggesting a role for variants influencing immune education. Also of note, DHSs active in brain tissue were moderately depleted (~10%) for MS-associated variants, suggesting that neural regulatory elements do not play a substantial role in MS pathogenesis, as proposed (31). Analogously, analysis of variants associated with the continuously varying trait of QRS duration revealed similarly specific enrichment within fetal heart DHSs (Fig. 5C). Importantly, in all three cases, the results were obtained without any prior knowledge of physiological mechanisms. These data suggest a generally applicable approach, and highlight the value of extensive maps of regulatory DNA for gaining insights into disease physiology and pathogenesis.
