Both MDD and heart disease exhibit significant sex differences in prevalence and presentation [1, 13, 15], and heart disease remains the number one killer of females in the United States [14]. Our analyses revealed that genetic risk for MDD and loneliness conferred a higher risk of CAD in females than in males, and that the risk in females was robust to adjustment for the major known risk factors. There are two possible, non-mutually exclusive, explanations for this finding. First, genetic predisposition to MDD or loneliness may be a chronic risk factor for females but an acute risk factor for males, as was previously suggested in a study of 30,000 twins from the Swedish population-based twin registry [43]. Second, the conventional risk factors identified in most epidemiological studies may be poorer predictors of CAD for females than they are for males. Non-traditional and female-specific CAD risk factors (e.g., rheumatoid arthritis, preterm delivery) may contribute to sex differences in CAD prevalence, presentation, and mortality [15], but have only recently been interrogated and so we did not include them in our multivariable models.
