MDD and loneliness are genetically correlated [10]. Our conditional analyses, however, suggested that genetic risk factors specific to loneliness increased CAD risk independent of the genetic risk factors that are shared between MDD and loneliness (Fig. 1). This finding is congruent with the physiological effects of chronic loneliness in humans and in animal models [37]. Loneliness induces a state of self-preservation in anticipation of being without the protection of others: it triggers depressive symptoms that signal the need for support and connection from peers [9]; disrupts sleep to maintain a state of alertness at night [38]; raises blood pressure [39]; and activates the hypothalamic pituitary adrenal axis [37, 40–42], which regulates cortisol, a key hormone in stress reactions, metabolism, digestion, immunity, and energy storage. While these responses may be advantageous for being alone in the short term, health problems ensue when loneliness is chronic and the biological response is sustained [37].
