Genetic Modification of the Effects of Exercise Behavior on Mental Health

Anxiety and depressive disorders are amajor contributor to the global diseaseburden (1). Although these disorders differin duration and intensity, they are oftenchronic and treatment options includemedication, psychotherapy, or a combina-tion of both. In addition,regular exercise isargued to be effective in reducing anxiousand depressive symptoms. Results fromseveral meta-analyses indicate that exer-cise has a moderate to large antidepressanteffect in clinical populations (2–6). Basedon these studies, one might easily concludethat exercise consistently has beneﬁcialcausal effects on anxious and depressivesymptoms (7). The question remains whether this con-clusion is also valid with regard to thegeneral population as, despite these ben-eﬁcial psychological effects,the majority ofthe population is not engaging in leisure-time exercise activities (8,9) and popu-lation studies on the association betweenexercise and mental health are scarce.Secondly, there may be mechanisms thatonly mimic causal effects. The observedassociation between exercise and anxious–depressive symptoms might be due tounderlyingfactorsthatinﬂuencebothexer-cise behavior and symptoms of anxietyand depression. These factors can reside inthe environment or in our genes. Under-lying genetic factors might for instancehave a detrimental effect on regular exer-cisebehaviorwhilesimultaneouslyincreas-ing the risk for depression, a mechanismknown as genetic pleiotropy. The effectof these genetic factors on exercise behav-ior could even precede their effects ondepression, thereby nearly perfectly mim-icking a causal association. Only a fewresearch groups have the optimal resourcesto investigate these possible effects ina genetically informative design, whichrequires large population-based longitudi-naldatasetswithfamilydata,butpreferablytwin data.Results from population-based twinstudies that have tested the nature ofthe association between a lack of exerciseand anxious–depressive symptoms con-clude that the association is best explainedby underlying genetic effects. De Mooret al. (10) showed that within geneticallyidentical twins, a twin who exercised moredid not have fewer symptoms than his orher less exercising co-twin. This suggeststhat genetic factors independently causelow levels of exercise behavior as well asanxiousanddepressivesymptoms.Inaddi-tion, there is no evidence for causal inﬂu-ences of exercise behavior on feelings ofpsychological wellbeing, a phenotype pre-sumably at the other end of the emotionalscale,i.e.,the absence of anxious or depres-sive symptoms (11, 12). Taken together,these studies conclude that the associa-tion between regular exercise and psycho-logical wellbeing as well as the associa-tion between a lack of regular exercise andanxiety and depressive disorders largelyreﬂect the effects of common geneticfactors.In an effort to explain the mecha-nisms that contribute to the associationbetween exercise activities and mentalhealth in the general population, a modelwas proposed that accommodates geneticpleiotropic effects, but still allows exerciseto causally increase wellbeing in speciﬁcsubgroups of the population (13). As withany other behavior, for exercise behaviorto be repeated regularly, the net appeti-tive effects of exercise would need to out-weigh the net aversive effects. Individualswho experience greater exercise inducedmood enhancement are likely to repeat thebehavior and become regular lifetime exer-cisers. This assumption is supported byseveral studies, which show that a morepositive affective response during exercisewas associated with greater participationin (voluntary) moderate to vigorous exer-cise (14, 15) or the intention to engage involuntary exercise (16). Individual differ-encesintheseacutemoodeffectsof exercisecouldbestronglyco-determinedbygeneticfactors.In addition to differential acutemood effects, there could be a social-psychological mechanism that makes someindividuals more attracted to exercise thanothers.Individualswithhigherinnateexer-cise capacities will gain more in exerciseperformance than others at comparablelevels of training. The higher trainabil-ity and the superior exercise performancewill lead to feelings of competence andmastery. This increased conﬁdence, orself-efﬁcacy, may not only enhance thefrequency of exercise in individuals (17),but will also lead to higher self-esteem andin turn, in feelings of wellbeing. Vice versa,low trainability and lower levels of per-formance will lead to disappointmentand particularly in adolescents to shameand lowered self-esteem. Genetic varia-tion among people inﬂuencing exerciseability will therefore become associatedwith experiencing psychological beneﬁcialeffects of exercise activities and, as a conse-quence, with an increase in the frequencyof exercising.