Mediational pathways between aggregate genetic liability and nonfatal suicide attempt: A Swedish population-based cohort.

Despite recent progress in the genetics of suicidal behavior, the pathway by which genetic liability increases suicide attempt risk is unclear. We investigated the mediational pathways from family/genetic risk for suicide attempt (FGRS SA ) to suicide attempt by considering the roles of psychiatric illnesses. In a Swedish cohort, we evaluated time to suicide attempt as a function of FGRS SA and the mediational effects of alcohol use disorder, drug use disorder, attention-deficit/hyperactivity disorder, major depression, anxiety disorder, bipolar disorder, and non-affective psychosis. Analyses were conducted by sex in three age periods: 15-25 years (N females  = 850,278 and N males  = 899,366), 26-35 years (N females  = 800,189 and N males  = 861,774), and 36-45 years (N females  = 498,285 and N males  = 535,831). The association between FGRS SA and suicide attempt was mediated via psychiatric disorders. The highest mediation effects were observed for alcohol use disorder in males (15-25 years, HR total  = 1.60 [1.59; 1.62], mediation = 14.4%), drug use disorder in females (25-36 years, HR total  = 1.46 [1.44; 1.49], mediation = 11.2%), and major depression (25-36 years) in females (HR total  = 1.46 [1.44; 1.49], mediation = 7%) and males (HR total  = 1.50 [1.47;1.52], mediation = 4.7%). While the direct effect of FGRS SA was higher at ages of 15-25, the mediation via psychiatric disorders was more prominent in later adulthood. Our study informs about the psychiatric illnesses via which genetic liability operates to impact suicide attempt risk, with distinct contributions according to age and sex.