LAUSR

Background The link between serum cholesterol and suicide attempts is well established, several studies suggest that lower levels of cholesterol are associated with increased risk of mortality from suicide. However, the etiology of this association remains unknown. We present the first study to directly address whether the shared etiology is due to genetic factors. Methods All genetic analyses were conducted in SOLAR in a sample of 552 Mexican American individuals from extended pedigrees. The standardized genetic covariances between 23 lipid classes, acquired from 10 μl of plasma, and attempted suicide were calculated. The suicide phenotype was taken from the Suicidality section of the Mini International Neuropsychiatric Interview (MINI). In addition, plasma-based cholesterol efflux capacity (CEC; total, non-ABCA1, and ABCA1-specific) and Lecithin:cholesterol acyltransferase (LCAT) levels were available for all participants. Multilevel mediation analyses were conducted in R using the lme4 and lmerTest packages, this allows the clustering due to family structure to be taken into account. Results Both free cholesterol (β = -0.70, p = 2.9x10-04) and lyso-phosphatidylcholine (β = -0.65, p = 2.0-03) exhibited significant genetic overlap with attempted suicide after the application of a multiple comparison correction. Given that the movement of free cholesterol and lyso-phosphatidylcholine have established interactions in the glycerophospholipid metabolism pathway via efflux and LCAT respectively, we investigated these potential relationships in the data. Neither free cholesterol nor lyso-phosphatidylcholine showed an association with LCAT, and lyso-phosphatidylcholine did not show an association with CEC. However, there was a large and significant genetic correlation between free cholesterol and ABCA1-specific CEC (rhog = 0.64, p = 1.38x10-06). Mediation analysis indicated that the relationship between free cholesterol and attempted suicide was significantly mediated by ABCA1-specific CEC (β = 0.07, p = 0.035). Discussion While alterations in cholesterol levels have been previously associated with attempted suicide the present study is the first to demonstrate a shared genetic etiology between these two phenotypes. Moreover the results of this study imply that cholesterol efflux, an initial step in the process of reverse cholesterol transport, may be key to the association between free cholesterol and attempted suicide.