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Neuropsychopharmacology. 2018 Dec;43(13):2556-2563. doi: 10.1038/s41386-018-0162-1. Epub 2018 Jul 23.

Disentangling the genetic overlap between cholesterol and suicide risk.

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Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
South Texas Diabetes and Obesity Institute and Department of Human Genetics, University of Texas of the Rio Grande Valley School of Medicine, Brownsville, TX, USA.
Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.
Diabetes and Complications Therapeutic Area, Eli Lilly and Company, Indianapolis, IN, USA.
Department of Psychiatry, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA.
Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Olin Neuropsychiatric Research Center, Institute of Living, Hartford Hospital, Hartford, CT, USA.


Suicide is major public health concern; one million individuals worldwide die by suicide each year of which there are many more attempts. Thus, it is imperative that robust and reliable indicators, or biomarkers, of suicide risk be identified so that individuals at risk can be identified and provided appropriate interventions as quickly as possible. Previous work has revealed a relationship between low levels of circulating cholesterol and suicide risk, implicating cholesterol level as one such potential biomarker, but the factors underlying this relationship remain unknown. In the present study, we applied a combination of bivariate polygenic and coefficient-of-relatedness analysis, followed by mediation analysis, in a large sample of Mexican-American individuals from extended pedigrees [N = 1897; 96 pedigrees (average size = 19.17 individuals, range = 2-189) 60% female; mean age = 42.58 years, range = 18-97 years, sd = 15.75 years] with no exclusion criteria for any given psychiatric disorder. We observed that total esterified cholesterol measured at the time of psychiatric assessment shared a significant genetic overlap with risk for suicide attempt (ρg = -0.64, p = 1.24 × 10-04). We also found that total unesterified cholesterol measured around 20 years prior to assessment varied as a function of genetic proximity to an affected individual (h2 = 0.21, se = 0.10, p = 8.73 × 10-04; βsuicide = -0.70, se = 0.25, p = 8.90 × 10-03). Finally, we found that the relationship between total unesterified cholesterol and suicide risk was significantly mediated by ABCA-1-specific cholesterol efflux capacity (βsuicide-efflux = -0.45, p = 0.039; βefflux-cholexterol = -0.34, p < 0.0001; βindirect = -0.15, p = 0.044). These findings suggest that the relatively well-delineated process of cholesterol metabolism and associated molecular pathways will be informative for understanding the neurobiological underpinnings of risk for suicide attempt.

[Available on 2019-12-01]
[Indexed for MEDLINE]

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