Introduction
Heritability estimates of nicotine dependence (ND) range from 40-70%, but discovery GWAS of ND are underpowered and have limited predictive utility. In this work, we leverage genetically correlated traits and diseases to increase the accuracy of polygenic risk prediction.
Methods
We employed a multi-trait model using summary statistic-based best linear unbiased predictors (SBLUP) of genetic correlates of DSM-IV diagnosis of ND in 6,394 individuals of European Ancestry (prevalence = 45.3%, %female = 46.8%, µage = 40.08 [s.d. = 10.43]) and 3,061 individuals from a nationally-representative sample with Fagerström Test for Nicotine Dependence symptom count (FTND; 51.32% female, mean age = 28.9 [s.d. = 1.70]). Polygenic predictors were derived from GWASs known to be phenotypically and genetically correlated with ND (i.e., Cigarettes per Day (CPD), the Alcohol Use Disorders Identification Test (AUDIT-Consumption and AUDIT-Problems), Neuroticism, Depression, Schizophrenia, Educational Attainment, Body Mass Index (BMI), and Self-Perceived Risk-Taking); including Height as a negative control. Analyses controlled for age, gender, study site, and the first 10 ancestral principal components.
Results
The multi-trait model accounted for 3.6% of the total trait variance in DSM-IV ND. Educational Attainment (β=-0.125; 95% confidence interval (CI): [-0.149,-0.101]), CPD (0.071 [0.047,0.095]), and Self-Perceived Risk-Taking (0.051 [0.026,0.075]) were the most robust predictors. PGS effects on FTND were limited.
Conclusions
Risk for ND is not only polygenic, but also pleiotropic. Polygenic effects on ND that are accessible by these traits are limited in size and act additively to explain risk.
Twin studies indicate that 30–40% of the disease liability for depression can be attributed to genetic differences. Here, we assess the explanatory ability of polygenic scores (PGS) based on broad- (PGSBD) and clinical- (PGSMDD) depression summary statistics from the UK Biobank in an independent sample of adults (N = 210; 100% European Ancestry) who were extensively phenotyped for depression and related neurocognitive traits (e.g., rumination, emotion regulation, anhedonia, and resting frontal alpha asymmetry). The UK Biobank-derived PGSBD had small associations with MDD, depression severity, anhedonia, cognitive reappraisal, brooding, and suicidal ideation but only the association with suicidal ideation remained statistically significant after correcting for multiple comparisons. Similarly small associations were observed for the PGSMDD but none remained significant after correcting for multiple comparisons. These findings provide important initial guidance about the expected effect sizes between current UKB PGSs for depression and depression-related neurocognitive phenotypes.
Background and Aims
Cannabis use (CU) is an etiologically complex behavior with several social, temperamental, neurocognitive, and behavioral precursors. Biometrical and molecular studies suggest an interplay of environmental and pleiotropic influences. However, it remains unclear whether identified genetic effects related to behavioral and temperamental characteristics have developmentally direct or indirect mechanisms on CU behavior. The Transmissible Liability Index (TLI) is a measure of continuous liability based on developmental precursors of substance use disorders. This study aimed to examine if the TLI plays a role in understanding genetic risk for CU behaviors.
Design
Genome‐wide association studies (n > 10 000; European Ancestry [EA]) of CU, risk tolerance, neuroticism, anxiety, and depression were used to construct polygenic scores (PGSs). Analyses assessed whether PGSs indirectly impacted risk for repeated use via TLI.
Setting
United States of America.
Participants
From Add Health study, 4077 individuals of EA age 11 to 21 during baseline interview collection.
Measurements
Outcomes were initiation and repeated cannabis use (>5× in lifetime). The TLI was parameterized using a latent factor from 21 questions assessing for precursors of disordered use.
Findings
The marker‐based heritability of TLI, initiation, and repeated use were significant, but modest (14%, P = 0.033; 15%, P = 0.025; and 17%, P = 0.008, respectively). TLI and repeated use were genetically correlated (rg = 0.76, P = 0.033). The PGS for CU was associated with increased risk for repeated use and PGS for risk tolerance and depression were associated with TLI. Mediation analyses indicated significant, but very weak, indirect effects of PGS for risk tolerance and depression on repeated CU via the TLI.
Conclusions
Adolescent behavioral and temperamental characteristics (i.e. the Transmissible Liability Index) appear to be early indicators of repeated cannabis use in adulthood. Although polygenic scores for cannabis use directly increased risk for repeated cannabis use, weak evidence was found for the role of polygenic scores of other internalizing/externalizing traits acting through adolescent derived Transmissible Liability Index on cannabis use behavior.
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