Polygenic risk scores for cigarettes smoked per day do not generalize to a Native American population

- Polygenic risk scores (PRS) represent additive effects of common genetic variants.
- PRS for cigarettes per day (CPD) were derived from European ancestry GWAS data.
- PRS predicted liability for nicotine dependence (ND) in European ancestry subjects.
- PRS did not predict liability for ND in Native American ancestry subjects.
- Model linkage disequilibrium when creating PRS with different ancestral populations.

BackgroundRecent studies have demonstrated the utility of polygenic risk scores (PRSs) for exploring the genetic etiology of psychiatric phenotypes and the genetic correlations between them. To date, these studies have been conducted almost exclusively using participants of European ancestry, and thus, there is a need for similar studies conducted in other ancestral populations. However, given that the predictive ability of PRSs are sensitive to differences in linkage disequilibrium (LD) patterns and minor allele frequencies across discovery and target samples, the applicability of PRSs developed in European ancestry samples to other ancestral populations has yet to be determined. Therefore, the current study derived PRSs for cigarettes per day (CPD) from predominantly European-ancestry samples and examined their ability to predict nicotine dependence (ND) in a Native American (NA) population sample. Method: Results from the Tobacco and Genetics Consortium's meta-analysis of genome-wide association studies of CPD were used to compute PRSs in a NA community sample (N = 288). These scores were then used to predict ND diagnostic status. Results: The PRS was not significantly associated with liability for ND in the full sample. However, a significant interaction between PRS and percent NA ancestry was observed. Risk scores were positively associated with liability for ND at higher levels of European ancestry, but no association was observed at higher levels of NA ancestry. Conclusion: These findings illustrate how differences in patterns of LD across discovery and target samples can reduce the predictive ability of PRSs for complex traits.