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

Abstract

Background Recent 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.

The Influence of Peer Genotypes and Behavior on Smoking Outcomes: Evidence from Add Health

“…In Appendix A, we show that the polygenic score is positively correlated with and predicts smoking behavior in non-whites. This is confirmed by other studies that show overlapping SNPs in smoking GWAS conducted on African and European ancestry populations (Otto et al, 2016).…”

Genetic Influences on Evening Preference Overlap with Those for Bipolar Disorder in a Sample of Mexican Americans and American Indians

“…With the exception of the summary data on BMI, which was from a multi-ethnic sample, all GWAS summary statistics were derived from European populations. While these negative results may in part be due to the factors listed above (e.g., phenotype definition, limited power, and limited number of imputed variants), the predictive ability of GRSs are sensitive to differences in LD and MAF across base and target samples and previous work on our AI sample indicated that GRSs for smoking behaviors from a European population were only predictive in our sample for those subjects with a high proportion of European ancestry (Otto et al, 2016). The findings presented above highlight the need for both replication and large-scale studies of these minority populations to probe for ethnic-specific genetic risk factors and endophenotypes for complex diseases.…”

Association of FAAH p.Pro129Thr and COMT p.Ala72Ser with schizophrenia and comorbid substance use through next-generation sequencing: an exploratory analysis

“…These studies have identified correlations between the genetic risk of schizophrenia and substance use and have selected genetically correlated loci as a proxy for the genetic risk of comorbidity. [14][15][16][17][18] Schizophrenia-associated loci are highly correlated with substance use, and individuals with a higher genetic risk also have a higher prevalence of schizophrenia according to genetic risk scores (i.e., the score is estimated by the schizophrenia-associated variants an individual carries, pondered by the estimated effect in genome-wide association studies). 17,19 Therefore, the variants used to define the genetic score for schizophrenia are also of great interest due to their association with comorbid substance use.…”