Interaction between polygenic risk for cigarette use and environmental exposures in the Detroit neighborhood health study

Abstract

Cigarette smoking is influenced both by genetic and environmental factors. Until this year, all large-scale gene identification studies on smoking were conducted in populations of European ancestry. Consequently, the genetic architecture of smoking is not well described in other populations. Further, despite a rich epidemiologic literature focused on the social determinants of smoking, few studies have examined the moderation of genetic influences (for example, gene–environment interactions) on smoking in African Americans. In the Detroit Neighborhood Health Study (DNHS), a sample of randomly selected majority African American residents of Detroit, we constructed a genetic risk score (GRS), in which we combined top (P-value <5 × 10−7) genetic variants from a recent meta-analysis conducted in a large sample of African Americans. Using regression (effective n=399), we first tested for association between the GRS and cigarettes per day, attempting to replicate the findings from the meta-analysis. Second, we examined interactions with three social contexts that may moderate the genetic association with smoking: traumatic events, neighborhood social cohesion and neighborhood physical disorder. Among individuals who had ever smoked cigarettes, the GRS significantly predicted the number of cigarettes smoked per day and accounted for ∼3% of the overall variance in the trait. Significant interactions were observed between the GRS and number of traumatic events experienced, as well as between the GRS and average neighborhood social cohesion; the association between genetic risk and smoking was greater among individuals who had experienced an increased number of traumatic events in their lifetimes, and diminished among individuals who lived in a neighborhood characterized by greater social cohesion. This study provides support for the utility of the GRS as an alternative approach to replication of common polygenic variation, and in gene–environment interaction, for smoking behaviors. In addition, this study indicates that environmental determinants have the potential to both exacerbate (traumatic events) and diminish (neighborhood social cohesion) genetic influences on smoking behaviors.

133. Interplay Between Schizophrenia Polygenic Risk Score and Childhood Adversity in First-Presentation Psychotic Disorder: A Pilot Study

“…Similarly, in the GAP European subsample, cases had on average higher adjusted PRS than controls, with standardized mean difference of 0.54, following correction for population stratification, and the association significantly held for both schizophrenia (R 2 = 16.3%, p = 3.7 Ã 10 −7 ) and other psychoses groups (R 2 = 2.7%, p = 0.03) [24]. This is in line with previous studies [23] demonstrating that cumulative genetic risk predicted case-control status for psychosis across independent samples at a high significance level. The predictive power of the PRS, based on the much larger PGC dataset, allowed these questions to be investigated in a smaller dataset than would be required for candidate gene by environment analysis [37].…”

Assessment of first and second degree relatives of individuals with bipolar disorder shows increased genetic risk scores in both affected relatives and young At‐Risk Individuals

“…Many genomic variants together contribute to overall risk (termed polygenic risk) for a number of complex traits [Peterson et al, 2011; Hamshere et al, 2013; Meyers et al, 2013], and this genetic architecture is evident in a number of psychiatric conditions—including BP [Purcell et al, 2009; Lee et al, 2012, 2013; Smoller et al, 2013; Bramon et al, 2014]. While the elucidation of the genetic causes for BP has been challenging, the field is progressing in understanding the genetic architecture of this complex disorder (reviewed in [Craddock and Sklar, 2013]) and in identifying specific genes which increase risk [Sklar et al, 2011].…”

Gene-Environment Interplay and Substance Use: A Review of Recent Findings

“…In a majority African American sample from Detroit (n=399), the association between the genetic risk score and smoking was greater for those who had experienced a higher number of lifetime traumatic events and was diminished among individuals living in neighborhoods characterized by higher levels of social cohesion [12].…”

“…For example, Meyers et al [12] constructed a polygenic risk score comprising 6 variants that were significantly associated (at p<5×10…”

“…The effects of identified gene variants are small, with each SNP typically accounting for less than 2 % of the variance in the phenotype-far less than that implied by heritability estimates [11,12]. One possibility is that substance use and dependence phenotypes are influenced by multiple genes of small effect.…”