Can Genetics Predict Response to Complex Behavioral Interventions? Evidence from a Genetic Analysis of the Fast Track Randomized Control Trial

Abstract

Early interventions are a preferred method for addressing behavioral problems in high-risk children, but often have only modest effects. Identifying sources of variation in intervention effects can suggest means to improve efficiency. One potential source of such variation is the genome. We conducted a genetic analysis of the Fast Track randomized control trial, a 10-year-long intervention to prevent high-risk kindergarteners from developing adult externalizing problems including substance abuse and antisocial behavior. We tested whether variants of the glucocorticoid receptor gene NR3C1 were associated with differences in response to the Fast Track intervention. We found that in European-American children, a variant of NR3C1 identified by the single-nucleotide polymorphism rs10482672 was associated with increased risk for externalizing psychopathology in control group children and decreased risk for externalizing psychopathology in intervention group children. Variation in NR3C1 measured in this study was not associated with differential intervention response in African-American children. We discuss implications for efforts to prevent externalizing problems in high-risk children and for public policy in the genomic era.

Figure 1

Fast Track Randomized Controlled Trial Design.

Figure 2

Prevalence of Any Externalizing Psychopathology in European-American Fast Track Intervention and Control Children by Carriage of the rs10482672 “A” Allele. Notes: The G/G group carried no copies of the “A” allele. The “A” Carrier group carried one or two copies of the “A” allele.

Figure 3

Prevalence of Alcohol Abuse, Cannabis Abuse, Hard Drug Use, Attention Deficit/Hyperactivity Disorder, and Antisocial Personality Disorder in European-American Fast Track Intervention and Control Children by Carriage of the rs10482672 “A” Allele. Notes: The G/G group carried no copies of the “A” allele. The “A” Carrier group carried one or two copies of the “A” allele.

Figure 4

Delinquent Behavior, Problem Alcohol Use, and Cannabis Use in European-American Fast Track Control and Intervention Children by Carriage of the rs10482672 “A” Allele. Notes: The G/G group carried no copies of the “A” allele. The “A” Carrier group carried one or two copies of the “A” allele. Gene-by-intervention interaction effects were statistically significant (p<0.05) for mean levels of delinquency, alcohol use, and cannabis use and for change over time in alcohol and cannabis use. Details are reported in Appendix Table A5. (All appendices are available at the end of this article as it appears in JPAM online. Go to the publisher’s website and use the search engine to locate the article at: //ww3interscience.wiley.com/cgibin/jhome/34787.)

Appendix Figure A1

Pairwise Linkage Disequilibrium (R²) Between Candidate SNPs in NR3C1. Notes: Linkage disequilibrium plots were obtained from Haploview (Barrett et al., 2005). Values displayed in each box indicate the pairwise correlation (R²) between markers. Shading indicates the degree of correlation as measured by D', following the standard Haploview color scheme: high-confidence associations (LOD ≥ 2) are shaded from light pink to bright red based on the absolute value of D'; low-confidence associations (LOD < 2) are shaded white (D'<1) or blue (D'=1). Each subset of SNPs grouped within a black triangle is considered a “block” based on proximity and inter-correlation criteria defined by Gabriel et al. (2002). LOD is the log of the likelihood odds ratio, a measure of confidence in the value of D'.