1. SUMMARY

Conduct problems (CP) include behaviors such as bullying/intimidating, initiating physical violence towards others, assault (stealing with confrontation), theft, vandalism, and running away from home. An estimated 5-10% of youth engaging in CP follow an early onset and persistent (EOP) trajectory, and account for over 50% of crime within a given community (Moffitt, 2006). The cost to both victims and communities is considerable (Foster). Nevertheless, well designed longitudinal studies converge on the finding that the development of CP is a heterogeneous process: at least two other trajectories have been consistently identified (Barker & Maughan, 2009; Odgers et al., 2007; 2008; Raine et al., 2005), neither of which appear to be completely free of risk in childhood nor adjustment problems thereafter. Preliminary findings from epidemiology studies suggest that youth may encounter environmental risk at different developmental periods, and that these risks (or protective factors) may interact within an individual's genotype to confer the onset or offset of CP.

Using previously published CP trajectories from ALSPAC (Barker & Maughan, 2009) as an outcome, we propose to examine environmental risk exposures, from gestation to the teens, and potential gene-to-CP effects, and gene-environment interactions. With regard to candidate polymorphisms, we propose to examine certain single nucleotide polymorphisms (SNPs) and variable number tandem repeats (VNTRs) that have been shown to associate to variation in stress response and/or CP. We also propose to examine a meta-analytic genome wide association study (GWAS), between ALSPAC and the Twins Early Development Study.

2. BACKGROUND

Well designed longitudinal studies converge on the finding that the development of CP is a heterogeneous process: beyond the EOP subtype, at least two other trajectories of CP have been consistently identified (Barker & Maughan, 2009; Odgers et al., 2007; 2008; Raine et a., 2005), a childhood limited (CL) and an adolescent-onset (AO) subtype. Taken together, the results of these studies suggest heterogeneity in development poses a serious challenge for clinicians, interventionists, and researchers alike. Understanding etiologic pathways underlying these distinct trajectories is a significant public health concern and efforts should be focused not only on prevention, but on ensuring that children who present CP have the best possible outcomes.

Gaps in the current knowledge on the etiologies of these CP pathways are at least three. First, to date, studies typically have examined sets of risk at specific (or aggregated) developmental periods, but rarely have these risks incorporated the prenatal period and early postnatal periods, crucial times in child development that may bear on the timing and impact of important risks on the development of biological systems, and hence an individual's susceptibility to subsequent environmental risk exposure(s). Second, no matter the severity and duration of risks experienced by children, evidence highlights individual differences in response, with some individuals apparently protected, or more vulnerable, to later adverse outcomes (Rutter, 2009). That is, there is consensus that risk factors are likely to be complex and involve interplay amongst genetic vulnerabilities and environmental risk exposure. The third limitation is that most studies to date have examined the EOP pathway, highlighting the need for further studies to examine etiologies underlying the CL and AO pathways. Indeed, differences in the development of CP amongst these trajectories suggests that the variation and timing of environmental risk, and presumably genetic vulnerabilities (or protective factors), as key features for refining current knowledge of these taxons.

We propose to test the extent to which variations in development of CP is related to the developmental interplay of genetic and environmental child-based risks. Specifically, we propose to conduct theoretically driven analysis where the research focus includes environmental risk exposure during pregnancy (18 wks and 32 weeks), early postnatal (birth to age 2; age 2 to age 4), school entry (age 7-8), adolescence (age 15-16), as well as candidate genes.

3. METHODS

3.1 Overview

Phase 1. Examine developmental continuity (and discontinuity) of environmental risk exposures during the following developmental periods: antenatal, early childhood, primary school and adolescence.

Phase 2. Examine both direct effects (polymorphism-to-CP trajectory) and interactions between polymorphisms and the environmental risks (i.e., examine if the relationship between a polymorphism and a trajectory is moderated by environmental risk exposure). SNPS and VNTRs prioritized via previous CP studies and studies on variation in stress response will be typed in the Avon Longitudinal Study of Parents and Children (ALSPAC, PI: G. Davey-Smith; Golding, Pembrey, & Jones, 2001). These data will be used to test hypotheses of direct gene, gene-environment interaction and haplotype-environment interactions where the outcome is the the odds of following the different CP trajectories. The availability of prospective information on environmental exposure in this sample will allow hypotheses to be tested about the impact of timing of environmental stress for these different CP trajectories.

Phase 3. GWAS meta-analysis. I have negotiated access to the Twins Early Development Study (TEDS, PI R. Plomin; Trouton, Spinath, & Plomin, 2002). Dr. Beate Glaser, of ALSPAC, has agreed to collaborate and wil estimate the GWAS on ALSPAC. Dr. Glaser will also combine GWAS estimates obtained from TEDS with those from ALSPAC.

3.2 Data collection.

We propose to genotype SNPs and VNTRs, as well as haplotypes of CRH-R1 (e.g., Lake et al., 2003) in ALSPAC.

3.3 Existing Data Required

Environmental risks are located in the previous section. The SNPs and VNTRs we propose to genotype are located in the next section.

3.4 Data Analysis.

Phase 1: We will estimate and examine the configuration of risk within each development period by way of Latent Class Model (McCutcheon, 1987). Continuity of environmental risks will be examined via latent transition models (Muthen & Muthen, 2001-2006).

Phase 2: Examination of gene-environment processes

Phase 3: GWAS meta-analysis

3.5 Work already completed

We have already published a paper on the trajectories and antenatal and early postnatal risks associated to the EOP vs CL pathways (Barker & Maughan, 2009). We will soon submit a follow-up to this paper (Barker, Bonamy & Maughan, in preparation) for approval to the ALSPAC exec. These two papers create the substantive background for this application.

References

Barker, E. D., & Maughan (2009). Differentiating early-onset persistent versus childhood-limited conduct problem youth. American Journal of Psychiatry, 166, 900-908.

Barker, E. D., Bonamy, B., & Maughan, B. (in preparation). Time-varying covariates of conduct problem trajectories.

Golding, J., Pembrey, M., & Jones, R. (2001). ALSPAC--the Avon Longitudinal Study of Parents and Children. I. Study methodology. Pediatric and Perinatal Epidemiology, 15, 74-87.

Lake, S. L., Lyon, H., Tantisira, K., Silverman, K. E., Weiss, S. T., Laird, N.M., Schaid, D.J. (2003). Estimation and Tests of Haplotype-Environment Interaction when Linkage Phase Is Ambiguous. Human Heredity, 55, 56-65.

Moffitt, T. E. (2006). Life-course persistent versus adolescence-limited antisocial behavior. In D. Cicchetti & D. J. Cohen (Eds.), Developmental Psychopathology (2nd ed., Vol. 3: Risk, disorder, and adaptation, pp. 570-598). NY: Wiley.

Muthen, L. K., & Muthen, B. O. (1998-2006). Mplus. Statistical analyses with latent variables. User's guide (4.1 ed.). Los Angeles: Muthen & Muthen.

Odgers, C. L., Caspi, A., Broadbent, J. M., Dickson, N., Hancox, R., Harringthon, H., et al. (2007). Conduct problem subtypes in males predict differential adult health burden. Archives of General Psychiatry, 64, 476-484.

Odgers, C. L., Moffitt, T. E., Broadbent, J. M., Dickson, N., Hancox, R. J., Harrington, H., et al. (2008). Female and male antisocial trajectories: From childhood origins to adult outcomes. Development and Psychopathology, 20, 673-716.

Raine, A., Moffitt, T. E., Caspi, A., Loeber, R., Stouthamer-Loeber, M., & Lynam, D. R. (2005). Neurocognitive impairments in boys on the life-course persistent antisocial path. Journal of Abnormal Psychology, 114, 38-49.

Robins L. N. (1966). Deviant children grown up. Baltimore: Williams & Wilkins.

Trouton, A., Spinath, F. M., & Plomin, R. (2002). Twins Early Development Study (TEDS): A multivariate, longitudinal genetic investigation of language, cognition and behavior problems in childhood. Twin Research, 5(5), 444-448.