Genome-wide association study of the child behavior checklist dysregulation profile

Abstract

Objective: A potentially useful tool for understanding the distribution and determinants of emotional dysregulation in children is a Child Behavior Checklist profile, comprising the Attention Problems, Anxious/Depressed, and Aggressive Behavior clinical subscales (CBCL-DP). The CBCL-DP indexes a heritable trait that increases susceptibility for later psychopathology, including severe mood problems and aggressive behavior. We have conducted a genome-wide association study of the CBCL-DP in children with attention-deficit/hyperactivity disorder (ADHD).

Method: Families were ascertained at Massachusetts General Hospital and University of California, Los Angeles. Genotyping was conducted with the Illumina Human1M or Human1M-Duo BeadChip platforms. Genome-wide association analyses were conducted with the MQFAM multivariate extension of PLINK.

Results: CBCL data were available for 341 ADHD offspring from 339 ADHD affected trio families from the UCLA (N = 128) and the MGH (N = 213) sites. We found no genome-wide statistically significant associations but identified several plausible candidate genes among findings at p < 5E-05: TMEM132D, LRRC7, SEMA3A, ALK, and STIP1.

Conclusions: We found suggestive evidence for developmentally expressed genes operant in hippocampal dependent memory and learning with the CBCL-DP.

Figure 1

Manhattan Plot of Association Results. Note: Single Nucleotide Polymorphisms (SNPs) within 1 million base-pairs of suggestive leakage peaks for the Child Behavior Checklist – Dysregulation Profile (CBCL-DP) (1p21.1, 2q23, 6p21.3, 8q21.13) and meta-analyses of bipolar disorder (6q21 and 8q24.22) or ADHD (16q23.1) are highlighted in red.

Figure 2

Regional Association Plots for Genes Implicated in the Top 50 Associations. Note: The sentinel Single Nucleotide Polymorphism (SNP) (i.e. with the smallest p-value) is indicated by the green square. Any SNPs in linkage disequilibrium (LD) (r2≥0.8) with the sentinel SNP are marked with a red border. For SNPs with no additional SNPs in linkage disequilibrium (STIP1, TMEM132D) the r2 values available are depicted with text. Estimated recombination rates from the latest HapMap download (build 36) are depicted in light blue. Additional SNPs in LRRC7 and SEMA3A were also nominally significantly associated with the Child Behavior Checklist – Dysregulation Profile (CBCL-DP), but were in strong LD (r2≥0.8) with the sentinel SNPs (rs12037173 and rs797820, respectively) and likely represent single regions of association within these genes. Additional nominally significant SNPs in ALK, STIP1, and TEMEM132D, however, were not in strong LD with the sentinel SNPs (rs12996631, rs11607165, and rs11060369, respectively) as indicated by the r2 values. Although STIP1 was covered with only seven SNPs in our data, all but two were nominally statistically significant. Few additional SNPs in CDH13 were nominally associated with the CBCL-DP, and two of the three in LD (r2≥0.8) with rs1035569 were not statistically significant.