Suggestive linkage of the child behavior checklist juvenile bipolar disorder phenotype to 1p21, 6p21, and 8q21

Abstract

Objective: Several studies have documented a profile of elevated scores on the Attention Problems, Aggressive Behavior and Anxious/Depressed scales of the Child Behavior Checklist (CBCL) in youth with bipolar disorder. The sum of these scales, referred to as the CBCL Juvenile Bipolar Disorder (JBD) phenotype, has modest diagnostic utility, and high scores are associated with severity of psychopathology and poor outcome. Recently, a genomewide linkage scan of this measure in ADHD sibling pairs revealed a region of suggestive linkage on chromosome 2q21. The current study aimed to further identify quantitative trait loci that influence the CBCL-JBD phenotype by using a dense and thus, arguably, more powerful set of single-nucleotide polymorphism markers in a different ADHD sibling pair sample.

Method: Subjects were 765 individuals from 154 families with CBCL data enrolled in a linkage study of ADHD. Linkage analyses were completed using a multipoint maximum likelihood variance components approach implemented using the statistical program SOLAR.

Results: Heritability of the CBCL-JBD phenotype was estimated at .71. Although no regions of the genome surpassed empirically derived criteria for significant linkage (p = .000038), peaks on 1p21.1 (p = .00037; LOD = 2.76), 6p21.3 (p = .00054; LOD =2.60), and 8q21.13 (p = .00081; LOD = 2.44) surpassed the threshold for suggestive linkage (p = .002). These regions have been highlighted in genomewide scans of bipolar disorder in adults, schizophrenia, autism, and ADHD.

Conclusions: Findings raise the possibility that genes in these regions influence variation on the CBCL-JBD scale and the emotional and behavioral dysregulation associated with severe psychopathology.

Figure 1

Results of the genomewide linkage scan of the Child Behavior Checklist (CBCL) juvenile bipolar phenotype. Values on the Y-axis reflect the −log10 empirical point-wise p-value, with lines indicating thresholds for significant (p=0.000038) and suggestive (p=.002) linkage. Three regions surpassed the empirically-derived genomewide threshold for suggestive linkage: 1p21.1 (p=0.00037;LOD =2.76), 6p21.3 (p=0.00054;LOD =2.60) and 8q21.13 (p=0.00081;LOD =2.44).