Attention-deficit/hyperactivity disorder and comorbid disruptive behavior disorders: evidence of pleiotropy and new susceptibility loci.
BACKGROUND
Attention-deficit/hyperactivity disorder (ADHD) comorbid with oppositional defiant disorder (ODD) or conduct disorder (CD) and substance abuse/dependence seems to represent a specific subset within the phenotypic ADHD spectrum.


METHODS
We applied complex segregation and linkage analyses in a set of multigenerational families densely segregating ADHD comorbid with ODD, CD, alcohol abuse/dependence, and nicotine dependence.


RESULTS
Our data suggest that ADHD cosegregates with disruptive behaviors as a unique, phenotypically variable trait as evidenced by highly significant pair-wise linkages among: ADHD and ODD (logarithm of odds [LOD]=14.19), ADHD and CD (LOD=5.34), ODD and CD (LOD=6.68), and CD and alcohol abuse/dependence (LOD=3.98). In addition to previously reported ADHD susceptibility loci, we found evidence of linkage for comorbid ADHD phenotypes to loci at 8q24, 2p21-22.3, 5p13.1-p13.3, 12p11.23-13.3, 8q15, and 14q21.1-22.2. These results were replicated with an affected status phenotype derived from latent class clusters.


CONCLUSIONS
Patterns of cosegregation of ADHD with comorbidities can inform our understanding of the inheritance patterns not only of ADHD but also of disruptive behavioral disorders and alcohol abuse/dependence. Refining the comorbid ADHD phenotype by determining the cosegregation profile of specific comorbidities might be a powerful tool for defining significant regions of linkage.
Jain
Mahim
M
Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-3717, USA.
Palacio
Luis Guillermo
LG
Castellanos
F Xavier
FX
Palacio
Juan David
JD
Pineda
David
D
Restrepo
Maria I
MI
Muñoz
Juan F
JF
Lopera
Francisco
F
Wallis
Deeann
D
Berg
Kate
K
Bailey-Wilson
Joan E
JE
Arcos-Burgos
Mauricio
M
Muenke
Maximilian
M
D000293:Adolescent; D001289:Attention Deficit Disorder with Hyperactivity / Q000453:epidemiology* / Q000235:genetics*; D019958:Attention Deficit and Disruptive Behavior Disorders / Q000453:epidemiology* / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations; D002874:Chromosome Mapping; D015897:Comorbidity; D019955:Conduct Disorder / Q000453:epidemiology / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D010641:Phenotype; D012307:Risk Factors; D019966:Substance-Related Disorders / Q000453:epidemiology / Q000235:genetics