The Genetics of Pediatric-Onset Bipolar Disorder Stephen V. Faraone, Stephen J. Glatt, and Ming T. Tsuang Although bipolar disorder in adults has been extensively studied, early-onset forms of the disorder have received less attention. We review several lines of evidence indi- cating that pediatric- and early adolescent– onset bipolar disorder cases may prove the most useful for identifying susceptibility genes. Family studies have consistently found a higher rate of bipolar disorder among the rela- tives of early-onset bipolar disorder patients than in relatives of later-onset cases, which supports the notion of a larger genetic contribution to the early-onset cases. Comorbid pediatric bipolar disorder and attention-deficit/ hyperactivity disorder (ADHD) may also define a familial subtype of ADHD or bipolar disorder that is strongly influenced by genetic factors and may, therefore, be useful in molecular genetic studies. There are no twin and adoption studies of pediatric bipolar disorder, but the heritability of this subtype is expected to be high given the results from family studies. Thus, pediatric- and early adolescent– onset bipolar disorder may represent a genet- ically loaded and homogeneous subtype of bipolar disor- der, which, if used in genetic linkage and association studies, should increase power to detect risk loci and alleles. Biol Psychiatry 2003;53:970 –977 © 2003 Soci- ety of Biological Psychiatry Key Words: Bipolar disorder, mania, genetics, neuro- biology, epidemiology Introduction A lthough the diagnosis of mania in children has gen- erated much debate (Biederman 1998; Klein et al 1998), there is growing recognition that a group of seriously disturbed children with severe affective dysregu- lation and high levels of agitation, aggression, and dys- control show clinical features consistent with the diagnosis of bipolar disorder. Notably, several reviews of the liter- ature suggest that the diagnosis of bipolar disorder is warranted for at least some of these youth (Biederman et al 2000; Faedda et al 1995; Geller and Luby 1997; Weller et al 1995). Much of the controversy regarding apparently bipolar children derives from their clinical picture, which is atypical by adult standards. Bipolar children have a mixed presentation, a chronic course, poor response to mood stabilizers, and high levels of comorbidity with attention- deficit/hyperactivity disorder (ADHD) (Biederman 1998; Biederman et al 2000; Carlson et al 2000; Faraone et al 1997b; Schurhoff et al 2000; Wozniak et al 1995a). Yet, because a similar, atypical picture is seen in about one third of adults with bipolar disorder (McElroy et al 1992), we cannot rule out the diagnosis in children because of atypical signs. Because clinical features are limited in their ability to clarify nosological questions, it is useful to also examine other sources of external validation, such as follow-up studies, laboratory measures, and genetics (Robins and Guze 1970; Tsuang et al 1993). In this article, we first provide a context by summarizing the genetic epidemiol- ogy of bipolar disorder and then review genetic studies of early-onset bipolar disorder and its potential genetic rela- tionship to ADHD, whose comorbidity with bipolar dis- order has raised questions about the validity of the latter diagnosis. Overview: Genetic Epidemiology of Bipolar Disorder Family Studies of Bipolar Disorder If genes contribute to the development of bipolar disorder, then the relatives of bipolar patients should have a greater prevalence of the illness compared with relatives of nonpatients. Before examining family studies of bipolar disorder, it is useful to examine population-based epide- miologic data (Tsuang and Faraone 1990). Such studies are useful in this regard because they provide a context in which family study data can be interpreted. Early epide- miologic studies of “manic-depressive psychosis,” per- formed from 1938 to 1952, found the prevalence of the illness in the general population to range from .4% to 1.7%, with a mean risk of .7%. Relatively recent reports of From the Department of Psychiatry (SVF, MTT), Harvard Medical School, Massachusetts General Hospital; Harvard Institute of Psychiatric Epidemiology and Genetics (SVF, SJG, MTT); Johnson and Johnson Center for Pediatric Psychopathology at the Massachusetts General Hospital (SVF); Stanley Center for Pediatric Mania at the Massachusetts General Hospital (SVF); Department of Psychiatry (SJG, MTT), Harvard Medical School at Massachusetts Mental Health Center; and the Department of Epidemiology (MTT), Harvard School of Public Health, Boston, Massachusetts. Address reprint requests to Stephen V. Faraone, Ph.D., Harvard Medical School, Massachusetts General Hospital, WACC 725, 15 Parkman Street, Boston MA 02114-3139. Received July 10, 2002; revised November 6, 2002; accepted November 11, 2002. © 2003 Society of Biological Psychiatry 0006-3223/03/$30.00 doi:10.1016/S0006-3223(02)01893-0