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13


Challenges in the genetics of bipolar disorder
Kathleen Merikangas and Kelly Yu
National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA




Epidemiology of mood disorders
Major depressive disorder (MDD) is the leading cause of disability among those age 5
and over, and the second leading source of disease burden, surpassing cardiovascular
diseases, dementia, lung cancer, and diabetes (Murray and Lopez, 1996). The dramatic
impact of mood disorders on distress to the affected individual and his or her family,
lifetime disability, and suicide highlights the importance of etiologic research to
inform treatment and prevention.
Community-based rates of mood disorder are essential to deriving estimates of
population familial recurrence risk (l) (Risch, 1990). Population prevalence esti-
mates of mood disorders are available from two community surveys of the USA: the
Epidemiologic Catchment Area (ECA) study of five sites in the USA (Robins and
Regier, 1991), and the National Comorbidity Survey (NCS) of a probability sample
of the USA conducted 10 years later (Kessler et al., 1994). Estimates of base rates of
bipolar disorder (or manic episodes) were very low in both studies, averaging 0.8% in
ECA and 1.6% in NCS. In contrast, there is a very high lifetime prevalence of MDD
in the US population (females, 12% ECA; 21.3% NCS, and males, 5% ECA, 12.7%
NCS). Similar base rates of mood disorders have been obtained in international
studies as well (Weissman et al., 1996). With respect to demographic factors, the
differences between the bipolar and major depression subtypes of mood disorders
include the sex ratio that favors women for MDD but is nearly equal for men and
women for bipolar disorder, and the age of onset that occurs nearly a decade earlier in
MDD than in bipolar disorder (Weissman et al., 1991).
Manic episodes, bipolar disorder, and hypomania are generally rare in chil-
dren and adolescents. In the few studies reporting rates of these disorders, point,
12-month, and lifetime estimates ranged from 0% to 2.0% (Kashani et al., 1987;
Costello et al., 1996; Lewinsohn et al., 1998; Pine et al., 1998). The wide variation
in base rates has been attributed to methodologic differences rather than true
differences in prevalence. Likewise, the diagnostic criteria for bipolar disorder in
Cambridge University Press, 2005.
#
278 K. Merikangas and K. Yu


childhood have been quite controversial, and several prospective studies are now
under way to define the early manifestations of bipolar illness (National Institute
of Mental Health Research Roundtable on Prepubertal Bipolar Disorder, 2001).


Genetic epidemiology of mood disorders in adults
The role of genetic factors in the etiology of bipolar disorder has been suspected for
more than a century. Numerous reviews have demonstrated conclusively that
genetic factors are involved in the susceptibility to mood disorders, particularly
bipolar disorder (Tsuang and Faraone, 1990; Merikangas and Swendsen, 1997;
Moldin, 1997; Reus and Freimer, 1997; Sullivan et al., 2000).
Several study designs have been employed to assess the role of genetic factors in
disease etiology, including:
(1) family studies, which assess the degree of aggregation of a trait among relatives
of affected probands compared to expected rates from the general population
(2) twin studies, which compare concordance rates for monozygotic twins, who
have identical genotypes, with those among dizygotic twins, who share an
average of half of their genes
(3) adoption studies, which compare the degree of similarity between an adoptee
and his or her biological parents, from whom he or she was separated, and
between the adoptee and the adoptive parents
(4) association and linkage studies of genetic markers, which examine the rela-
tionships between a known genetic trait and disease status either across
families or within pedigrees.



Family studies
Although family studies cannot yield direct evidence for the involvement of genes
in the causation of a disease, they are a rich source of evidence for examining the
correspondence between the observed patterns of expression of a disease and the
patterns predicted by specific modes of transmission. A second application of
family studies, particularly with respect to clinically defined syndromes such as
mood disorders, is the investigation of the validity of diagnostic categories and
subtypes thereof through inspection of the degree to which particular symptoms
or symptom constellations breed true in families. Whereas the homogeneity of
expression of disorders is the goal of the latter studies, information on hetero-
geneity of expression within families may also be employed to identify variable
expressivity of transmitted disorders.
279 Challenges in the genetics of bipolar disorder


A major advantage of studying diseases within families is that the assumption of
homotypy of the underlying factors eliminates the effects of heterogeneity, which
are present in comparisons that are made between families. However, all indivi-
duals within a particular sibship are not expected to share equal genetic risk
because of independent segregation of genes. Nevertheless, if two members are

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