|
GENETICS OF RECURRENT EARLY-ONSET DEPRESSION (GenRED)
BACKGROUND AND SIGNIFICANCE
Genetic epidemiology of major depression. Major depression is a syndrome including 2 or more weeks of depressed mood and/or impaired enjoyment with symptoms such as disturbed sleep and appetite, psychomotor changes, reduced concentration, excessive guilt, and suicidal thoughts or acts. Lifetime prevalence is 5-10% based on family and epidemiological studies (Tsuang et al, 1994; Moldin et al, 1991), but estimates vary widely (Weissman et al, 1996)(see section C2).
A minority of individuals with major depression have bipolar disorder (BP), which includes episodes of mania characterized by elevated or irritable mood and symptoms such as rapid thoughts and/or speech, grandiose ideas, and reckless behavior. The lifetime prevalence of severe BP disorder (BP-I) is 0.5-1%. Thus "unipolar" major depressive disorder (MDD) is the most common major mood disorder. It is associated with severe morbidity as well as mortality, with 50% to 70% of people who commit suicide having had MDD, and an estimated 15% of patients hospitalized for severe recurrent MDD eventually dying by suicide (Sainsbury, 1986; Roy, 1993; Goodwin and Jamison, 1990). Pathophysiology is unknown. Somatic treatments (medications and electro-convulsive therapy) and various psychotherapies have efficacy, with the former more effective in severe cases. Many MDD patients suffer from chronic depression even after remission of acute episodes (Goodwin and Jamison, 1990). Thus, improved understanding of pathophysiology may lead to improved treatment.
Twin studies demonstrate that genetic factors account for 40-70% of risk for MDD. Most heritability estimates are 0.40-0.54 (McGuffin et al, 1991, 1996; Torgerson, 1986). In an analysis of 680 female twin pairs, when errors in measurement were modeled using sequential assessments, the MDD heritability estimate rose to 0.70 (Kendler et al 1993), and one twin study of depressive symptoms in adolescence produced a heritability estimate of 0.79 (Thapar and McGuffin, 1994). Adoption studies also confirm the role for genetic factors (Mendlewica and Rainer, 1977; Cadoret, 1978; Wender et al., 1986). A large number of family studies have consistently demonstrated an increased risk of MDD in relatives of MDD probands (usually 10-25%), with about a twofold increased risk to first-degree relatives compared with the prevalence in an appropriate control group (e.g., Gershon et al., 1982; Weissman et al., 1984a; and reviewed in Moldin et al., 1991). However, segregation analyses have not resolved the mode of inheritance (Moldin et al., 1991; Marazita et al., (1997). Price et al. (1987) and Rice et al. (1987a) reported some support for a single major locus (SML) effect with non-mendelian transmission probabilities. Marazita et al. (1997) studied relatives of 50 probands with recurrent MDD and onset before age 25, and found evidence for non-Mendelian inheritance of a recessive SML effect with a narrow diagnosis (recurrent MDD), and evidence for a Mendelian codominant major locus with residual parental and spousal effects using a broader diagnostic definition.
Family studies demonstrate that risks of BP-I and unipolar MDD are at least partially genetically distinct, since relatives of BP-I probands have a substantially increased risk of BP-I (5-9%), but relatives of MDD probands do not, and unipolar MDD is more common in females (about 2:1) but BP-I is not. The genetic relationship between these syndromes is unresolved: there is a similarly increased risk of MDD in first-degree relatives of BP-I and of MDD probands. Despite clinical lore that sleep and appetite may be increased rather than decreased in bipolar depression, no clinical profile significantly differentiates MDD relatives of BP and MDD probands (Endicott et al, 1985; Goodwin and Jamison, 1990, pp. 67-69; Blacker et al., 1996). It can also be difficult to differentiate recurrent MDD from BP-II disorder, characterized by recurrent MDD and mild manic episodes (hypomanias). Current diagnostic methods are often not adequately sensitive for hypomania (Rice et al., 1985), BP-II may be related genetically to BP-I (Simpson et al., 1993; Heun and Maier, 1993; Endicott et al., 1985), BP-II cases lie between BP-I and MDD in clinical features (Coryell et al., 1985) and in co-segregation of BP-I and MDD in families (Gershon et al., 1982; Endicott et al., 1985). BP-II is most common in relatives of BP-II probands, suggesting that liability to manic episodes might be heterogeneous (Heun and Maier, 1993; Endicott et al., 1985). It is not known to what extent the liability to major depressive episodes overlaps in unipolar MDD, BP-I and BP-II disorders.
Introduction
|
|
