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Phenotype: Modern psychiatric nosology follows Leonhard's [110] suggestion to subdivide mood disorders into bipolar disorder -- where episodes of mania or both mania and depression occur -- and unipolar depressive disorder -- where episodes of depression alone occur. Symptoms of mania are expansive, elevated, or irritable mood; inflated self-esteem; grandiosity; decreased need for sleep; increased talkativeness; racing thoughts; distractibility; increased goal-directed activity; and excessive involvement in pleasurable activities with a high potential for painful consequences. Depressive symptoms consist of depressed mood, diminished interest or pleasure in activities, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue or loss of energy, feelings of worthlessness or excessive guilt, inability to concentrate or act decisively, and recurrent thoughts of death or suicide. Interrater reliability is excellent (kappa=0.83) [111], and test-retest reliability over a 6-year period is moderate (kappa=0.60) [112]. Several mental disorders, including variants of schizoaffective disorder, recurrent unipolar depression, and hypomania (bipolar II disorder), have been proposed as alternate expressions of a bipolar genotype [113-115]. Regarding these "spectrum" disorders, it is important to note that familial aggregation is not specific to bipolar disorder [116, 117] (i.e., etiologic heterogeneity is likely) and that interrater reliability is generally less than for the diagnosis of bipolar disorder proper [111, 118].
Epidemiology: The age-corrected lifetime morbid risk of bipolar disorder in the United States is about 0.8 percent [119, 120]. A recent report of population-based epidemiologic studies used similar methods and found age-corrected lifetime risks that ranged from 0.3 percent to 1.5 percent, with equal risks to men and women in 10 countries as divergent as Lebanon and Korea [121]. It seems that lifetime rates of bipolar disorder may be increasing in more recently born cohorts [115], but this is not a universal finding [122].
Family Studies: Data from more than 40 family and twin studies spanning six decades consistently show that the risk to relatives of those with the disorder is greater than the risk to relatives of normal controls [113, 119, 123-125]. The risks for both bipolar and unipolar depressive disorders are higher in the relatives of bipolar probands, while the first-degree relatives of unipolar depressive probands have a higher rate of unipolar depression alone [125-130]. Assuming a lifetime risk of 1 percent, recurrence risk ratios ( λ ) for type R relatives as estimated from epidemiological, family, and twin studies of bipolar disorder are as follows: λ=7, λ=60 [131]. Reliable estimates are not available for more distant relatives.
Twin Studies: Four twin studies have specifically investigated the concordance for bipolar disorder [132-135], and the respective ranges for MZ and DZ probandwise concordance rates were 33 percent to 80 percent and zero to 8 percent, with heritability estimates ranging from 30 percent to 80 percent. The respective MZ and DZ probandwise concordance rates in the largest and most methodologically rigorous study [134] were 62 percent and 8 percent, with a heritability estimate of 59 percent.
Adoption Studies:Two adoption studies provide support for the involvement of genetic factors in the familial transmission of bipolar disorder [136, 137].
Mode of Inheritance: Some early pedigree analyses yielded evidence for vertical familial transmission, but results in general were not consistent with inheritance under a single major gene [125]. In some studies [115, 138-140], segregation analyses provide limited support for major locus transmission of bipolar disorder, but not in others [141-143]. Familial risks for bipolar disorder are not consistent with single locus models [131, 144], and none of the two-locus heterogeneity or epistatic models considered by Neuman and Rice [144] provided a good explanation for observed data, although the epistatic models were closest. Multiplicative models involving three or more loci are more consistent [131]. A three-locus symmetric multiplicative model (each locus has an equal effect) offers a good fit, with a locus-specific recurrence risk ratio of 2 [131].
In summary, the mode of inheritance is complex and likely involves multiple interacting genes. The number of susceptibility loci, the recurrence risk ratio conferred by each locus, and the degree of interlocus interaction are all unknown, but it is clear that a single major locus does not account for a large proportion of the familial aggregation of bipolar disorder.
Molecular Genetic Studies: Studies are interpreted on the basis of Lander and Kruglyak's thresholds for "suggestive" or "significant" evidence of linkage [145]. Several reports by Mendlewicz and colleagues [146] produced sizable lod scores linking bipolar disorder with color blindness and G6PD deficiency, while others [147, 148] have reported significant evidence for Xq linkage. However, methodological criticisms have been raised about many of the earlier studies, and multiple failures to replicate have been reported [125, 149, 150]. A lod score of 7.5 was obtained in a methodologically rigorous study of five Israeli families [151] but subsequent additional analysis of these families led to a diminution of the linkage evidence [152].
Linkage to 11p was reported in an analysis of Amish family data [153], but the lod score (4.9) diminished to nonsignificance when pedigrees were extended and members reevaluated [154]. Suggestive evidence was found for linkage to 18p [155,156]. Another report found suggestive evidence of linkage about 10 Mb away on 18p and also found significant evidence of linkage to another region about 48 Mb away on 18q; both findings were in 11 paternally transmitting pedigrees only (probands' fathers or uncles were affected) [157]. Analysis of the full data set [157] resulted in less than suggestive evidence of 18q linkage but suggestive evidence of 18p linkage. Interpreting these results is difficult, given that evidence has been presented for a maternal effect in the transmission of bipolar disorder in these [158] and other [159] families and given that evidence of linkage in this sample [157] is highly dependent on which age correction is employed [160].
Although suggestive evidence of a locus on 18q was obtained in association analyses [161], the implicated region was over a 5 Mb region and other markers in between provided evidence against linkage. The region implicated was at least 15 Mb away from the 18q region for which significant evidence of linkage was previously reported [157]. Thus, an 80 Mb region encompassing most of both arms of chromosome 18 has been implicated.
At least four nonreplications of chromosome 18 linkage have been reported [162-165]. A lod score of 3.41 (genome-wide p value 0.04) was found in 1 of 47 bipolar families for localization to 21q [166] and analysis of the entire sample resulted in suggestive evidence (lod score=2.80). Suggestive [167] and less than suggestive [168] evidence has been reported in other samples, but, unfortunately, the strongest evidence of 21q linkage in Detera-Wadleigh and colleagues' study [167] was to a region more than 15 Mb away from that implicated earlier [166]. Also, three non-replications have been published [163, 164, 169].
Significant evidence of linkage to 4p was reported in a single pedigree [170], but a failure to replicate occurred in other pedigrees from the same population. Suggestive evidence has been reported for other linkages to 5p [171], 6p [172], 10q [173], 12q [174], 16p [175], and 22q [176]. Finally, anticipation has been reported [177], but this finding may reflect ascertainment bias [178]; a report of an association between trinucleotide repeat expansions and bipolar disorder [179] has not been followed by identification of a specific expanded gene [180].
In conclusion, no region identified as the loca-tion of a bipolar susceptibility locus has been convincingly replicated. The strongest evidence of linkage to date is consistent with susceptibility loci on chromosomal regions 18p, 18q, and 21q, but the methodological issues discussed above and the nonreplications demonstrate that these are clearly not confirmed, convincing findings. The inability to obtain more compelling evidence may have resulted because (1) genes on 18 and 21 confer susceptibility to bipolar disorder, but they have such a small relative effect on risk that a very large sample is required for detection; (2) genes on 18 and 21 confer susceptibility in a small number of families (failures to replicate reflect the confounding effects of genetic heterogeneity); or (3) the reported positive results are due to chance. Unfortunately, these three explanations are indistinguishable. Suggestive evidence of linkages to other autosomes (4, 5, 6, 10, 12, 16, 22) and the X chromosome is less compelling.
Animal Studies: A QTL for a hyperactivity phenotype (spontaneous activity, locomotor reactivity to a novel environment, and rearing in the open field) has been localized to rat chromosome 8 and explains 29 percent of the variance of an intercross between the Wistar-Kyoto and Wistar-Kyoto hyperactive strains [53]. The implicated region maps to mouse chromosome 9.
Source: National Institute of Mental Health
next: Scientists Close in on Multiple Gene Sites for Bipolar Disorder
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