Family studies of affective disorders have continually demonstrated aggregation of illness in relatives (Table 6-2). In a study at the National Institute of Mental Health, 25% of relatives of bipolar probands were found to have bipolar disorder or unipolar illness (depression) themselves, compared to 20% of relatives of unipolar probands and 7% of relatives of control subjects. In the same study, 40% of the relatives of schizoaffective probands demonstrated affective illness at some point in their lives. These data demonstrate increased risk in relatives of patients; they also show that the various forms of affective illness appear to be related in a hierarchical way. Relatives of schizoaffective probands may have schizoaffective illness themselves but are more likely to have bipolar or unipolar illness. Relatives of bipolar probands have either bipolar or (more likely) unipolar illness.
If pedigrees of patients with affective disorders are considered as a group, it has generally not been possible to fit single-gene models to them. Some data have supported multifactorial models. These models imply multiple factors: genetic, environmental, or both. An alternative explanation is heterogeneity. In other words, single major genes are important in at least some families, but it is not the same gene in each family.
Age at onset may be useful in dividing affective illness into more genetically homogeneous subgroups. Relatives of early-onset probands seem to be at increased risk of illness.
A birth cohort effect has been observed in recent family studies: There is an increasing incidence of affective illness among persons born more recently. The cohort effect appears to be true for schizoaffective, bipolar, and unipolar illness. The cohort effect is also true among relatives, who are at greater risk than the general population; that is, we are now seeing an increased manifestation of illness among vulnerable persons or (if vulnerability is a single locus defect) greater penetrance. A series of neuropsychiatric conditions has been shown to be related to expansion of short repeated sequences within genes as they are passed from one generation to the next (eg, expanded trinonucleotide repeats). This type of gene expansion may be associated with anticipation (increased severity or earlier onset in younger generations). Anticipation might cause an apparent cohort effect.
Twin studies show consistent evidence for heritability (Table 6-3). On average, MZ twin pairs show concordance 65% of the time, and DZ twin pairs show concordance 14% of the time.
Several adoption studies have focused on affective illness. The results have been generally consistent with genetic hypotheses. In one study, the risk for affective disorder in the biological relatives of bipolar probands was 31% as op-posed to 2% in the relatives of control probands. The risk in biological relatives of adopted bipolar probands was similar to the risk in relatives of bipolar probands who were not adopted away (26%). Adoptive relatives did not show increased risk. Adoption studies that used a broader class of affective probands showed evidence for genetic factors but also possible environmental influences. In some of these studies, adoptive relatives of affective probands had a greater tendency to develop affective illness themselves, compared to the adoptive relatives of control subjects. These data suggest that genetic factors are more prominent in bipolar illness than in other forms of affective illness.
Genetically Related Disorders
Bipolar II Disorder
Most investigators have found that bipolar II disorder is genetically related to bipolar I disorder and unipolar illness. Some evidence from recent family studies indicates a specific increase of bipolar II disorder in relatives of bipolar II probands. Bipolar II disorder tends to be a stable lifetime diagnosis (ie, patients do not frequently convert to bipolar I disorder).
Bipolar Disorder with Rapid Cycling
Bipolar disorder with rapid cycling has been the subject of great theoretical and clinical interest. The diagnosis is given to patients with four or more episodes of mania or depression per year; individual patients have been described who have regular cycles of 48 hours. The disorder is relatively resistant to lithium prophylaxis. A link with thyroid pathology has been proposed. Bipolar disorder with rapid cycling appears to arise from factors that are separable from genetic vulnerability to bipolar illness and that do not lead to aggregation within families.
The diagnosis of unipolar mania describes patients with bipolar I disorder who have no history of major depression. They tend to be male, are responsive to lithium, and on further history or follow up are usually found to have at least subclinical depressions. This group is not distinguishable from other bipolar I patients on the basis of family pattern of illness.
Cyclothymic disorder, which involves repetitive high and low mood swings that generally do not require clinical attention, is probably genetically related to bipolar disorder.
Patients with psychotic symptoms, intermittently or chronically, between mood episodes may share genetic vulnerability factors for schizophrenia and affective illness. Schizoaffective disorder (bipolar type) appears to be more closely related to mood disorder, whereas schizoaffective disorder (depressed type) may be more closely related to schizophrenia.
Some studies have found an increased prevalence of depression in relatives of schizophrenic patients. Bipolar illness has generally not been found, nor is schizophrenia more prevalent in relatives of bipolar probands than in control subjects. Evidence indicates that there may be some common genetic factors in bipolar disorder and schizophrenia (discussed later in this chapter).
Family studies of anorexia and bulimia have generally found an increased prevalence of affective illness in relatives of patients with these disorders. The risk of affective disorders in relatives of anorexic patients may be similar to that in relatives of bipolar probands.
Attention-Deficit/Hyperactivity Disorder (ADHD)
The relatives of children with ADHD are more likely to have depression than are control subjects. The opposite has not been demonstrated (ie, bipolar and unipolar probands have not been reported to have increased risk of ADHD in their offspring).
Alcoholism is probably genetically distinct from bipolar illness, but overlapping vulnerability traits may exist. Winokur assembled evidence that unipolar depressive patients with alcoholic or sociopathic relatives (depressive spectrum disorder) are distinct from those without. Alcoholism appears to be comorbid with unipolar and bipolar disorders. Some evidence indicates that alcoholism with comorbid affective disorder may aggregate within families.
Linkage studies in affective disorder have been both newsworthy and controversial (Table 6-4). One study reported linkage to markers on the short arm of chromosome 11 in a large Amish family; however, a number of investigators failed to find similar results. Failure to replicate a linkage finding in a separate family is not necessarily a disconfirmation. It may simply indicate heterogeneity. X-chromosome linkage has been reported by some investigators and a meta-analysis suggests a gene of partial effect at Xq26.
Researchers have reported a linkage between bipolar illness and markers on chromosome 18p near the centromere. This finding is supported by data from several other investigators, although there is also evidence for an 18q locus. Another study reported linkage to markers on chromosome 21. This observation has been partially replicated by several other researchers. Loci on 4p and 12q have also been reported. Some findings appear to be common to bipolar disorder and schizophrenia. The 13p32 region has a confirmed schizophrenia susceptibility locus, and there is a statistically robust report of linkage at this locus in bipolar disorder.
Velocardiofacial syndrome (VCFS) is characterized by conotruncal cardiac defects, facial dysmorphology, cleft palate, and learning disabilities. The majority of patients have an interstitial deletion on chromosome 22q11. In addition to physical abnormalities, a variety of psychiatric illnesses have been reported in patients with VCFS, including schizophrenia, bipolar disorder, and ADHD. The psychiatric manifestations of VCFS could be due to disruption of a gene within 22q11. There are several reports of bipolar disorder and schizophrenia linkage to the 22q11–13 region.
Potential Biological Vulnerability Markers
The quest for the physiologic basis of genetic vulnerability to mood disorder has led in many different directions. Most putative biological vulnerability markers have not passed the tests of heritability and association with illness within pedigrees. A discussion of some of the more notable work in this area follows:
The lithium erythrocyte-plasma ratio may be higher in some cases of familial bipolar disorder.
Cholinergic REM Induction
Sleep disturbance is common in depression; one of the most consistent observations is the shortening of rapid eye movement (REM) latency. REM may be induced in volunteer subjects by an injection of a small dose of physostigmine or arecoline during sleep. A series of studies showed that bipolar patients are more sensitive than are control subjects to the REM-inducing effects of arecoline, even when the patients are euthymic and are not taking medication. Further studies have shown that sensitivity to REM induction may be heritable and that it associates with affective disorder within pedigrees. These studies suggest the possibility of central muscarinic cholinergic supersensitivity in brainstem areas in bipolar illness. Methodologic issues require resolution, and the precise neurochemical and anatomic interpretation of these studies remains to be elucidated.
Some studies have found that, in comparison to control subjects, patients with bipolar disorder, and their offspring, are more sensitive to light suppression of melatonin secretion by the pineal gland. This observation may be found more consistently in bipolar I disorder.
Summary & Empirical Data for Genetic Counseling
Molecular genetic studies hold great promise for families with affective disorder, particularly bipolar disorder. The availability of DNA markers would make genetic counseling for these disorders much more precise. Such counseling has already begun for families with Huntington’s disease. At present, however, the field has not reached the point at which such markers are clinically useful for affective disorder. This is also the case for etiologic markers. Consequently genetic counseling must be based on empirical risk figures.
The lifetime risk for severe affective disorder is about 8% (about 5–6% for unipolar disorder and 2–3% for bipolar I and bipolar II disorders). Risk is increased to about 20% in first-degree relatives of unipolar patients and to 25% in first-degree relatives of bipolar patients. Risk appears to be 40% in relatives of schizoaffective patients. The risk to offspring of two affectively ill parents is more than 50%. Overall risk figures appear to be rising in recent years, more so in relatives of patients than in the general population.