Unipolar disorder (UP)

Unipolar disorder or major depression is an affective disorder characterized by a persistent depressed mood and a serious loss of interest in almost all daily activities.

A person is diagnosed with major depressive disorder if he or she has had an episode of depression lasting at least two weeks with at least five of the nine following symptoms:
At least one of the two core symptoms has to be present:

• A seriously depressed mood most of the day, nearly every day
• A markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day

In addition, at least three or four of the following symptoms have to be present:

• A decrease or increase in appetite, or a significant weight loss (when not dieting) or weight gain
• Difficulty falling or staying asleep (insomnia), or sleeping more than usual (hypersomnia)
• Behavior that is agitated or slowed down
• Fatigue or loss of energy
• Feelings of worthlessness or excessive or inappropriate guilt
• Diminished ability to think or concentrate, or indecisiveness
• Recurrent thoughts of death or suicide

These symptoms are sufficiently severe to cause marked impairment of the person’s normal functioning, and are not due to physical illness, alcohol or drug abuse, or a normal grief over the death of a loved one.

Bipolar disorder (BP)

Bipolar disorder (also known as manic depression) is characterized by mood that alternates between two emotional extremes, or poles: the sadness of depression and the euphoria of mania. Both the depressive and manic episodes may be accompanied by psychotic symptoms, such as hallucinations and delusions.

A manic episode is described as a distinct period of abnormally and persistently elevated, expansive, or irritable mood, lasting at least 1 week. During this period, at least three or four of the following symptoms have been significant and enduring:

• An inflated self-esteem or grandiosity
• A decreased need for sleep
• More talkative than usual or pressure to keep talking
• A flight of ideas or subjective experience that thoughts are racing
• Distractibility
• An increase in goal-directed activity or psychomotor agitation
• An excessive involvement in pleasurable activities that have a high potential for painful consequences

The mood disturbance is sufficiently severe to cause marked impairment of the person’s normal functioning, and is not due to physical illness, alcohol or drug abuse.

A depressive period is characterized by the same symptoms as unipolar disorder.

Schizophrenia

Schizophrenia is a chronic psychiatric condition characterized by loss of contact with reality and major disturbances of thought, emotion and perception.
This loss of reality is manifested by the so-called “positive symptoms”:

• Delusions (a fixed, false belief about external reality)
• Hallucinations (sensory perceptions in the absence of a stimulus)
• Strange and bizarre behavior

In addition to these psychotic symptoms, there is a decline in the person’s social functioning, which is expressed by the so-called “negative symptoms”:

• Affective flattening
• Apathy
• Asocial behavior
• Attention deficits
• Diminished capacity to experience pleasure
• Poverty of speech

Linkage analysis

Linkage analysis is a method used to determine the chromosomal location of disease genes, using families with the disease of interest. The goal is to identify a part of a chromosome of known location that is inherited by all family members affected by the disorder being studied, and is not inherited by any of the unaffected family members. This DNA region is said to be 'co-inherited' with the disease phenotype, and most likely harbors a gene contributing to disease susceptibility.

Association studies

In genetic association studies, disease susceptibility alleles are identified by searching for significant differences between large groups of patients on one hand and healthy individuals on the other hand. More specifically, the frequency of certain genetic variants will be compared between patients and controls. In case the frequency of a particular variant is much higher in patients than in controls, that variant is said to be ‘associated’ with the disease. In the DNA region around the associated variant lies a potential risk factor for the disorder.

Candidate genes and regions

Using a genome wide linkage analysis, we analyzed nine multigenerational families with BP and UP, ascertained in an isolated population from northern Sweden. We identified a linked region on chromosome 9q, which could be further narrowed to a candidate region of 1.6 million bases. This region is currently under further investigation in order to identify genetic variants underlying BP and/or UP. Another linkage analysis in ten Belgian families of Jewish origin identified a candidate region on chromosome 10q. Further investigation of this locus will allow us to identify a susceptibility gene for psychiatric disorders.
Using a genetic association study, we studied the role of the brain-specific isoform of the tryptophan hydroxylase 2 gene in UP and BP in a northern Swedish population. Tryptophan hydroxylase plays an important role in the biosynthesis of serotonin (a neurotransmitter involved in mood, self-confidence, sleep and emotion), and is therefore considered an interesting candidate gene for psychiatric disorders. Our study provided evidence for a genetic protective involvement of specific tryptophan hydroxylase 2 variants in BP as well as UP, supporting a central role of this gene in the pathogenesis of psychiatric disorders.