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Depression (Wray, 2018)

STUDY TITLE: Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression

SUMMARY: Genetic variants in genes expressed in the brain are associated with major depressive disorder.

DESCRIPTION: Major depressive disorder (MDD), or depression, is a common mental disorder characterized by intense feelings of sadness for extended periods of time that impacts the mood, behavior, sleep, and appetite of an individual. It may also be accompanied by an increased risk of suicide or suicidal thoughts and a general disinterest for activities that used to cause excitement. Genetics are a known factor in a person’s risk of developing depression. This study examined 480,359 individuals of European ancestry to identify genetic variants associated with depression. The majority of the variants identified in this study are in genes that are expressed in brain regions known for their role in depression. This study also found that individuals with lower educational attainment and higher body mass are more likely to develop depression.

DID YOU KNOW? You may be able to decrease your risk factor of depression by exercising regularly, developing a strong support system, managing your stress, and avoiding alcohol and drugs. [SOURCE]

SAMPLE RESULTS: Learn more about the Nebula Research Library.

Depression sample results.

MDD-ASSOCIATED VARIANTS: rs12552, rs1432639, rs8025231, rs12129573, rs115507122, rs12958048, rs61867293, rs915057, rs11135349, rs1806153, rs4904738, rs7430656, rs10149470, rs34215985, rs11682175, rs10959913, rs4869056, rs8063603, rs116755193, rs5758265, rs7856424, rs17727765, rs7198928, rs2389016, rs4261101, rs62099069, rs12666117, rs11663393, rs1354115, rs7200826, rs1226412, rs4143229, rs10950398, rs1833288, rs7029033, rs9402472, rs4074723, rs9427672, rs159963, rs11643192

Major Depressive Disorder
Depression and the Brain

WEEKLY UPDATE: August 2, 2019

Depression Information

Depression is a mental disorder (or mood disorder). Typical symptoms of depression are depressed mood, brooding, a feeling of hopelessness and a diminished drive. Frequently, joy and feelings of pleasure, self-esteem, performance, empathy and interest in life are lost. Quality of life is often impaired as a result.

These complaints occur in healthy people in the context of grief after a loss experience and appear as depression; however, they usually pass by on their own. Illness is present when the symptoms persist for a disproportionate length of time or when their severity and duration are out of proportion.

In psychiatry, depression is assigned to affective disorders. The diagnosis is made according to symptoms and course (e.g. single or repeated depressive episodes). The standard treatment of depression includes psychotherapy and, in extreme cases, the use of antidepressants.

Medically, depression is a serious mental illness and medical condition that requires treatment and often has many consequences, which cannot be influenced by the willpower or self-discipline of the person affected. Depression is a major mental health crisis and is a major cause of incapacity to work or early retirement and is a leading cause of suicide.


In an international comparative study of 2011, the frequency in high-income countries was compared with that in middle and low-income countries. Lifetime prevalence of depression was 14.9 % in the first group (ten countries) and 11.1 % in the second group (eight countries). The ratio of women to men was approximately 2:1.

In the United States, depression affects nearly 7% of the population. With the age of onset being an average of 31 years old.

The burden of illness due to depression, for example in older adults that presents in the incapacity to work, inpatient treatment and early retirement, has risen sharply in recent years. It is assumed that the actual incidence of illness has changed much less severely and that the increased incidence is due to better recognition and less stigmatization of people with mental disorders. Results of long-term studies, on the other hand, tend to indicate a real increase, which is associated with various societal influencing factors.


The main symptoms of depression are:

  • Depressed, depressed mood: Depression is characterized by a narrowing of the mood or, in the case of severe depression, the “feeling of numbness” or the feeling of persistent inner emptiness.
  • Loss of interest and joylessness: Loss of the ability to feel joy or sadness; loss of affective resonance, i.e. the patient’s mood cannot be brightened up by encouragement
  • Lack of drive and increased fatigue: Another typical symptom is drive inhibition. In a severe depressive episode, people affected can be so severely inhibited in their drive that they are no longer able to perform even the simplest activities such as personal hygiene, shopping or washing up.

Additional symptoms can be:

  • reduced concentration and attention
  • Decreased self-esteem and self-confidence (feeling of insufficiency)
  • Feelings of guilt and inferiority
  • Negative and pessimistic future prospects (hopeless): Characteristic are exaggerated concern about the future, possibly exaggerated anxiety due to minor disturbances in the area of one’s own body (see hypochondria), the feeling of hopelessness, helplessness or actual helplessness
  • Suicidal thoughts or actions: Severely affected persons often feel that their life is completely meaningless. Often this agonizing state leads to latent or acute suicidal tendencies.
  • Insomnia
  • reduced appetite
What is depression? Types, symptoms, causes, diagnosis, and treatment -  Insider
Symptoms of Depression, Source

People with depression often experience physical symptoms, pain in very different parts of the body, most typically with an agonizing feeling of pressure on the chest. During a depressive episode the susceptibility to infection is increased. Social withdrawal is also observed, thinking is slowed down (inhibition of thinking), senseless circling of thoughts (compulsion to brood), disturbances of the sense of time. Irritability and anxiety often exist. In addition, hypersensitivity to noise can be a problem. Bipolar Disorder is also a subgroup of depression, and occurs when patients experience severe bouts of mania, followed by prolonged depressive and anxiety spells. Depression can also occur with anxiety disorders.


Severity is classified according to the number of symptoms:

  • Mild depression: two main symptoms and two additional symptoms
  • Moderate depression: two main symptoms and three to four additional symptoms
  • Severe depression: three main symptoms and five or more additional symptoms

Gender differences

The symptoms of depression can manifest themselves in different ways depending on gender. The differences in the core symptoms are small. While in women, phenomena such as despondency and brooding are more common, in men there is clear evidence that depression can also be reflected in a tendency to behave aggressively. In a 2014 study, the different manifestations in women and men were associated with differences in the biological systems of the stress response.

7 Most Common Types of Depression
Types of Depression, Source


The causes of depressive disorders are complex and only partially understood. There are both predispositions and acquired susceptibilities (predispositions) to the development of depression. Acquired susceptibilities can be triggered by biological factors and by life-historical social or psychological stress. Season Affective Disorder is also a specific type of depression that correlates with seasonal changes.

Depression | Psychological Health Center of Excellence
There are many causes of depression, Source

Is Depression Genetic?

Twin studies showed that the genetic component is only one factor. Even with identical genetic make-up (identical twins), those with a sibling with depression tend to only fall ill in less than half of the cases. In the meantime, differences between affected and non-affected twin partners have also been found in the subsequent (epigenetic) alteration of the genetic information, i.e. influences of life history on the control of the genetic information. This is also impacting my parents or siblings with depression. In any case, a full family history will help to address the genetic basis of each patients case in order to find family members with depression. However, it is possible that the affected relative never develop depression symptoms.

Furthermore, there is a gene-environment interaction between genetic factors and environmental factors the impact people who develop depression. For example, genetic factors can cause a certain person to often maneuver himself or herself into difficult life situations through a great willingness to take risks. Conversely, whether a person copes with a psychosocial burden or becomes depressed can depend on genetic factors.

A significant genetic vulnerability factor for the occurrence of depression is suspected to be a variation in the promoter region of the serotonin transporter gene 5-HTTLPR. 5-HTTLPR stands for Serotonin (5-HT) Transporter (T) Length (L) Polymorphic (P) Region (R). This “depression gene” is located on chromosome 17q11.1-q12 and occurs in different forms in the population (so-called “different length polymorphism” with a “short” and a “long allele”). Carriers of the short allele react more sensitively to psychosocial stress and are said to have up to twice the risk (disposition) of developing depression than carriers of the long allele.

In two meta-analyses in 2011, the association between the short allele and the development of depression after stress was confirmed. In a meta-analysis in 2014, significant data were found in connection with depression for a total of seven candidate genes: 5HTTP/SLC6A4, APOE, DRD4, GNB3, HTR1A, MTHFR, and SLC6A3. However, certain abnormalities that are decisive for the development of depression have not yet been found despite an extremely extensive search.


After the introduction of reserpine as a drug in the 1950s, it was observed that some patients showed depressive symptoms after being treated with it. This was attributed to the lowering of neurotransmitters in the brain. It is considered that certain that signal transmission is particularly involved in the monoaminergic neurotransmitters serotonin, dopamine and noradrenaline. Other signaling systems are also involved, and their mutual influence is highly complex. Although monoaminergic influencing drugs (antidepressants) can change depressive symptoms, it remains unclear to what extent these transmitter systems are causally involved in the development of depression. Thus, about one third of patients do not respond or respond only insufficiently to drugs that influence monoaminergic systems.

Depression Overview: Emotional Symptoms, Physical Signs, and More
Example of Neurological Changes in a Depressed Brain, Source


Depression can be successfully treated in the majority of patients. Possible treatment options include drug treatment with antidepressants, psychotherapy or a combination of drug and psychotherapeutic treatment. This is increasingly being supplemented and supported by online therapy programs. Other therapy methods for persistent depressive disorder, such light therapy or sleep therapy, sports and exercise therapy complement the treatment options.

The current national treatment guidelines consider antidepressants to be equivalent to psychotherapy for moderate to severe depressive periods. For severe depression, a combination of psychotherapy and antidepressant medication is recommended. Ultimately, the approach to treat depression is handled by health care professionals on a case by case basis.

A combination of psychotherapy and drug treatment can be carried out by physicians (usually specialists in psychiatry or psychosomatics, sometimes also general practitioners and other specialties) with psychotherapeutic training, or by a cooperation of physicians and psychotherapists on an outpatient basis or in psychiatric clinics or specialized hospitals.

In cases of high suffering and an unsatisfactory response to outpatient therapy and psychotropic drugs – but especially in cases of imminent suicide – treatment in a psychiatric clinic should be considered. This is known as clinical depression. Such a treatment offers the patient a daily structure and the possibility of more intensive psychotherapeutic and medical measures, including those that cannot be billed on an outpatient basis and are therefore not possible, especially in the health insurance scheme.


Common drugs used to treat depression, Source


The signal transmission from the axon of one neuron (top) to the dendrite of another neuron (bottom) is increased, e.g. by blocking transporters that return released neurotransmitters to the axon. This increases the amount of transmitters in the synaptic cleft between the cells and thus the signal transmission from cell to cell. Drugs that block such transporters are typical for antidepressants.

The effectiveness of antidepressants is strongly dependent on the severity of the disease. While the effectiveness is absent or low in mild and moderate severity, it is clear in severe depression. In the most severe forms, up to 30% of the treated patients benefit from antidepressants beyond the placeborates. [29] Metastudies indicate that antidepressant drugs show great differences in their effectiveness from patient to patient. In some cases a combination of different drugs can have advantages.

Selective reuptake inhibitors

These active ingredients inhibit the reuptake of the neurotransmitters serotonin, norepinephrine or dopamine into the presynapses. Direct effects on other neurotransmitters are significantly weaker with these selective agents than with tricyclic antidepressants.

The selective serotonin reuptake inhibitors (SSRIs) are the most commonly used drugs for depression today. They are effective for a duration of two to three weeks. They (largely) selectively inhibit the reuptake of serotonin at the presynaptic membrane. This results in a “relative” increase in the messenger substance serotonin during signal transmission.

Monoaminooxidase (MAO) inhibitors

MAO inhibitors work by blocking the monoamine oxidase enzymes. These enzymes cleave monoamines such as serotonin, norepinephrine and dopamine. This reduces their availability for signal transmission in the brain. The MAO inhibitors inhibit these enzymes, which increases the concentration of monoamines and thus of neurotransmitters. This enhances signal transmission between the nerve cells.

MAO inhibitors are divided into selective or non-selective and reversible or irreversible. Selective inhibitors of MAO-A (e.g. moclobemide, reversible) only inhibit type A monoamine oxidase and show an antidepressant effect. They are generally well tolerated, including with significantly less disturbance of digestive and sexual functions than SSRI’s.


In depressive emergencies (suicide risk), several studies confirmed a rapid antidepressant effect of ketamine. This is an antagonist at the glutamate NMDA receptor complex. Study results showed a significant improvement over a period of up to seven days when administered once. There are recommendations for low-dose prescription. Which in contrast to using as an anesthetic or dissociative, shows hardly any side effects.

Alternative Approaches

  • Light therapy
  • Exercise
  • Nutrition
  • Sleep Monitoring
  • Sleep Deprivation
  • Meditation

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