Genetics of depression - molecular genetics of affective disorders in childhood and adolescence

Genetic database BioMD-Y

Major depression during childhood and adolescence

Major depression is one of the most common psychological disorders with approximately 300 million people being affected worldwide. Major depression can already occur during childhood. During adolescence, the prevalence of major depression increases to 3-7%. Major depression during childhood and adolescence is often associated with particular severe psychosocial and health-related consequences, such as impairments in social relationships, difficulties at school and a highly increased risk of relapse.

What do we already know about the development of major depression during childhood and adolescence?
To date, it is not yet sufficiently studied why some children and adolescents develop major depression while others do not. Many different factors increase the risk of developing the disorder, such as a genetic vulnerability. The risk of developing major depression is especially high when stressors, such as stressful life events, add to a heightened genetic vulnerability. In particular, very severe stressful life events (such as the loss of a loved-one) are associated with an elevated risk of major depression. In addition, also less severe and more daily stressors can heighten the risk of developing major depression, particularly when many of them occur or when they are experienced over a longer period of time. Examples of these daily stressors are difficulties at school or quarrels (e.g., with friends). Furthermore, also family and parental factors can increase the likelihood of developing major depression during childhood and adolescence. Those factors include, e.g., a conflictual family climate. In contrast, factors, such as social support by the family or environment, can protect against developing major depression.

Aims of the genetics database BioMD-Y
To date, only a few studies have investigated the role of different molecular genetic factors, as well as their interplay with psychosocial risk and protective factors in the context of child and adolescent major depression. The genetic database BioMD-Y of the Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy of the LMU University Hospital contains data of more than 400 children and adolescents with a diagnosis of major depression, a sample of more than 250 healthy controls, as well as data of more than 500 parents of those children and adolescents with major depression. The ongoing development of this database should make a significant contribution to increase our knowledge of molecular genetic factors contrib-uting to major depression during childhood and adolescence.

The database is unique in its approach and extent:
We investigate different molecular genetic factors (e.g., candidate genes, polygenic risk scores, epigenetic factors), as well as hormonal factors in a clinically very well-characterized sample of children and adolescents with major depression, as well as healthy controls between the age of 8 and 18 years. Genetic factors are also investigated in parents of children and adolescents with major depression. Risk and protective factors of the children/adolescents, as well as their families are assessed by extensive questionnaires.
The course of the disorder is investigated during a 5-year follow-up study. This investigation focuses on epigenetic changes, as well as clinical (e.g., severity, length and frequency of the depressive episode) and psychosocial factors (e.g., stressful life events) predicting the course of the disorder.

Contact
Herr Prof. Dr. Gerd Schulte-Körne
Gerd.Schulte-Koerne@med.uni-muenchen.de
Tel +49 (0)89 4400 55901

Partners
Prof. Dr. Dr. med. univ. Elisabeth Binder, Max Planck Institute of Psychiatry, Department of Translational Research in Psychiatry
Dr. Marcus Ising, Max Planck Institute of Psychiatry

Research team
Prof. Dr. Gerd Schulte-Körne, principal investigator
PD Dr. Ellen Greimel, head of the working group
Dr. Lisa Feldmann, research associate
Petra Wagenbüchler, study nurse
Dr. Aline D. Scherff, research assistant

Former members of the research team
Verena Pehl
Prof. Dr. Antje-Kathrin Allgaier
Dr. Charlotte Piechaczek
Peggy Quickenstedt-Reinhardt
Sarah Kunze

Publications
Halldorsdottir T, Piechaczek C, de Matos APS, Czamara D, Pehl V, Wagenbüchler P, Feldmann L, Quickenstedt-Reinhardt P, Allgaier A-K, Freisleder FJ, Greimel E, Kvist T, Lahti J, Räikkönen K, Rex-Haffner M, Arnarson EÖ, Craighead WE, Schulte-Körne G, Binder EB.
Polygenic risk: predicting depression outcomes in clinical and epidemiological cohorts of youths. Am J Psychiatry. 2019; 176:615-625. doi: 10.1176/appi.ajp.2019.18091014.

Link to zher article: https://ajp.psychiatryonline.org/doi/full/10.1176/appi.ajp.2019.18091014

More information about the article:
https://www.psych.mpg.de/2470840/news_publication_13295888?c=25056
https://www.uni-muenchen.de/forschung/news/2019/schulte_koerne_score_interview.html

Short summary: Genome-wide association studies (GWAS) with adults could show that many thousands of genetic variants are implicated in depression. Polygenic risk scores (PRS) can be calculated based on results of these studies, assuming that genetic vulnerability for depression increases with rising PRS. In our study we could demonstrate for the first time that children and adolescents with a heightened PRS (i.e., with an increased genetic vulnerability) have a heightened probability of being diagnosed with major depression. We also showed that higher PRS for depression are associated with more severe forms of major depression. A heightened PRS was also linked to an earlier age of onset. During a 2-year course, heightened PRS predicted elevated depressive symptoms in adolescents who did not show heightened depressive symptoms initially. Furthermore, we could demonstrate that experiences of abuse also contribute to major depression, in addition to genetic vulnerability.

Piechaczek CE, Greimel E, Feldmann L, Pehl V, Allgaier A-K, Frey M, Freisleder FJ, Halldors-dottir T, Binder EB, Ising M, Schulte-Körne G.
Interactions between FKBP5 variation and envi-ronmental stressors in adolescent Major Depression.
Psychoneuroendocrinology. 2019; 106:28-37. doi: 10.1016/j.psyneuen.2019.03.025.

Link to the article: https://www.sciencedirect.com/science/article/abs/pii/S0306453018310163

This study focuses on the FKBP5 gene, which plays an important role in the bodily reaction to stress. There are two variants of this gene: the "risk variant" is less common in the population and can be associated with a heightened probability of major depression. The more common variant, in contrast, is not associated with an elevated depression risk. It is known from previous studies that individuals who carry at least one "risk variant" have a slightly increases risk for developing major depression. This risk is additionally heightened when they also experience many stressors.

In our study we investigated stressors of different kinds and severities. We could show that adolescents who experienced many stressors of different kinds and severities had a higher probability of being diagnosed with major depression. This probability was even higher when they carried at least one "risk variant" of the FKBP5 gene. The same pattern of results could be shown when adolescents experienced a heightened amount of moderate and sociodemographic stressors.

Piechaczek CE, Pehl V, Feldmann L, Haberstroh S, Allgaier AK, Freisleder FJ, Schulte-Körne G, Greimel E.
Psychosocial stressors and protective factors for major depression in youth: evidence from a case-control study.
Child Adolesc Psychiatry Ment Health. 2020; 14.

Link to the article: https://link.springer.com/article/10.1186/s13034-020-0312-1

Children and adolescents with major depression experience stressful life events (such as experi-ences of violence or the loss of a parent) more often than their non-depressed peers.
In this study we investigated various stressors in different areas of life in children and adoles-cents.

We could show that children and adolescents with major depression experienced more stressors than non-depressed peers: changes at home or at school (e.g., separation of the parents, repeating a grade), experiences of violence, delinquent behavior. Moreover, we could show that children and adolescents with major depression experienced more stressors related to sociodemographic factors. More children and adolescents with major depression, as compared with non-depressed peers, had a family member with an affective disorder (e.g., depression) and more mothers of children and adolescents with major depression reported of psychosocial stressors during or after pregnancy (e.g., emotional stress during pregnancy). Children and adolescents with major depression experienced less social support and a less positive family climate, as compared with typically developing children and adolescents.