Families, genes, and psychiatric disorders

Peter MolemanArticles, Genes and heredity, PsychiatryLeave a Comment

Translated by Rumia Bose

I am acquainted with a family where some members have a severe form of bipolar disorder and red-green colour blindness. This colour blindness is known to be linked to the X chromosome. This seems to indicate a genetic basis for the bipolar disorder. About forty years ago some researchers thought that they had identified the cause of the bipolar disorder: a gene on the X chromosome. But other researchers could not establish a relation between the X chromosome and bipolar disorder within carefully selected families with the combination of bipolar disorder and colour blindness. This created a point of discussion.
At the time it was commonly believed that a variant of one gene could cause a psychiatric disorder. Currently it is clear that each psychiatric disorder is associated with many hundreds or thousands of genetic variants1. It is also clear that people with the same disorder do not have the same variants. Each individual suffering from a disorder has only a limited number of those variants2. Families do tend to show much similarity in the variants within their members. That is understandable, because you inherit those variants from your parents. The variants tend to differ much more between different families.This means that a genetic variant in the X chromosome can be associated with a bipolar disorder in one family but not in another.

What are genetic variants?

I have been talking about genetic variants. Often there is talk of gene mutations. The genetic variants do not however always involve the genes, which are the sections of DNA which code for proteins. DNA is only partly composed of genes. It also contains operators which regulate the activity of genes, as well as other regulatory units. Variants in such sections of DNA are more often associated with psychiatric disorders than variants in genes. ” Genetic variants” therefore refers to genes as well as those other sections of DNA.
Furthermore, I have been talking about variants and not about mutations, because the latter refers to recently changed sections of DNA. Most of the hundreds or thousands of genetic variants which are associated with psychiatric disorders are not recent, but are passed from parents to children through many generations.
Genetic mutations do however play a role. You do not inherit these from your parents. These mutations can occur in a sperm cell or- less frequently-in an ovum, or after conception or after birth. Some patients with severe forms of a psychiatric disorder belong to families without psychiatric disorders or to families with only mild forms of a psychiatric disorder, except the patient himself, of course. It appears that these patients often have a genetic mutation with a pronounced impact.
Each genetic variant that you inherit from your parents has but a very small role in your vulnerability to develop a psychiatric disorder, less than a thousandth of the whole. A genetic mutation can play a much bigger role in this vulnerability, but these are rare because the carriers of these mutations suffer from a serious illness3.

Bipolar disorder and other psychiatric disorders

Members of families susceptible to bipolar disorders all have a large number of genetic variants. It may seem ominous that all members have variants which make them vulnerable to a psychiatric disorder. But everyone has such variants, even in families without any psychiatric disorder. Whether someone will develop a bipolar disorder depends on the combination of genetic variants and mutations and also the circumstances while growing up and later in life.
Although a bipolar disorder has a clear genetic component, the relation between genetic variants and mutations on the one hand and the disorder on the other hand is indirect and far from clear. It is not known how they contribute to the susceptibility to the disorder, via neurotransmitters, hormones or brain development4. And it gets more complicated. Because ” bipolar” families also show a higher rate of other DSM disorders such as schizophrenia, various forms of depression and autism. This is because several variants and mutations involved also cause susceptibility to other DSM disorders.
This indicates that the DSM classification of disorders and the genetic basis for psychiatric disorders are not compatible.

The story so far

Many genetic variants and mutations play a role in bipolar disorder, differing between different people and families. Many of the variants and mutations also play a role in other psychiatric disorders. Susceptibility to psychiatruc disorders is partly inherited and related to DNA, but as yet we have no idea what this relation is. This relation however is of importance for research into psychiatric disorders as also for the clinical practice.

New directions

What we need is a better defined search in the genetic haystack. For this, the groups under examination need to be more homogenous. But the question is what sort of homogeneity is related to genetic characteristics. This is not the case in groups which are homogenous for signs and symptoms, which are prominent criteria in the DSM clasification. Genetic homogeneity can be approximated by researching families with larger numbers of patients with psychiatric disorders. This happens incidentally. One example concerns research where a number of rare genetic variations were discovered in families with bipolar disorders and schizophrenia5.
Not only the research, but much of the organisation of health care does not take these developments into account. Departments specialised in the treatment of bipolar disorders, depression, anxiety disorders or schizophrenia, appear to be outdated.
Clusters based on families with related disorders may be a possibility. This may even be a first step towards personalised medicine. Those patients with bipolar disorders and colour blindness, for example, seem to respond specifically to Lithium. The idea also facilitates preventive medicine. All unaffected members of these high-risk families also carry these genetic variants, and thereby have a higher than average risk of developing psychiatric disorders.

Conclusions

My vision of the future of psychiatry, as regards both patient care and research, is based on the developments as described above.

  • Clustering families of patients  with severe disorders based on similar genetics, presentation and perhaps response to treatment. 
  • Signs and symptoms are important, but not the primary basis for categorising psychiatric disease.
  • Special attention to preventive measures in the health care provision for these families.
  • Specific attention to early diagnosis in the children and attention for psychological and social aspects for all members is important.
  • A search for biological mechanisms within such clusters in relation to presentation, (non)response to treatment, and the relative susceptibility to external influences such as stress, neglect and traumas.
  • The focus on families should not be too exclusive, as severe disorders – for instance through genetic mutations – also appear in isolation.
References

Raballo A, Poletti M, Preti A (2021): Applying Transgenerational Scientific Evidence to the Next Wave of Early Identification Strategies for Psychopathological Risk—Transdiagnostic, Developmental, and Personalized. JAMA Psychiatry DOI: 10.1001/jamapsychiatry.2021.1901

van Dijk MT, Murphy E, Posner JE, Talati A, Weissman MM (2021): Association of Multigenerational Family History of Depression With Lifetime Depressive and Other Psychiatric Disorders in Children: Results from the Adolescent Brain Cognitive Development (ABCD) Study. JAMA Psychiatry 78:778.

Abdellaoui A, Verweij KJH (2021): Dissecting polygenic signals from genome-wide association studies on human behaviour. Nat Hum Behav DOI: 10.1038/s41562-021-01110-y

Lee PH, Feng Y-CA, Smoller JW (2021): Pleiotropy and Cross-Disorder Genetics Among Psychiatric Disorders. Biological Psychiatry 89:20–31.

Crouch DJM, Bodmer WF (2020): Polygenic inheritance, GWAS, polygenic risk scores, and the search for functional variants. Proceedings of the National Academy of Sciences of the United States of America 117:18924–18933.

Singh T, Poterba T, Curtis D, Akil H, Eissa MA, Barchas JD, et al. (2020): Exome sequencing identifies rare coding variants in 10 genes which confer substantial risk for schizophrenia. medRxiv, DOI: 10.1101/2020.09.18.20192815.

Smoller JW, Andreassen OA, Edenberg HJ, Faraone SV, Glatt SJ, Kendler KS (2019): Psychiatric genetics and the structure of psychopathology. Mol Psychiatry 24:409–420.

O’Brien NL, Fiorentino A, Curtis D, Rayner C, Petrosellini C, Al Eissa M, et al. (2018): Rare variant analysis in multiply affected families, association studies and functional analysis suggest a role for the ITGΒ4 gene in schizophrenia and bipolar disorder. Schizophr Res 199:181–188.

Mitchell K (2018): Life after GWAS – where to next, for psychiatric genetics? [cited 2018 Nov 6]; Available from: http://www.wiringthebrain.com/2018/11/life-after-gwas-where-to-next-for.html

Mitchell K. (2018): If genomics is the answer, what’s the question? A commentary on PsychENCODE http://www.wiringthebrain.com/2018/12/if-genomics-is-answer-whats-question.html

Mitchell KJ (2018): Innate; How the Wiring of Our Brains Shapes Who We Are. Princeton University Press. ISBN 978-0-691-17388-7

Frances AJ (2016): What You Need To Know About The Genetics of Mental Disorders. Psychology Today [cited 2021 Mar 31]; Available from: https://www.psychologytoday.com/blog/saving-normal/201604/what-you-need-know-about-the-genetics-mental-disorders

Hou L, Bergen SE, Akula N, Song J, Hultman CM, Landén M, et al. (2016): Genome-wide association study of 40,000 individuals identifies two novel loci associated with bipolar disorder. Hum Mol Genet 25:3383–3394.

Baron M (1991): Bipolar Pedigrees. Archives of General Psychiatry 48:671–673.

Berrettini WH, Goldin LR, Gelernter J, Gejman PV, Gershon ES, Detera-Wadleigh S (1990): X-chromosome markers and manic-depressive illness. Rejection of linkage to Xq28 in nine bipolar pedigrees. Arch Gen Psychiatry 47:366–373.

Baron M, Rainer JD, Risch N (1981): X-linkage in bipolar affective illness. Perspectives on genetic heterogeneity, pedigree analysis and the X-chromosome map. J Affect Disord 3:141–157.

Mendlewicz J, Linkowski P, Guroff JJ, Van Praag HM (1979): Color blindness linkage to bipolar manic-depressive illness. New evidence. Arch Gen Psychiatry 36:1442–1447.

  1. See The basis for most of the severe mental disorders is clear
  2. See also Autism is hereditary, but you don’t inherit autism
  3. These mutants often disappear as a result of “survival of the fittest”
  4. See “The basis for most of the severe mental disorders is clear
  5. See references, O’Brien et al.

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