Translated by Rumia Bose
We are beginning to understand how most of the severe mental disorders develop: schizophrenia, bipolar disorder, autism, ADHD, depression and anxiety disorders. The basis is laid during the early development of the brain till pre-school age or thereabouts. The brain grows extremely rapidly in this period in order to learn and embed basic life and survival skills.1see Growth and pruning: the brain of a child. Hundreds, thousands of genes play a role in this. They help make the substances which direct the growth of the brain. Genes differ from person to person, and this contributes to the difference in brain development within children. Unfavorable variants of these genes lead to suboptimal growth of the brain. This is in fact always the case, no-one has a perfectly developed brain. If you inherit many unfavorable variants then this increases the chance of your manifesting a severe mental disorder during your lifetime2see Autism is hereditary, but you don’t inherit autism.
Genes and severe mental disorder
You may think that if genes are an important factor3I am not contesting the role of other factors such as what you experience and learn, where and how you grow up; see the end of this article., we also know which particular genes they are, and how these unfavorable variants work. This is unfortunately not the case. For each disorder there are several hundreds or thousands of genes with unfavorable variants involved. And we are talking about different combinations of genes in different people manifesting such a disorder.
Therefore, in someone with ADHD, the basis for this in their brain can vary considerably from that of another person with ADHD. The same holds for other severe mental disorders. And it gets even more curious: many of the genes involved play a role in other disorders, some of these are probably ubiquitous. This means that the genetic basis overlaps; there is no sharp delineation between ADHD and autism, between schizophrenia and bipolar disorder, between autism and schizophrenia, between depression and anxiety disorders, between schizophrenia and depression, between depression and ……. The current classification of severe mental disorder may be useful for psychiatrists and psychologists, but it is not based on the genetic background of those disorders or the development of the brain.
You inherit genes with unfavorable variants from your parents. But that is not the whole story. Usually someone with a severe mental disorder also has one or more genes with adverse variants that neither of their parents has. These are new (de novo) mutations, changes, that arise in sperm or ova (egg cells) or during cell division after fertilization. New mutations can also arise later in life, but these are of much less consequence in the (almost) fully-matured brain.
Genes and spectrum disorders
So far I have been talking about severe mental disorders. The qualification as “severe” stands in relation to the categorization as a “spectrum” which currently is used frequently (for instance “autism spectrum disorder” or “disorder in the depression spectrum”). These also include disorders that are not that severe, or do not as clearly display the characteristic symptoms of one particular disorder. People with a severe disorder generally have inherited a large number of unfavourable gene variations from their parents, and in addition developed one or more relevant spontaneous mutations. People with a less severe disorder usually appear to have inherited a relatively limited number of unfavourable gene variations.
Disease: the spectrum from no disorder to severe disorder
There is still discussion over when to identify the appearance of symptoms of schizophrenia, bipolar disorder, autism, ADHD, depression or anxiety as a disorder. When should you call it a disease, and when may you call it a disease? Till now I have consistently used the term “disorder”. By this I refer to a state of disorder in the organism. This does not say what the consequences are for the person with the disorder. A severe disruption of the organism will almost certainly have consequences for the person with the disorder. His functioning in daily life will clearly be limited, such that he needs medical, psychiatric care. The term “disease” is then appropriate.
But this does not mean that someone with a disease is of a different category than one without disease. He is located on the extreme of the continuum “disorder” that reaches from severe to almost absent. In each human being there is always some degree of disruption by unfavorable gene variants during the early development of the brain. If the person and his environment do not experience any problems because of this, then they are called “normal”. The more unfavorable gene variants an individual has inherited, the larger the chance that the early development of their brain is significantly disrupted and that he later will manifest problems due to a disorder. The line we draw between “diseased” and “normal” in this continuum is largely socially and culturally determined and not biological, genetic or medical.
Severe mental disorders are hereditary, and hundreds, thousands of genes play a role. But no single gene that you inherit from your parents plays a decisive role. It is about the combined effect of all these involved genes, and this combination varies in each individual. The genes are indeed the basis, but the development of the brain is not entirely defined by this, because it is a complex system. The genes are not a blueprint for the brain, but more like a recipe that never produces the exact same flavour each time the dish is made4see Why are monozygotic twins not identical? Chance!. The genes and their variants that play a role in severe mental disorders are to a certain extent identical. Which means that we will never find THE cause of these disorders, because there is no single cause.
This article is about genes and early development of the brain as the basis for severe mental disorders. The importance of early development was underestimated till recently. That is especially true for schizophrenia, bipolar disorder, depression and anxiety disorders that only manifest themselves clearly in puberty or later. During early development, in addition to genes and brain growth, an important role is played by what a child experiences, such as malnutrition, violence, mental and physical neglect, traumas. The influence of genes, brain growth and what a child experiences cannot be individually identified, because they are inextricably involved in a mutually influencing process. What a child experiences affects the growth of the brain, and how the brain of a child develops determines the impact of what that child experiences5see Nature and nurture: congenital and acquired.
Hammerschlag AR, Leeuw CA de, Middeldorp CM, Polderman TJC (2019): Synaptic and brain-expressed gene sets relate to the shared genetic risk across five psychiatric disorders. Psychological Medicine :1–11. DOI 10.1017/S0033291719001776
Schork AJ, Won H, Appadurai V, Nudel R, Gandal M, Delaneau O, et al. (2019): A genome-wide association study of shared risk across psychiatric disorders implicates gene regulation during fetal neurodevelopment. Nature Neuroscience :1.
Howard DM, Adams MJ, Clarke T-K, Hafferty JD, Gibson J, Shirali M, et al. (2019): Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions. Nature Neuroscience :1.
Wray NR, Wijmenga C, Sullivan PF, Yang J, Visscher PM (2018): Common Disease Is More Complex Than Implied by the Core Gene Omnigenic Model. Cell 173:1573–1580.
Mitchell KJ (2018): Innate; How the Wiring of Our Brains Shapes Who We Are. Princeton University Press. ISBN 978-0-691-17388-7
Mitchell K (2018): Life after GWAS – where to next, for psychiatric genetics? [Internet] [cited 2018 Nov 6];Available from: http://www.wiringthebrain.com/2018/11/life-after-gwas-where-to-next-for.html
Mitchell K (2018): Wired that way: genes do shape behaviours but it’s complicated – Kevin Mitchell | Aeon Ideas [Internet]Aeon [cited 2018 Dec 1];Available from: https://aeon.co/ideas/wired-that-way-genes-do-shape-behaviours-but-its-complicated
Lam M, Chen C-Y, Li Z, Martin A, Bryois J, Ma X, et al. (2018): Comparative genetic architectures of schizophrenia in East Asian and European populations. bioRxiv :445874.
Consortium TB, Anttila V, Bulik-Sullivan B, Finucane HK, Walters RK, Bras J, et al. (2018): Analysis of shared heritability in common disorders of the brain. Science 360:eaap8757.
O’Brien HE, Hannon E, Hill MJ, Toste CC, Robertson MJ, Morgan JE, et al. (2018): Expression quantitative trait loci in the developing human brain and their enrichment in neuropsychiatric disorders. Genome Biology 19:194.
Andlauer TFM, Guzman-Parra J, Streit F, Strohmaier J, Gonzalez MJ, Flores SG, et al. (2018): Bipolar multiplex families have an increased burden of common risk variants for psychiatric disorders. bioRxiv :468975.
Flint J, Munafò M (2014): Schizophrenia: genesis of a complex disease. Nature 511:412–413.
Schizophrenia Working Group of the Psychiatric Genomics Consortium (2014): Biological insights from 108 schizophrenia-associated genetic loci. Nature 511:421–7.
Turkheimer E (2012): Genome Wide Association Studies of Behavior are Social Science, in Plaisance KS, Reydon TAC (eds): Philosophy of Behavioral Biology. Dordrecht, Springer Netherlands, pp 43–64.
I’ve long intuitively sensed this. These are ‘merely’ clusters of symptoms, somewhat arbitrarily delineated. I have ADD but likely some HFA (it’s a spectrum after all). It’s no coincidence there’s an overlap. One brain area impaired leads to widespread dysfunction.