The hereditary foundation of depression and its implications for treatment.
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Clinical depression affects countless individuals globally. Its cost to productivity is greater than for any other medical condition except anxiety. The onset of depression is influenced by a combination of genetic, biological, and environmental factors. Research increasingly implicates genetics in depression’s emergence, with heritability estimates from 40-50%. Understanding this biological foundation is the key to revolutionizing care by designing individualized treatment.
Teasing out the genetic underpinnings of depression is an extraordinarily complex task as depression arises from not a single gene, nor from a few genes, but from large networks of interacting genes. This results in vast genetic diversity from one individual to another. This complexity is what makes the field both challenging and promising, as it holds the key to unlocking highly effective, personalized treatments for those affected.
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Can Depression’s Genetic Component be Untangled?
Depression’s genetic landscape is intricate, with diverse genetic factors affecting susceptibility. Interactions between polymorphisms (variations) in genes such as IL6 and the serotonin transporter gene (SLC6A4), for example, can substantially influence symptom progression in some groups. This highlights the need to comprehend personalized genetic profiles for effective treatment. (Caution: The genetic tests for medication selection that are now on the market do not test for these genes and are not effective. Both the FDA and the American Psychiatric Association advise against their use.)
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Each of us harbors a distinctive network of dozens to hundreds of genes that predispose everyone in varying degree to major depression and anxiety disorders. This predisposition, coupled with life stresses and other non genetic elements, can trigger depressive episodes. The challenge in making genetics applicable to the clinical world is in identifying a manageably small number of the most important genetic variants that influence depression, and in then understanding the kinds of interactions they have both with each other and with the environment that together lead to overt symptoms.
The fact that depression and anxiety (and all other psychiatric conditions) are influenced not by single genes but by large networks of genes has important implications that might not be at first evident:
First, depression and anxiety are not sharply defined conditions in the way that say appendicitis is, but rather “spectrum” conditions. Let’s look at an extremely simplified model. Say that there are just six genes that influence mood and each of these genes has two variants—one that tends to produce stable moods (the s-variant) and one that tends to produce depressive moods (the s-variant). Let’s make the model even simpler by assuming no interactions between any of these six genes and that each gene produces the same risk for the same kind of depression. There would then be the following possible genetic combinations in people, each with a particular “weight” of depression (number of d variants) referring to depth, duration and frequency of depressive episodes, combined into a single measure of “severity,” which is the “weight”—the number of d variants:
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Assume for further simplicity that the odds of having the S or D variant are 50:50 for all six genes. Then we see that the incidence in the population for severity of depression are
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Here is a graph illustrating the above distribution in terms of the probability of having 0,1,2,3,4,5 or 6 depression gene variants. On the left (vertical) axis the above percentages are translated into decimal fractions, on the horizontal axis the number of depression gene variants:
![Screenshot 2024 07 17 at 10.45.13 AM The Genetic Tapestry of Depression: A Future of Individualized Care](https://sterlinginstitute.org/wp-content/uploads/2024/07/Screenshot-2024-07-17-at-10.45.13 AM.png)
This will lead to the following conclusions.
About one third (31%) of the population has a proportion of depression genes (three out of six) such that the severity of “symptoms” would be considered average—the typical tendency of most people to become sad, or pessimistic, or unmotivated to a degree from time to time. Over human history society itself will have become structured to accommodate this degree of “depression” and it would never even be called anything special nor thought of as a disorder.
The reason that so much of the population has three of six depression genes is that there are so many different ways that one may have three—twenty different ways. This is same reason that in flipping sixty-four coins it is so probable that about half will be heads and half tails. Of course this is not perfectly so, and therefore there is a large proportion of people with a small imbalance of either s or d. The total proportion of people with an average, that is to say, normal degree of depressive mood, plus those with a clinically insignificant imbalance is 23.4% + 31.3% + 23.4% = 77%, more than ¾ of the population. These are people with 2,3, or 4 d genes. There are two other groups with unusually few d genes and these, too, will not be diagnosed as having depression—those with one or no d genes, adding another 11% to the “normal group” which is now almost 90% of the population.
This leaves only two groups that will be diagnosed as having depression, their symptoms being worse than 90% of the population. Those with 5 or 6 d genes. But note that there are 7 different ways that this may occur. And there is a much larger group with five than with six. But still there is a spectrum of severity already emerging with just six genes.
The number of possibilities grows extremely fast as the number of genes involved increases. Suppose instead of 6 genes there were 200, again with only two variants.
![Screenshot 2024 07 17 at 10.45.57 AM The Genetic Tapestry of Depression: A Future of Individualized Care](https://sterlinginstitute.org/wp-content/uploads/2024/07/Screenshot-2024-07-17-at-10.45.57 AM-1000x1024.png)
![Screenshot 2024 07 17 at 10.49.19 AM The Genetic Tapestry of Depression: A Future of Individualized Care](https://sterlinginstitute.org/wp-content/uploads/2024/07/Screenshot-2024-07-17-at-10.49.19 AM.png)
Then the total number of possible variations would be more than 1.6 nonadecillion:
1,606,938,044,258,990,275,541,962,092,341,162,602,522,202,993,782,792,835,301,376
to be exact!
The probability of someone having either all depressive variants or none would be 1 divided by the above number—zero for all practical purposes.
They would be distributed as follows:
![Screenshot 2024 07 17 at 10.46.52 AM The Genetic Tapestry of Depression: A Future of Individualized Care](https://sterlinginstitute.org/wp-content/uploads/2024/07/Screenshot-2024-07-17-at-10.46.52 AM-1024x609.png)
The gradations of severity are now extremely fine-grained, creating a very smooth spectrum, and the number of possible different individual variations for depression are astronomical. The “normal” number of gene variants will also be astronomical, clustering around some near-average number and falling off sharply in both the worse-than-normal and better-than-normal directions. There is essentially no chance whatsoever that anyone in the world, ever in its history, has or has had, or will ever have, all depressive gene variants or none.
And yet—the real-world version of this analysis is even more complex! This is because the different genes do not contribute equally nor in the same fashion to depression, the number of variations (polymorphisms) per gene is many more than two; the odds of a given polymorphism vary widely; and the genes interact (meaning the presence of some particular two genes can contribute more than two times either gene alone or less than either gene alone—they contribute in what is called “non-linear” fashion, meaning they do not simply add together).
What does this mean for genetic inheritance? Thinking of our oversimplified model, roughly speaking each parent will contribute half of its d weight to a child and the child will end up with a weight of d genes halfway between the parents’ respective weights. But there will be a very large number of possible depressive configurations for this midway weight.
Neither is the disentangling of depression from anxiety fully possible because the gene networks are actually overlapping with as many as 40% of the genes being shared.
Inherited Risk and Family History
Having relatives with depression multiplies one’s own chances about two to threefold. Yet the connection between family history and the risk of actual depressive episodes is intricate, molded by many genetic and environmental influences.
The complex interplay between genetics and environment shapes depression risk in nuanced ways. Subtle variations in genes like IL1B and IL6 can influence biological processes tied to mood, yet stressful life events also play a role. Early losses or trauma may trigger physiological changes leaving some predisposed to depression down the line, and others not.
Disentangling these interactive effects is pivotal to enhanced prevention and treatment strategies. Personalized approaches aimed at an individual’s genetic profile and life experiences could optimize management and outcomes. Genetic testing (of crucial portions of the actual underlying gene network) may predict response to select therapies, leading to more successful recovery.
This customized care may likewise guide at-risk people. Knowledge of their genetic predispositions and how to moderate stressful circumstances could potentially ward off depression onset. Understanding genetics in this disorder aims not just to treat but prevent suffering in vulnerable groups
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