Depression can have multiple physiological causes. Often it is hard to see the forest for the trees when trying to find the right solution here.
This article ties together 9 separate articles on depression. It’s a huge topic, so stick with me here. There isn’t a single cause of depression and the connection between genetics and physiological factors can get complicated. So, my goal is to simplify your task of sorting through genetic data to target the right cause(s) of depression for you.
Depression’s Root Causes: Through a glass darkly
Genetics may be able to help you narrow down what is likely causing or adding to your depression on a physiological level.
That is an exciting concept, but first a couple of caveats.
- It’s important to keep in mind that your genetic data only showing part of your genome (23andMe, AncestryDNA).
- Genetics is only part of the picture (abuse, lifestyle, diet, chronic disease all contribute to depression)
So what you find from your genetic data is what you can know – but you still don’t know what you don’t know. Clear as mud?
Caveats aside: USE what you can know from your genetic data.
It’s a starting point:
- the place to start researching
- a target for diet or supplements
- a starting point for talking with your doctor
Genetic Causes of Depression:
- Depression, genetics, and mitochondrial function
- Inflammation as a cause of depression
- Serotonin: How your genes affect this neurotransmitter
- Depression, Genetics, and Circadian Rhythm
- Tryptophan Genes: Serotonin, Melatonin, and Kynurenine
- MTHFR and Depression
- The Interaction Between BDNF and Serotonin
- Genetics of Seasonal Affective Disorder
- HPA Axis Dysfunction: Cortisol and Stress
As you can see, genetics points to a number of root causes of depression. Some of these overlap and interact, so there isn’t necessarily a single genetic cause.
Here’s one way to look at the interconnected root causes of depression:
Pinpointing depression’s root cause:
If you have several variants highlighted in the articles below, this could indicate a physiological link to depression for you.
Most people will have one or two variants in the topics below. Some are really common variants. So what you are looking for is a bunch of variants, all pointing to the same cause.
Example case study:
If your Inflammation and Depression results look like this:
Steps to take:
- Read through the article on inflammation and depression.
- Look for sources of chronic inflammation such as eating junk food or exposure to toxicants and clean that up.
- Read through the Lifehacks for how to decrease inflammation specific to your genetic variants.
- Before implementing any supplement options, be sure to check with your doctor or pharmacist if you are on any medications.
9 Causes to Investigate:
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Click the article link for further information, including the background science as well as research-backed lifehacks.
Inflammation and Depression:
One of the root causes of depression and anxiety is inflammation. Targeting inflammation may be a way to reduce depression and anxiety symptoms, for some people.
| Gene | RS ID | Risk Allele | YOU | Notes about the Risk Allele: |
|---|---|---|---|---|
| TNF | rs1800629 | A | — | Increased TNF, increased risk of suicide in depression |
| IL6 | rs1800796 | G | — | GG: higher IL6, increased depression |
| IL6 | rs1800795 | C | — | CC: increased risk of depression with stressful life events |
| IL6 | rs1800797 | A | — | higher IL6, increased depression risk |
| IL6R | rs4129267 | C | — | CC: increased risk of anxiety, depression |
| IL1B | rs16944 | G | — | GG: increased IL1B |
| IDO1 | rs9657182 | C | — | Higher depression risk |
| KMO | rs1053230 | C | — | CC: common genotype, higher risk of depression than T allele |
Depression, genetics, and mitochondrial function
For some people with major depressive disorder, mitochondrial dysfunction in the brain is a physiological cause. Please talk with your doctor before making any lifestyle or supplement changes.
| Gene | RS ID | Risk Allele | YOU | Notes about the Risk Allele: |
|---|---|---|---|---|
| SOD2 | rs4880 | A | — | AA only: higher chronic inflammation, increased depression risk |
| GSTA1 | rs3957357 | A | — | Low/ non-functioning enzyme; increased risk of psychiatric illness |
| BDNF | rs6265 | T | — | CC: decreased BDNF; decreased hippocampus volume if exposed to early life stress |
| TOMM40 | rs2075650 | G | — | Mitochondrial protein; increased susceptibility to depression |
| MTHFD1L | rs11754661 | A | — | Increased risk of rumination and depression |
| ATP6V1B2 | rs1106634 | A | — | Increased risk of MDD |
| FKBP5 | rs1360780 | T | — | Increased relative risk for depression, incomplete cortisol recovery |
| FKBP5 | rs3800373 | C | — | Increased risk MDD(slight) |
| CRHR1 | rs110402 | G | — | GG: elevated cortisol in people exposed to childhood trauma |
| CRHR1 | rs242924 | G | — | GG: elevated cortisol in people exposed to childhood trauma |
| CRHR1 | rs242941 | A | — | Slightly increased risk of depression |
| CRHR1 | rs242939 | C | — | Increased risk of depression |
Depression, Genetics, and Circadian Rhythm
For some, circadian disruption can be at the heart of depression or mood disorders.
| Gene | RS ID | Risk Allele | YOU | Notes about the Risk Allele: |
|---|---|---|---|---|
| CRY1 | rs10861688 | T | — | Increased risk of depression |
| CRY2 | rs10838524 | G | — | Increased risk of depression |
| PER2 | rs934945 | T | — | Increased risk of severity in psychotic disorders |
| PER3 | rs139315125 | G | — | Increased risk of depression, delayed sleep disorder |
| PER3 | rs228697 | G | — | Increased risk of depression |
| NPAS2 | rs11123857 | G | — | Increased risk of depressive disorders |
| NR1D1 | rs2314339 | T | — | Increased risk of depression, bipolar disorder |
| OPN4 | rs2675703 | T | — | Significantly increased risk of seasonal depression; sensitivity to lower light levels |
BDNF, Serotonin, and Mood Disorders
Genetic variants in the BDNF and serotonin receptor genes combine to increase the risk of depression and anxiety. Learn more about BDNF and how these variants interact — and check your genetic data to see how this applies to you.
| Gene | RS ID | Risk Allele | YOU | Notes about the Risk Allele: |
|---|---|---|---|---|
| BDNF | rs6265 | T | — | Decreased BDNF levels |
| HTR1A | rs6295 | G | — | Increased risk of depression with BDNF variant |
Seasonal Depression
Seasonal Affective Disorder (SAD) is characterized by recurrent depression with a change in the season, usually in fall/winter for most. Scientists think this is possibly due to an aberrant response to light – either not enough brightness to the sunlight or not enough hours of light. Your genes play a significant role in this responsiveness to light.
| Gene | RS ID | Risk Allele | YOU | Notes about the Risk Allele: |
|---|---|---|---|---|
| PER3 | rs139315125 | G | — | Decreased PER3, increased risk of SAD (seasonal depression) |
| PER3 | rs150812083 | G | — | |
| PER3 | rs228697 | G | — | Evening preference, increased risk of SAD |
| OPN4 | rs2675703 | T | — | Greatly increased risk of SAD, responsive to day length |
Serotonin Genes
Serotonin is a neurotransmitter that is important in depression, sleep, and many other aspects of health. Learn how your genetic variants in the serotonin receptor genes impact their function.
| Gene | RS ID | Risk Allele | YOU | Notes about the Risk Allele: |
|---|---|---|---|---|
| SLC6A4 | rs2129785 | T | — | Combo of TT for rs2129785 and AA for rs11867581 predicts short 5-HTTLPR; linked to increased risk of depression |
| SLC6A4 | rs11867581 | A | — | |
| DDC | rs6592961 | A | — | Conversion of 5-HTP to serotonin (B6 is a cofactor) |
| HTR1A | rs6295 | C | — | Serotonin receptor variant linked to higher impulsivity |
| HTR1B | rs6296 | G | — | Serotonin receptor linked to increased risk of depression |
MTHFR & Depression
The MTHFR gene codes for a key enzyme in the folate cycle.
| Gene | RS ID | Risk Allele | YOU | Notes about the Risk Allele: |
|---|---|---|---|---|
| MTHFR C677T | rs1801133 | A | — | Two copies of either variant is linked to an increased risk of depression. |
| MTHFR A1298C | rs1801131 | G | — |
Tryptophan – Conversion to Serotonin vs. Kynurenine
Tryptophan is an amino acid that the body uses to make serotonin and melatonin. Genetic variants can impact the amount of tryptophan that is used for serotonin. It can influence mood, sleep, neurotransmitters, and immune response.
| Gene | RS ID | Risk Allele | YOU | Notes about the Risk Allele: |
|---|---|---|---|---|
| IDO1 | rs3808606 | A | — | AA only: more conversion to kynurenine |
| IDO1 | rs9657182 | C | — | (probably) more conversion to kynurenine |
| KMO | rs1053230 | T | — | Increased conversion to kynurenine |
| TPH2 | rs4570625 | G | — | Less conversion of tryptophan to serotonin |
| TPH2 | rs11178997 | A | — | Increased risk of depression |
| TPH2 | rs1843809 | G | — | Decreased risk of depression |
| TPH2 | rs1386494 | T | — | TT only: decreased depression risk |
| TPH2 | rs4290270 | T | — | TT only: circadian disruption more likely in people with depression |
Cortisol and HPA Axis Dysfunction
Cortisol is a hormone produced by the adrenal glands in times of stress, and it also plays many roles in your normal bodily functions. It is a multi-purpose hormone that needs to be in the right amount (not too high, not too low) and at the right time. Your genes play a big role in how likely you are to have problems with cortisol.
| Gene | RS ID | Risk Allele | YOU | Notes about the Risk Allele: |
|---|---|---|---|---|
| NR3C1 | rs6189 | T | — | Glucocorticoid receptor mutation linked to cortisol resistance (important) |
| NR3C1 | rs6190 | T | — | |
| NR3C1 | rs6191 | A | — | GR variant linked to some resistance to cortisol |
| NR3C1 | rs10052957 | A | — | Linked to hypersensitivity to cortisol. |
| NR3C2 | rs5522 | C | — | Associated with resistance to cortisol, depression. |
| CRHR1 | rs110402 | G | — | Elevated adult cortisol if exposed to childhood trauma; increased risk of depression, anxiety |
| CRHR1 | rs242924 | G | — | |
| CRHR1 | rs242941 | A | — | Increased risk of depression |
| CRHR1 | rs242939 | C | — | |
| FKBP5 | rs1360780 | T | — | Incomplete cortisol recovery, risk of depression, anxiety |
| FKBP5 | rs4713916 | G | — | |
| FKBP5 | rs3800373 | C | — |
Bringing it all together:
To recap:
- Depression can have physiological causes along with triggering life events.
- Targeting the root physiological cause may help.
- If you are under the care of a physician, talk with your doctor/psychiatrist, especially before adding supplements in with medications.
A holistic view of depression treatment can include
- therapy (if needed)
- medications (if needed)
- diet
- lifestyle
- supplements (if needed)
Instead of just taking a stab in the dark, use your genetic data to formulate a plan. If you’re like me, writing down the plan can help. Here’s a printable form for keeping track of supplements.
Kind in mind that this process can take time, and you might find the need to switch up your strategy and plan. Resolving our health questions can take a while, so be patient in finding what works best for you.
If you are in the US and find yourself or a loved one struggling with depression, you can call the national treatment referral service hotline (confidential): 1-800-662-HELP (4357) or visit the website. https://www.samhsa.gov/find-help/national-helpline.