Identify Your Root Cause(s) of Depression

When it comes to depression, there’s no one-size-fits-all answer. It’s not always easy to pinpoint the root cause of your depression, as different genetic factors, life events, and environmental factors can all play a role. My goal here is to simplify your task of sorting through genetic data to target the right cause(s) of depression for you.

Depression: 9 genetic pathways to check

Genetics may be able to help you narrow down what is likely causing or adding to your depression on a physiological level.

Genomics is a good starting point!

  • the place to start researching, learning about solutions
  • a targeted way to make diet or supplement changes
  • a starting point for talking with your doctor

That is an exciting concept! But I do want to point out a couple of caveats here:

  1. It’s important to keep in mind that your genetic data only shows part of your genome (23andMe, AncestryDNA)./li>
  2. Genetics is only part of the picture. Your genes interact with your lifestyle, diet, abuse, chronic disease, etc —  all coming together to change your neurotransmitters.

Caveats aside: USE what you can learn from your genetic data.

Disclaimer: This information is truly for educational purposes. Please, talk with your doctor or psychiatrist for medical advice.

Can depression be genetic?

Genetics plays a role in depression for everyone, but there are multiple pathways that can cause the physiological changes that cause someone to feel depressed.

I’ve gone in-depth on all of theses genetic causes in separate articles (links below). In this overview article, you’ll be able to hone in on which of these root causes to target.

What do I mean by root causes?

Recent research shows that for people with long-term psychiatric illnesses, such as major depressive disorder, bipolar disorder, or schizophrenia, there are structural changes that take place in the brain.[ref]  Th

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:

Flow diagram of multiple causes of depression linked to genetics


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 show multiple risk alleles highlighted:

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 section for suggestions on 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.

Depression Genotype Report: 9 Causes

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Not a member? Join here. Membership lets you see your data right in each article and also gives you access to the members-only information in the Lifehacks sections.


Click the article link for further information, including the background science as well as research-backed solutions that match the genetic variants.

Inflammation and Depression:

When inflammation is chronically high, it can cause changes in neurotransmitters and in behavior. Think about how an animal acts when sick — it instinctively retreats from others, sleeps more, and seems sad. This is a hardwired mechanism when inflammatory cytokines are high.

Targeting inflammation may be a way to reduce depression and anxiety symptoms, for some people.

Remember – if you see a lot of highlights here, read through the full inflammation and depression article.

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

Your mitochondria create most of the ATP that your cells use for energy. Without enough energy in your brain, depression symptoms can occur.

For some people with major depressive disorder, mitochondrial dysfunction in the brain is a physiological cause.

There’s a lot more to this topic than can be explained in two sentences, so if you see a lot of risk alleles highlighted below, jump over and read the full article.

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 are 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.

Flow diagram of multiple causes of depression linked to genetics

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 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.


Related Articles and Genes:

MTHFR and Migraines
The MTHFR C677T variant increases the risk of migraines. Learn how to check your genetic data and how to mitigate the risk.

PMS, Genetics, and Solutions
A lot of women know the moodiness and brain fog that comes with premenstrual syndrome (PMS). Studies estimate that PMS is up to 95% heritable – which means that it has a huge genetic component. Learn about the genes and find out which solutions may actually work for you. (Member’s article)

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.

Histamine Intolerance
High histamine levels can cause a variety of symptoms including migraines, hives, sinus drainage, and stomach problems.


About the Author:
Debbie Moon is the founder of Genetic Lifehacks. Fascinated by the connections between genes, diet, and health, her goal is to help you understand how to apply genetics to your diet and lifestyle decisions. Debbie has a BS in engineering and also an MSc in biological sciences from Clemson University. Debbie combines an engineering mindset with a biological systems approach to help you understand how genetic differences impact your optimal health.