Depression Causes: Genetic Overview

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
Disclaimer: I’m not a doctor. I’m definitely not your doctor. Please take this information as it is intended: for educational purposes. Talk with your doctor or psychiatrist for medical advice.

Genetic Causes of Depression:

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 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:

Not seeing your data below? Select your data file on the member’s dashboard. Not a member? Join now.

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.

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 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.


Author Information:   Debbie Moon
Debbie Moon is the founder of Genetic Lifehacks. She holds a Master of Science in Biological Sciences from Clemson University and an undergraduate degree in engineering from Colorado School of Mines. Debbie is a science communicator who is passionate about explaining evidence-based health information. Her goal with Genetic Lifehacks is to bridge the gap between the research hidden in scientific journals and everyone's ability to use that information. To contact Debbie, visit the contact page.