What methylation is
Methylation means adding a small chemical unit, a methyl group (one carbon and three hydrogens), to another molecule. Your body does it constantly: to make creatine and phosphatidylcholine, to break down neurotransmitters and hormones, to switch genes up or down, and to recycle an amino acid called homocysteine back into methionine. The universal methyl donor is a molecule called SAMe, and your cells rebuild it through two linked loops, the folate cycle and the methionine cycle. These loops run on a handful of nutrients: folate (vitamin B9), vitamin B12, vitamin B6, riboflavin (B2), choline and betaine.
A word of caution about vocabulary. The methylation discussed here is a set of nutrient-processing chemical reactions. It is not the same as your "DNA methylation age" from an epigenetic clock test, and the gene variants on a consumer DNA chip do not measure it.
The genes involved
Genes give the instructions for the enzymes and transporters in these loops. Common variants in them can make an enzyme somewhat faster or slower, or change how much of a nutrient you need. Below are the genes we read in our reports, in two groups. Each links to its gene page.
Group 1: the folate and B12 machinery
| Gene | Variants we read | What it does |
|---|---|---|
| MTHFR | rs1801133, rs1801131, rs2274976 | Makes the active form of folate that feeds homocysteine recycling |
| MTR | rs1805087 | Turns homocysteine back into methionine, using vitamin B12 |
| MTRR | rs1801394 | Keeps the B12 used by MTR in its active form |
| SHMT1 | rs1979277 | Feeds one-carbon units from the amino acid serine into the folate cycle |
| SLC19A1 | rs1051266 | Helps carry folate into cells |
| TCN2 | rs1801198 | Carries vitamin B12 in the blood to your cells |
| FUT2 | rs601338, rs602662 | Linked to differences in circulating vitamin B12 and gut bacteria |
Group 2: methyl donors and methyl consumers
| Gene | Variants we read | What it does |
|---|---|---|
| BHMT | rs3733890 | A second route that recycles homocysteine, using betaine from choline and foods such as beetroot |
| PEMT | rs12325817 | Makes choline in the body; in studies linked to how much dietary choline a person needs |
| CBS | rs234706 | Moves homocysteine onward to cysteine, using vitamin B6 |
| COMT | rs4680, rs4633 | Breaks down dopamine, adrenaline and oestrogens using a methyl group |
MTHFR: the famous one, in proportion
MTHFR gets most of the attention. The best-known variant, C677T (rs1801133), makes the enzyme less heat-stable and less active. In laboratory studies, people with two copies (the "TT" genotype) keep roughly 30% of normal activity and people with one copy roughly 65%. TT is common: about one European in ten, and more in some Hispanic populations, so it is far from a rare defect.
What matters is the context. The effect on homocysteine shows up mainly when folate intake is low; with a folate-rich diet the difference is much smaller. And the clinical value of the test is limited: since 2013 the American College of Medical Genetics and Genomics has advised against routine MTHFR C677T and A1298C testing in the work-up of blood clots or recurrent pregnancy loss. Our MTHFR article goes deeper.
What your DNA cannot tell you
- Your actual status. A genotype says how an enzyme is built, not how much folate, B12 or homocysteine is in your blood today. That depends on diet, alcohol, medication, gut health, age and more.
- Whether you need a supplement. Evidence that choosing methylfolate over ordinary folic acid because of an MTHFR result improves outcomes is limited. More is not better either: long-term high-dose vitamin B6, for example, can damage nerves. Decisions about supplements belong with a doctor or dietitian who can see your blood results.
- That lowering homocysteine will protect your heart. High homocysteine is associated with cardiovascular and cognitive risk, but large trials of B vitamins that lowered it did not clearly reduce heart attacks or strokes.
- The whole picture. These genes sit alongside dozens of others, and any single variant usually moves the odds only a little.
Food first: the nutrients behind methylation
The same foods support this pathway whatever your genotype. A variant may make it more worthwhile to eat them regularly, but rarely changes which ones.
| Nutrient | Role | Food sources |
|---|---|---|
| Folate (B9) | Carries the one-carbon units | Leafy greens, legumes, citrus fruit, avocado, fortified grains |
| Vitamin B12 | Needed by MTR to recycle homocysteine | Fish, meat, eggs, dairy. People on a vegan diet need a reliable source (fortified foods or a supplement) whatever their genes. |
| Vitamin B6 | Needed by CBS | Poultry, fish, potatoes, chickpeas, bananas |
| Riboflavin (B2) | Cofactor of the MTHFR enzyme | Dairy, eggs, almonds, mushrooms |
| Choline | Feeds the betaine route | Eggs, soybeans, fish, liver, cruciferous vegetables |
| Betaine | Methyl donor for BHMT | Beetroot, spinach, quinoa, whole wheat |
Heavy alcohol use is the classic drain on folate and B12, and some common medicines also affect them, so mention your diet and drinking to your doctor if a blood test looks off.
How to check how it is working
If you want to know how your methylation-related nutrients are doing, ask a doctor about blood tests: vitamin B12, folate and homocysteine are the standard ones. They measure your current status, which is what actually matters, and they can be repeated after a change in diet. A DNA result can then help explain a pattern. It should not be the starting point for treatment.
In the Complete report and Ultimate report these genes appear in the methylation pathway with food-based guidance. You can upload the raw file from any of the major providers; see how to get your raw DNA file.