Genetics, decoded

A 287-base-pair insertion (I) or deletion (D) in the ACE gene, which affects levels of angiotensin-converting enzyme, a regulator of blood pressure. The D allele (more ACE) has been linked to power and strength, and the I allele to endurance, though study results are mixed.

The gene for alpha-actinin-3, a structural protein found only in fast-twitch muscle fibres. The R577X variant (rs1815739) is a nonsense variant. About 18% of Europeans are XX and make none of the protein. RR/RX is over-represented in elite sprint and power athletes, while XX shows up somewhat more often in endurance athletes.

A harmful, unintended response to a medicine at normal doses. Some ADRs are strongly genetic, e.g. HLA-B*57:01 with abacavir or HLA-B*15:02 with carbamazepine, and are tested for before prescribing.

One version of a gene or DNA position. At a SNP where people carry either C or T, C and T are the two alleles. You inherit one allele from each parent at every autosomal position.

An inherited shortage of alpha-1 antitrypsin, a protein that shields the lungs from the immune enzyme neutrophil elastase (a serine protease). ZZ genotypes can cause early emphysema, especially in smokers, and liver disease.

Any allele that differs from the reference at a position. In a VCF, 0 means reference and 1 means the first alternate allele, so a genotype of 1/1 is homozygous alternate.

The cell that makes enamel. Ameloblasts secrete the enamel protein matrix and then remove it as the enamel hardens. They are lost when the tooth erupts, which is why enamel can’t regenerate, only remineralise at the surface.

One of the 20 building blocks of protein. Nine are “essential” and must come from food. Variant names like Val158Met record an amino acid swap: valine to methionine at position 158.

The receptor that testosterone and DHT bind to. The gene is on the X chromosome and contains a CAG repeat of variable length. Shorter repeats generally make the receptor more sensitive and longer repeats less sensitive, so two people with the same testosterone level can respond differently.

A substance that kills or slows the growth of microorganisms: bacteria, viruses, fungi or parasites. Antibiotics, antivirals and antifungals are antimicrobial drugs. The body makes its own antimicrobial peptides and enzymes too, such as lysozyme, lactoferrin and histatins in saliva, and defensins in skin and gut.

A substance that neutralises reactive oxygen species. The body’s own antioxidants are enzymes (SOD, catalase, glutathione peroxidase) and glutathione. Dietary ones include vitamins C and E, carotenoids and polyphenols. Selenium, zinc, copper and manganese are needed as enzyme cofactors.

A gene for a protein that carries cholesterol and fats in the blood and brain. Two SNPs (rs429358 and rs7412) define the ε2, ε3 and ε4 alleles. ε4 is linked to higher LDL cholesterol and a substantially higher risk of late-onset Alzheimer’s disease. ε2 is linked to lower LDL but, rarely, a lipid disorder.

The enzyme that converts androgens into estrogens (testosterone to estradiol, androstenedione to estrone), in the ovaries, fat tissue, brain and bone. More body fat means more aromatase activity. Aromatase inhibitors block it in breast cancer treatment.

When the immune system attacks the body’s own tissues, as in celiac disease, type 1 diabetes, rheumatoid arthritis, Hashimoto’s thyroiditis and lupus. HLA genes are the strongest genetic risk factor for most autoimmune conditions, but environmental triggers are also needed.

An inheritance pattern where one altered copy of a gene on an autosome (chromosomes 1–22) is enough to cause the condition. An affected parent has a 50% chance of passing it to each child, regardless of sex. Penetrance and severity can vary.

Examples: Marfan syndrome, Huntington’s disease, familial hypercholesterolemia, Lynch syndrome and BRCA1/2-related cancer risk.

An inheritance pattern where both copies of a gene must be altered for the condition to appear. People with one altered copy are carriers and usually have no symptoms.

When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier and 25% of inheriting neither altered copy. Examples: cystic fibrosis, sickle cell disease, Tay-Sachs disease and hereditary hemochromatosis.

Files of sequencing reads that have been aligned to the reference genome. CRAM is a more compressed version of BAM. Variant calling runs on these files to produce a VCF.

Two bases on opposite DNA strands that bind each other (A–T or C–G). Genome size and positions are counted in base pairs: the human genome has about 3.1 billion of them per set of chromosomes.

Turning plant beta-carotene into vitamin A (retinal), done by the BCO1 enzyme (gene formerly BCMO1). Common variants can cut conversion by half or more. Poor converters may need preformed vitamin A from animal foods to meet their needs.

Betaine (trimethylglycine) is found in beets, spinach and whole grains and is also made from choline. The liver enzyme BHMT uses it to remethylate homocysteine without needing folate or B12, as a backup route next to the folate pathway.

A cofactor needed to make serotonin, dopamine, norepinephrine and nitric oxide, and to process phenylalanine. Its recycling depends on folate metabolism, which links methylation status to neurotransmitter production.

Using software, statistics and databases to analyse biological data. In genomics this means aligning sequencing reads, calling variants, imputing missing genotypes, annotating variants with what is known about them and turning the result into reports.

The share of positions on a chip or panel that produced a confident genotype. Good consumer files typically have call rates above 98%.

Someone with one disease-causing copy of a recessive (or X-linked) gene. Carriers are usually healthy but can pass the variant on. Most people carry a few recessive variants.

Testing to see whether you carry variants for recessive conditions, usually before or during a pregnancy. When both partners carry a variant in the same gene, there is a 25% chance with each pregnancy that the child is affected.

An autoimmune reaction to gluten that damages the small intestine. Almost everyone with celiac disease carries HLA-DQ2 or HLA-DQ8, but so do about 30–40% of people overall, and only a small minority of them develop it. Genetics is therefore most useful for ruling celiac out: without DQ2 or DQ8, celiac disease is very unlikely.

An essential nutrient (eggs, liver, fish, soy) needed for cell membranes (phosphatidylcholine), the neurotransmitter acetylcholine and, via betaine, methylation. The liver can make some through the enzyme PEMT, which estrogen switches on. PEMT variants and low estrogen (men, post-menopausal women) increase dietary needs.

A long, tightly packaged DNA molecule. Humans have 23 pairs: 22 pairs of autosomes (numbered 1–22) and one pair of sex chromosomes (XX or XY).

A public NIH database where labs submit their interpretations of variants (pathogenic, VUS, benign and so on), with the supporting evidence and a review-status star rating.

The part of a gene that is translated into protein: its exons, minus untranslated ends.

A group of three DNA (or RNA) letters that codes for one amino acid or a stop signal. There are 64 codons for 20 amino acids, so most amino acids have several codons.

A non-protein helper an enzyme needs to work, often a vitamin or mineral: B2 for MTHFR, B12 for methionine synthase, B6 for CBS, magnesium for COMT, copper for DAO. Getting enough of a cofactor is one way to support a lower-activity enzyme.

The most abundant protein in the body, giving strength to skin, bone, tendons and blood vessels. Type I collagen (COL1A1/COL1A2) dominates skin and bone. Vitamin C is needed to make it. Collagen production declines with age and UV exposure. Rare variants cause osteogenesis imperfecta and some forms of Ehlers-Danlos syndrome.

Having two different disease-causing variants in the same gene, one on each copy. For a recessive condition this can cause disease just like having two identical variants. Phasing (or testing the parents) shows whether two variants are on opposite copies.

An enzyme that uses SAMe to break down dopamine, norepinephrine, epinephrine and catechol estrogens. The Val158Met variant (rs4680) lowers activity several-fold in Met/Met carriers. That leaves more dopamine in the prefrontal cortex, which can help working memory but may increase stress sensitivity. This is often described as “worrier vs. warrior”.

Having parents who are blood relatives. Because related parents are more likely to carry the same recessive variant, children of consanguineous couples have a higher chance of a recessive condition. Long runs of homozygosity in your DNA can reflect this.

A stretch of DNA that is present in more or fewer copies than usual. Examples that matter for health: GSTM1 “null” (both copies deleted), CYP2D6 duplications (ultrarapid metabolism) and the variable number of AMY1 salivary amylase genes.

An international group that publishes peer-reviewed guidelines on adjusting drug choice or dose for a known genotype. It covers pairs such as CYP2C19–clopidogrel, CYP2D6–codeine and SLCO1B1–simvastatin. The FDA and the Dutch DPWG publish similar guidance.

The main enzyme that clears caffeine, and also some drugs (clozapine, olanzapine, melatonin). The rs762551 A allele is linked to faster, more “inducible” metabolism, which smoking and cruciferous vegetables boost further. Slow metabolisers keep caffeine in their system longer.

An enzyme that activates clopidogrel and breaks down many SSRIs (citalopram, escitalopram, sertraline), proton-pump inhibitors and voriconazole. The common *2 allele inactivates it, and *17 increases its activity.

An enzyme that clears warfarin, many NSAIDs (e.g. celecoxib), phenytoin and some diabetes drugs. The *2 and *3 alleles slow it down, so standard doses can build up. Considered together with VKORC1 for warfarin dosing.

A liver enzyme that metabolises around 20–25% of common drugs, including many antidepressants and antipsychotics, beta-blockers, tamoxifen, and codeine and tramadol (which it activates). It is highly variable: some people have no working copies, and others have extra gene copies that make them ultrarapid metabolisers.

The most abundant drug-metabolising enzyme, involved in roughly half of all medications as well as steroid hormones. Its activity is changed more by other drugs and foods (grapefruit inhibits it, St John’s wort induces it) than by genetics. Its partner CYP3A5 is strongly genetic and matters for tacrolimus dosing.

A family of more than 50 enzymes, mainly in the liver, that carry out phase I metabolism of drugs, hormones and toxins. A handful (CYP2D6, CYP2C19, CYP2C9, CYP3A4, CYP1A2) handle most prescription drugs, and several have common variants that change their speed.

Small signalling proteins (interleukins, interferons, TNF, chemokines) that immune and other cells use to coordinate inflammation and immunity. Promoter variants in genes like IL6 and TNF affect how strongly a person mounts an inflammatory response.

The enzyme that breaks down histamine from food in the gut lining, coded by the AOC1 gene (formerly ABP1). It needs copper and vitamin B6 (with vitamin C as support). Alcohol, some medications and gut inflammation block it. Reduced-function AOC1 variants are linked to lower DAO activity and histamine intolerance.

The NIH database of known human variants. It assigns rsIDs and records alleles, positions and population frequencies.

A new variant that appears for the first time in a person, arising in a parent’s egg or sperm or early in development, rather than being inherited. Everyone has around 50–100 de novo variants, almost all harmless.

Tooth decay, caused when plaque bacteria (notably Streptococcus mutans) ferment sugars into acid that dissolves enamel. Risk depends on diet, oral hygiene, fluoride and saliva, plus genes for enamel formation (AMELX, ENAM), taste and immunity.

The molecule that stores genetic information. DNA is a double helix of two strands built from four bases: adenine (A), cytosine (C), guanine (G) and thymine (T). A always pairs with T and C with G, so each strand is the mirror image of the other.

Reduced expression or activity of a gene or protein. It can happen at many levels: less transcription (often through DNA methylation or repressor proteins), less translation, faster breakdown, or inhibition of the protein itself. Receptors are also downregulated when overstimulated. This is part of how tolerance to some drugs develops.

The gene for dihydropyrimidine dehydrogenase, which breaks down the chemotherapy drugs 5-fluorouracil and capecitabine. Reduced-function variants can cause severe or fatal toxicity, so dose reductions are guideline-recommended.

How big a variant’s impact is, as opposed to how statistically certain it is. Expressed as an odds ratio, a change in a measurement (e.g. +0.4 BMI units per allele) or a change in enzyme activity.

The proteins ameloblasts secrete to build enamel. Some are glycoproteins, carrying sugar chains. Amelogenin (AMELX) makes up about 90% and organises the growing hydroxyapatite crystals. Enamelin (ENAM) and ameloblastin (AMBN) control crystal growth and cell attachment. As enamel matures, the proteases MMP20 and KLK4 break these proteins down and remove them, leaving tissue that is about 96% mineral.

Rare variants in these genes cause amelogenesis imperfecta (thin or soft enamel). Common variants are linked to differences in cavity risk.

How enamel becomes the hardest tissue in the body. In the secretory stage, ameloblasts lay down a protein matrix (amelogenin, enamelin, ameloblastin) in which long, thin hydroxyapatite crystals (a calcium phosphate mineral) start to grow. In the maturation stage, proteases remove the proteins while the crystals thicken, until enamel is about 96% mineral by weight.

After the tooth erupts, enamel can’t be rebuilt, but its surface constantly loses minerals during acid attacks and regains them from saliva. Fluoride makes the regained mineral more acid-resistant.

A protein that speeds up a specific chemical reaction. Many genes in NutraHacker reports code for enzymes: MTHFR, COMT, DAO, the CYP450 family and more.

How fast an enzyme does its job, often given as a percentage of typical activity. Variants can reduce it (e.g. MTHFR TT at roughly 30% of typical) or increase it.

Changes in gene activity that don’t alter the DNA sequence, mainly DNA methylation and histone modifications. Epigenetic marks respond to diet, age, smoking and stress. Methyl-donor nutrients like folate and choline feed the DNA methylation system.

How the body breaks estrogen down: phase I hydroxylation by CYP1A1/CYP1B1 into 2-, 4- or 16-hydroxy forms, then phase II methylation (COMT), glucuronidation and sulfation for excretion. The 4-hydroxy route produces more reactive metabolites, so COMT and antioxidant capacity matter for clearing them.

Proteins inside cells that bind estrogen and then switch target genes on or off. ER-alpha (ESR1) dominates in the uterus, breast, liver and bone. ER-beta (ESR2) dominates in the ovary, prostate and parts of the brain. Common variants in these genes have been studied for bone density and menopausal symptoms.

Reduced or absent estrogen-receptor signalling, so tissues respond weakly to estrogen even when hormone levels are normal or high. Complete inherited loss of ER-alpha is extremely rare and causes “estrogen resistance”: tall stature from unfused growth plates and low bone density. Milder reductions from common variants are much more subtle.

The term is also used in cancer: “ER-negative” breast tumours don’t express the receptor, so they don’t respond to drugs that work through it, such as tamoxifen (which blocks the receptor) and aromatase inhibitors (which lower estrogen). Some endocrine-disrupting chemicals also interfere with receptor signalling.

A part of a gene that is kept in the final RNA message and, in protein-coding genes, translated into protein. Exons make up only about 1–2% of the genome.

Genes for the desaturase enzymes that convert plant omega-3 (ALA) into EPA and DHA, and omega-6 linoleic acid into arachidonic acid. Common variants strongly affect how well you convert. Low converters rely more on direct sources of EPA and DHA, such as fish or algae.

The raw output of a sequencer: millions of short DNA reads, each with a quality score for every base. FASTQ files are not yet aligned to the genome and are very large (tens of GB for a 30x genome).

How the body stores, releases and burns fat:

• Lipolysis: fat cells break stored triglycerides into fatty acids and glycerol.
• Beta-oxidation: mitochondria cut fatty acids into acetyl-CoA, which feeds the citric acid cycle to make ATP.
• Lipogenesis: the liver and fat tissue turn excess carbohydrate into new fat.

Genes such as APOE, FTO, PPARG and FADS1/2 shape blood lipids and how people respond to dietary fat.

A form of programmed cell death, described in 2012, driven by iron-dependent peroxidation of fats in cell membranes. It happens when the glutathione/GPX4 defence fails, for example when cysteine or glutathione runs low, or when free iron and polyunsaturated fats in membranes are high.

Ferroptosis is being studied in neurodegeneration, heart and kidney injury, and cancer, where researchers try to trigger it in tumour cells.

A protein in the top layer of skin that binds keratin and breaks down into natural moisturising factors. Loss-of-function variants (e.g. R501X, 2282del4), carried by about 10% of Europeans, weaken the skin barrier. They are the strongest known genetic risk factor for eczema and are linked to dry skin.

Folate (vitamin B9) is the natural vitamin in leafy greens, legumes and liver. Folic acid is the synthetic form in fortified foods and many supplements. The body converts folic acid through DHFR and then, via MTHFR, into active 5-methylfolate. Folate is essential for DNA synthesis and for preventing neural tube defects.

A variant that is unusually common in a population descended from a small group of ancestors. Examples: several Tay-Sachs and BRCA variants among Ashkenazi Jewish people, and HFE C282Y in northern Europeans.

An insertion or deletion that shifts the three-letter reading frame. Every codon after it is read wrongly, which usually destroys the protein.

The gene with the strongest common association with body weight. Each copy of the rs9939609 A allele adds on average around 0.3–0.4 BMI units and is linked to appetite and food preferences. The effect is noticeably smaller in physically active people.

A variant that makes a protein more active, active at the wrong time, or gives it a new activity. CYP2C19*17, which speeds up the enzyme, is an example.

A stretch of DNA that holds the instructions for one product, usually a protein. Humans have roughly 20,000 protein-coding genes. Gene names are written in italic capitals by convention (e.g. MTHFR), and the protein in plain type.

How much a gene is switched on, i.e. how much RNA and protein it produces in a given tissue at a given time. Expression responds to diet, hormones, stress and drugs.

A healthcare professional trained in genetics and counseling who helps interpret results, arranges confirmatory testing and talks through implications for you and your family. Recommended for any significant finding from consumer data.

The complete set of DNA in a cell, including all genes and the much larger non-coding portion. Humans have two copies of the nuclear genome (one from each parent) plus mitochondrial DNA.

A study that scans hundreds of thousands to millions of SNPs across many people to find variants that are more common in people with a trait or disease. GWAS hits show association, not necessarily causation, and each usually has a small effect.

The pair of alleles you carry at a position, written as two letters such as CT or TT. Your raw data file lists one genotype per row.

A statistical method that estimates genotypes you weren’t directly tested for. It matches the pattern of SNPs on your chip against a reference panel of fully sequenced genomes. Because nearby variants are inherited in blocks (linkage disequilibrium), ~650,000 measured SNPs can be expanded to millions of estimated ones.

Each imputed genotype comes with a quality score. Accuracy is highest for common variants and for ancestries well represented in the panel, and lowest for rare variants.

The cell’s master antioxidant, a three-amino-acid peptide (glutamate, cysteine, glycine). It neutralises reactive oxygen species (with GPX enzymes), recycles vitamins C and E, and is attached to toxins by GSTs. Making it depends on cysteine supply, which links it to homocysteine metabolism.

Phase II enzymes that attach glutathione to toxins, carcinogens and oxidised molecules. About half of Europeans lack both copies of GSTM1 (“null”), and GSTT1 null is common in East Asians. GSTP1 Ile105Val changes activity.

A database of variant frequencies from hundreds of thousands of sequenced people, broken down by ancestry. A variant common in gnomAD is very unlikely to cause a rare severe disease.

A selenium-dependent enzyme that uses glutathione to turn hydrogen peroxide into water, completing the job SOD starts. The Pro198Leu variant (rs1050450) is linked to lower activity. Its relative GPX4 protects cell membranes and prevents ferroptosis.

A set of alleles at nearby positions that sit together on the same chromosome copy. HLA types and pharmacogene star alleles are haplotypes.

Working out which of your alleles sit together on the copy of a chromosome from your mother and which on the copy from your father. A standard raw data file lists genotypes without this information, so CT at one SNP and AG at another could be arranged C-A/T-G or C-G/T-A.

Phasing is done statistically (using reference panels) or directly from long sequencing reads. It is the first step of genotype imputation.

An autosomal recessive tendency to absorb too much iron, which can damage the liver, heart, pancreas and joints over decades. Most cases are HFE C282Y homozygotes (about 1 in 200 northern Europeans), though penetrance is incomplete. C282Y/H63D compound heterozygotes have a milder risk. It is easy to monitor with ferritin and transferrin saturation tests, and easy to treat by giving blood.

Carrying two different alleles at a position (e.g. CT). For a recessive condition, a heterozygous person is a carrier.

A signalling molecule made from the amino acid histidine. It triggers allergic and inflammatory responses, stimulates stomach acid, acts as a wake-promoting neurotransmitter and dilates blood vessels. It is also found in aged, fermented and leftover foods. The body breaks it down with DAO (outside cells, mostly in the gut) and HNMT (inside cells).

Symptoms from more histamine than the body can break down, usually because of low DAO activity combined with high-histamine foods. Symptoms include headaches, flushing, hives, a stuffy nose, digestive upset and palpitations after wine, aged cheese or cured meats. It is different from an allergy, which is a specific immune reaction.

A cluster of highly variable genes on chromosome 6 (the human MHC) for the molecules that display fragments of proteins to T cells. Class I (HLA-A, -B, -C) presents to cytotoxic T cells. Class II (HLA-DR, -DQ, -DP) presents to helper T cells. Your HLA type affects transplant matching, autoimmune risk, infection response and some severe drug reactions.

A class II HLA molecule on antigen-presenting cells (dendritic cells, macrophages and B cells). It is made of an alpha chain (HLA-DQA1) and a beta chain (HLA-DQB1), both on chromosome 6 and both extremely variable. HLA-DQ displays protein fragments to helper T cells to start an immune response.

Particular combinations are strongly tied to autoimmunity: DQ2.5 and DQ8 to celiac disease and type 1 diabetes, and DQ6.2 (DQB1*06:02) to narcolepsy. Consumer data usually infers HLA-DQ types from tag SNPs, which works well for celiac-relevant types.

The enzyme that inactivates histamine inside cells, including in the brain, airways and liver, by adding a methyl group from SAMe. This ties histamine clearance to methylation capacity. The Thr105Ile variant (rs11558538) lowers its activity.

Homocysteine is an amino acid made when methionine gives up its methyl group (via SAMe). The body clears it two ways:

• Remethylation back to methionine, by methionine synthase (needs methylfolate and B12) or by BHMT (needs betaine).
• Transsulfuration into cystathionine and then cysteine by CBS (needs vitamin B6). Cysteine feeds glutathione production.

Raised blood homocysteine (hyperhomocysteinemia) is linked to cardiovascular disease, pregnancy complications and cognitive decline. It is a useful lab test alongside methylation genetics.

Carrying two identical alleles at a position (e.g. CC or TT). In reports, “homozygous for the risk allele” means both copies carry the variant being discussed.

A chemical messenger released into the blood by a gland to act on distant tissues. Steroid hormones (estrogen, testosterone, cortisol) are made from cholesterol. Peptide hormones (insulin, oxytocin) are made from amino acids. Genes affect how hormones are made, transported, sensed and cleared.

The body’s defence against pathogens and damaged cells, in two layers:

• Innate: fast and non-specific. It includes skin and mucous barriers, inflammation, complement, neutrophils, macrophages and mast cells.
• Adaptive: slower and highly specific. T cells recognise antigen fragments presented by HLA molecules, and B cells make antibodies. It leaves memory cells behind for faster responses next time, which is the principle behind vaccines.

Cytokines coordinate the two. Too weak a response leaves you open to infection. Too strong or misdirected a response causes allergies and autoimmunity.

A 0–1 score for how confidently a genotype was imputed. Scores of 0.8 and above are generally considered reliable. Many pipelines drop variants below about 0.3–0.5.

A small insertion or deletion of DNA letters, typically 1–50 bases. An indel in a coding region that isn’t a multiple of three causes a frameshift.

The body’s protective response to injury or infection: redness, heat, swelling and pain as blood flow and immune cells increase. Short-lived (acute) inflammation heals. Low-grade chronic inflammation, measured with markers such as hs-CRP, is involved in cardiovascular disease, diabetes and depression.

A stretch inside a gene that is copied into RNA and then spliced out before the protein is made. Variants in introns can still matter if they disrupt splicing or regulation.

How the body absorbs, moves, stores and recycles iron. Iron is absorbed in the duodenum (heme iron from meat more easily than non-heme iron from plants, and vitamin C helps the latter). Transferrin carries it in blood, ferritin stores it, and hepcidin, a liver hormone, is the master regulator that limits absorption when stores are full. The body has no active way to excrete excess iron.

Imbalances cause iron-deficiency anaemia on one side and iron overload (hemochromatosis) on the other.

Continuing to make lactase in adulthood. In Europeans it is mainly caused by the −13910 T allele (rs4988235), which sits in an enhancer inside the neighbouring MCM6 gene and keeps LCT switched on. Different persistence variants arose independently in East African and Middle Eastern pastoralist groups.

Digesting lactose, the milk sugar, which is made of glucose and galactose. Lactase, an enzyme on the lining of the small intestine, splits it so both sugars can be absorbed. If lactase is low, undigested lactose reaches the colon, where bacteria ferment it and cause gas, bloating and diarrhoea (lactose intolerance).

Most adults worldwide gradually lose lactase after weaning. This is the ancestral, normal pattern and is most common in East Asian, West African, Native American and many Mediterranean populations. Continued lactase production into adulthood is called lactase persistence.

Body weight minus fat: muscle, bone, organs and water. It is estimated with DXA scans, bioelectrical impedance (BIA, as in smart scales) or skinfold equations. Higher lean mass, especially muscle, is linked to better metabolic health, strength and healthy ageing.

Lean body mass isn’t the same as muscle mass, though muscle is its largest changeable part. It responds to resistance training and adequate protein, and genes influence how quickly.

Converting positions from one genome build to another (e.g. GRCh37 to GRCh38). It is needed when a file and a database use different builds. A small share of positions can’t be mapped across.

The tendency of nearby variants to be inherited together, because recombination rarely splits them. A SNP in strong LD with a causal variant can act as its stand-in (a “tag SNP”). Imputation relies on LD.

A variant that reduces or abolishes what a gene product normally does. Partial loss (e.g. lower enzyme activity) is common and often mild. Complete loss of both copies causes many recessive disorders.

The volume of air the lungs can hold. Total lung capacity (about 6 L in an average adult man, less in women) is the vital capacity, i.e. the most you can breathe out after a full breath in, plus the residual volume that always stays in the lungs.

Spirometry measures how much you can blow out (FVC) and how fast (FEV1). Residual volume needs body plethysmography or gas dilution. Capacity depends largely on body size, sex, age and genetics. Training improves breathing-muscle strength and efficiency more than the size of the lungs themselves. Smoking and lung disease reduce function.

An enzyme on the X chromosome that breaks down serotonin, norepinephrine and dopamine, and dietary tyramine. Promoter variants (uVNTR) change how much is made. MAO inhibitor drugs block it, which is why tyramine-rich foods are restricted with them.

An immune cell in skin, gut and airway tissue that stores histamine and other mediators in granules and releases them in response to allergens, injury, stress, heat and certain foods or drugs.

A condition in which mast cells release mediators too easily, causing recurring symptoms across several organ systems. It is diagnosed clinically with lab markers (e.g. tryptase). It is distinct from histamine intolerance, which is about breaking histamine down rather than releasing too much.

Zinc-dependent enzymes that break down collagen and other structural proteins during normal tissue remodelling. UV light and smoking switch them on in skin. The MMP1 2G promoter variant increases expression and is linked to faster collagen breakdown.

A receptor on pigment cells that switches melanin production from red/yellow pheomelanin to brown/black eumelanin. Loss-of-function variants (R151C, R160W, D294H and others) cause red hair, freckling and fair skin, and raise the risk of sunburn and melanoma even in people without red hair.

A condition caused mainly by variants in one gene, inherited in predictable patterns: autosomal dominant, autosomal recessive or X-linked. Cystic fibrosis and Huntington’s disease are examples.

A label for how fast you process drugs through a given enzyme, predicted from your star alleles:

• Poor: little or no activity. Drugs can build up, and prodrugs may not work.
• Intermediate: reduced activity.
• Normal: typical activity (formerly “extensive”).
• Rapid / Ultrarapid: higher activity. Drugs may clear too fast, and prodrugs can over-activate.

A compound that supplies methyl groups. SAMe hands them on directly to most reactions. Methylfolate (via B12-dependent methionine synthase), betaine/TMG (via BHMT) and choline (converted to betaine) donate them to homocysteine to regenerate methionine and then SAMe.

Adding a methyl group (one carbon and three hydrogens, −CH₃) to a molecule. The body runs billions of these reactions to control DNA (epigenetics), make neurotransmitters, creatine and phosphatidylcholine, clear estrogens and histamine, and recycle homocysteine.

The “methylation cycle” (one-carbon metabolism) is the network of folate, B12, B6, B2, choline and betaine reactions that produces SAMe, the body’s main methyl donor.

The active form of folate that circulates in blood and gives its methyl group to homocysteine (with B12) to make methionine. It doesn’t need MTHFR to be activated, which is why it is often chosen by people with reduced MTHFR activity.

The technology behind 23andMe, AncestryDNA, MyHeritage and similar tests. A chip with probes reads a pre-selected set of roughly 600,000–700,000 SNPs. It is cheap and accurate for common SNPs, but it misses rare variants and anything not on the chip, and it handles deletions and duplications poorly.

How common the less common allele at a position is in a population, from 0 to 0.5. MAF often differs a lot between ancestries, so a variant that is rare in one group may be common in another.

The complementary strand to the reference (plus) strand, running in the opposite direction. Every A on the plus strand is a T on the minus strand, and every C is a G.

“Minus” is not the same as “antisense” or “template”. Those terms describe a gene’s own orientation: for about half of all genes the coding sequence sits on the minus strand. To compare your plus-strand genotype with such a gene’s literature, you take the complement (A↔T, C↔G).

A single-letter change that swaps one amino acid for another in the protein. The effect ranges from none to severe, depending on where it lands. MTHFR C677T (alanine to valine) and COMT Val158Met are missense variants.

A small circular genome (16,569 base pairs) inside mitochondria, the cell’s energy producers. It is inherited only from the mother and is used for maternal ancestry.

The enzyme that makes 5-methylfolate, the form of folate used to turn homocysteine back into methionine. C677T (rs1801133) is the best-studied variant: CT carriers have about 65% and TT about 30% of typical activity, especially when folate or riboflavin (B2) is low. A1298C (rs1801131) has a milder effect.

Caused by many genes plus environment and lifestyle, rather than one gene. Most common conditions (type 2 diabetes, depression, heart disease) and traits (height, BMI) are multifactorial.

Skeletal muscle mixes slow-twitch (type I) fibres, which are fatigue-resistant, mitochondria-rich and suited to endurance, with fast-twitch (type II) fibres, which are powerful, fatigue quickly and suit sprinting and lifting. The ratio is partly genetic and partly trainable.

A phase II enzyme that acetylates drugs (isoniazid, hydralazine, some sulfonamides) and aromatic amines from tobacco smoke and charred meat. Around half of Europeans are slow acetylators, who clear these compounds more slowly.

A chemical messenger between nerve cells, such as serotonin, dopamine, norepinephrine, GABA, glutamate, acetylcholine or histamine. Genes for making, breaking down, transporting and sensing neurotransmitters are central to mood and depression reports.

A position where the test couldn’t determine your genotype, usually shown as “--” or “00” in a raw data file. It is a missing value, not a result. Imputation can often fill it in.

DNA that doesn’t code for protein: about 98% of the genome. It includes introns, promoters, enhancers and genes for regulatory RNAs. Most disease-associated SNPs found by GWAS sit here.

A person with two non-working copies of FUT2, most often homozygous for the W154X nonsense variant (rs601338 AA) in Europeans, or for other variants in East Asians. Non-secretors don’t put blood-group antigens into saliva or mucus. About 20% of Europeans are non-secretors.

A change that creates an early stop codon, so the protein is cut short and usually doesn’t work. The common FUT2 non-secretor variant and ACTN3 R577X are nonsense variants.

A single building block of DNA or RNA: a sugar, a phosphate and one base (A, C, G or T; RNA uses U instead of T). A SNP is a difference in one nucleotide.

The study of how genetic variation changes a person’s response to food and nutrients. Well-established examples include lactase persistence (dairy), MTHFR (folate needs), HFE (iron) and CYP1A2 (caffeine).

The flip side of nutrigenetics: how nutrients and food compounds change gene expression. Examples: sulforaphane from broccoli switching on detox enzymes, or omega-3s dampening inflammatory genes.

A measure of how strongly a variant is associated with an outcome. An OR of 1.2 means the odds are 20% higher in carriers. That is a relative increase: a 20% higher odds of a 1-in-100 condition is still close to 1 in 100.

An imbalance where reactive oxygen species (ROS) outpace the body’s antioxidant defences and damage lipids, proteins and DNA. Small, short bursts (as in exercise) are useful signals. Chronic oxidative stress contributes to ageing, inflammation and many diseases.

The five-tier system from the American College of Medical Genetics and Genomics for whether a variant causes disease: pathogenic, likely pathogenic, uncertain significance (VUS), likely benign and benign. It applies to single-gene conditions, not to common SNPs with small effects.

The share of people with a given genotype who actually develop the related trait or condition. HFE C282Y homozygosity, for example, has low clinical penetrance: many carriers never develop iron overload disease.

Keeping body fluids within a narrow acid/alkaline range. Blood is held at pH 7.35–7.45 by three systems:

• Buffers: mainly bicarbonate, which absorbs excess acid or base within seconds.
• Lungs: breathing out CO₂ (which forms carbonic acid in blood) adjusts pH within minutes.
• Kidneys: excreting acid and reclaiming bicarbonate fine-tunes pH over hours to days.

Other compartments have their own pH: stomach acid around 1.5–3.5, and saliva around 6.5–7.5. When the mouth drops below about 5.5, tooth enamel starts to dissolve.

The study of how genetic variation affects drug response: how fast a drug is broken down, whether a prodrug gets activated, and the risk of side effects. CPIC publishes guidelines on adjusting the drug or dose by genotype.

The first step in clearing drugs, hormones and toxins, mostly carried out by CYP450 enzymes. They add or expose a reactive group (often by oxidation). The intermediate can be more reactive than the original compound, so phase II needs to keep up.

The second step: attaching a water-soluble group so a compound can be excreted in urine or bile. The main routes are glutathione conjugation (GSTs), glucuronidation (UGTs), sulfation (SULTs), acetylation (NAT2) and methylation (COMT, HNMT).

An observable trait or characteristic: eye colour, cholesterol level, how fast you clear caffeine. A phenotype comes from genotype, environment and their interaction.

Skin ageing caused by UV exposure rather than time alone: wrinkles, pigment spots, loss of elasticity and broken capillaries. It comes from UV-induced oxidative stress, MMP activation and DNA damage. Pigmentation genes (MC1R), collagen genes and antioxidant genes all influence how fast it happens.

In genomics, “plus” and “minus” describe orientation relative to the reference genome, not a gene’s function. The plus (forward) strand is the one whose sequence is written in the reference, read 5′ to 3′ from the start of each chromosome (the tip of its short arm). Most consumer raw data files (23andMe, AncestryDNA) and VCFs report genotypes on the plus strand.

A gene can sit on either strand. Papers often describe a SNP from the gene’s own point of view, so for genes on the minus strand the letters in a study can be the complement of the letters in your file: a study’s C/T can appear as G/A in your data.

A single number that adds up the small effects of many variants (sometimes millions) to estimate genetic predisposition for a common trait such as heart disease or height. PRSs are most accurate in the ancestry they were built from and describe probability, not destiny.

A medicine that is inactive until an enzyme converts it to its active form. Codeine (activated by CYP2D6 to morphine), clopidogrel (CYP2C19) and tamoxifen (CYP2D6) are prodrugs. Genetics flips the usual logic here: poor metabolisers may get too little effect, and ultrarapid metabolisers too much.

The DNA region just upstream of a gene where transcription starts. Variants in promoters can raise or lower how much of a gene is made (e.g. the MMP1 1G/2G promoter variant).

A chain of amino acids folded into a working shape. Enzymes, receptors, transporters, hormones like insulin and structural molecules like collagen are all proteins.

The downloadable text file from a consumer DNA test. Each row holds one SNP: rsID, chromosome, position and your two-letter genotype. This is the file you upload to NutraHacker.

Unstable oxygen-containing molecules such as superoxide, hydrogen peroxide and the hydroxyl radical. They are a by-product of energy production in mitochondria, are made on purpose by immune cells, and are increased by UV, smoking and pollution.

How many sequencing reads cover a given position. More depth means more confidence in the genotype call. “30x” means each position is read about 30 times on average.

The base found in the reference genome at a position. It is not always the most common allele and says nothing about whether an allele is healthy.

The standard human sequence that everyone’s DNA is compared against and that defines positions. Two builds are in use: GRCh37 (hg19, used by most consumer tests) and the newer GRCh38 (hg38). The same SNP has different coordinates in each build.

A large set of fully sequenced, phased genomes used as the template for imputation, e.g. 1000 Genomes, HRC or TOPMed. Larger and more ancestrally diverse panels impute more accurately.

The allele at a SNP that is associated with the outcome being studied. It is not necessarily the rare allele and not necessarily “bad”: the same allele can be a risk in one context and protective in another.

The identifier dbSNP gives a known variant, such as rs1801133 (MTHFR C677T). An rsID points to the same variant across tests, genome builds and studies, which is why reports list them.

The fluid from three pairs of major salivary glands (parotid, submandibular, sublingual) and hundreds of minor ones, about 0.5–1.5 L a day. Saliva lubricates food, starts digestion (amylase for starch, lingual lipase for fat) and defends the mouth with antimicrobial proteins (lysozyme, lactoferrin, histatins, IgA). Its bicarbonate buffers plaque acid. Its calcium and phosphate repair early enamel damage, along with fluoride from toothpaste and water.

Reduced saliva (dry mouth, xerostomia), from medications, Sjögren’s syndrome, radiation or ageing, sharply raises the risk of cavities. People also differ genetically, e.g. in the number of AMY1 amylase gene copies they carry.

The universal methyl donor, made from methionine and ATP. After giving up its methyl group it becomes SAH, then homocysteine. The SAMe:SAH ratio is a key measure of methylation capacity. SAMe is also sold as a supplement for mood and joints.

A person with at least one working copy of FUT2, who therefore secretes blood-group antigens into body fluids. About 80% of people of European ancestry are secretors.

Whether you release ABO blood-group antigens into saliva, mucus, breast milk and the gut lining. This is controlled by the FUT2 gene (fucosyltransferase 2), which adds the sugar fucose to make the H antigen in secretions. Secretor status is separate from your blood type and doesn’t affect blood donation or transfusion.

It shapes the gut microbiome (fucose is food for beneficial bacteria) and is linked to vitamin B12 levels, Crohn’s disease risk and susceptibility to some infections. Non-secretors are largely resistant to the most common norovirus strains.

An enzyme that cuts proteins using a serine amino acid in its active site, working with histidine and aspartate (the “catalytic triad”). Members include trypsin and chymotrypsin (digestion), thrombin and plasmin (clotting and clot breakdown), neutrophil elastase (immunity) and KLK4, which clears enamel proteins as teeth mature. Alpha-1 antitrypsin is the body’s main inhibitor of serine proteases.

A liver protein that carries testosterone, DHT and estradiol in the blood and keeps them inactive while bound. Only the unbound (“free”) fraction acts on tissues. SHBG levels are strongly genetic and are also affected by insulin, thyroid hormone, liver fat and age.

A one-letter variant at a specific position, shared by a meaningful share of people (usually at least 1%). The human genome has millions of SNPs. Most have no known effect, some change how a protein works, and some are markers that sit next to the variant that matters. Rare one-letter changes are usually called SNVs (single-nucleotide variants).

The gene for a liver transporter that pulls statins out of the blood. The rs4149056 C allele (*5) reduces uptake and raises the risk of muscle side effects, especially with high-dose simvastatin.

The mitochondrial antioxidant enzyme that turns superoxide into hydrogen peroxide, using manganese. The Ala16Val variant (rs4880) changes how efficiently the enzyme reaches the mitochondria.

The naming system for pharmacogene haplotypes: *1 is usually the typical, fully working version, and other numbers are defined combinations of variants (e.g. CYP2C19*2). Your two star alleles together (a diplotype such as *1/*2) are translated into a metabolizer status.

A SNP whose two alleles are each other’s complement (A/T or C/G). Flipping the strand gives the same pair of letters, so the file alone can’t tell you which strand was used. Tools resolve these using allele frequencies or the chip manifest.

A large change in DNA structure, usually more than 50 bases: big deletions, duplications, inversions or translocations. Microarrays detect few of these reliably. Whole genome sequencing finds many more.

Intake of dietary sugars. Excess free sugars (sugars added to foods and drinks, plus those in honey, syrups and fruit juice) are linked to weight gain, type 2 diabetes, cardiovascular disease and tooth decay. The WHO recommends keeping free sugars below 10% of daily energy, ideally below 5%. Sugars inside whole fruit and milk don’t count towards this limit.

Genes influence sweet-taste perception and preference (e.g. TAS1R2, GLUT2) and how quickly oral bacteria get to work on sugar.

A change in a codon that still codes for the same amino acid. Usually harmless, though some affect splicing or how efficiently the protein is made.

Tooth formation (odontogenesis) starts around the sixth week of embryonic development, when a thickened band of mouth lining (the dental lamina) produces tooth buds. Each bud passes through the bud, cap and bell stages as two cell types interact: ameloblasts, which form enamel, and odontoblasts, which form dentin. The pulp holds nerves and blood vessels.

Baby teeth form before birth. Permanent teeth keep forming until the late teens (wisdom teeth into the early twenties). Genes such as MSX1, PAX9 and AXIN2 control tooth number. Variants in them cause missing teeth (hypodontia).

Genes for enzymes that inactivate thiopurine drugs (azathioprine, mercaptopurine, thioguanine). People with low activity can develop dangerous bone-marrow suppression at standard doses, so testing before treatment is standard.

A non-invasive technique that passes a weak direct current (typically 1–2 mA) through scalp electrodes to nudge the excitability of the brain region underneath. It has been studied for depression, chronic pain, stroke rehabilitation and cognitive enhancement, with mixed but promising results. It is generally well tolerated. Mild tingling, itching or skin redness are common.

Copying a gene’s DNA into RNA. RNA polymerase reads the template (antisense) strand and builds an RNA whose sequence matches the gene’s coding (sense) strand.

Building a protein from an RNA message. Ribosomes read the RNA three letters (one codon) at a time and add the matching amino acid.

A phase II enzyme that attaches glucuronic acid to bilirubin, some hormones and drugs such as irinotecan. The *28 variant lowers its activity and causes Gilbert syndrome: harmless, mildly raised bilirubin, but greater sensitivity to some drugs.

Increased expression or activity of a gene or protein, in response to a signal such as a hormone, nutrient, drug or stressor. Upregulation can be helpful (more antioxidant enzymes during exercise) or harmful (an oncogene switched on).

When people with the same variant show the condition with different severity or features. Common in dominant connective tissue and heart conditions.

Any difference from the reference genome at a position. Geneticists prefer “variant” to “mutation” because most differences are common and harmless. Variants range from single-letter SNPs to indels and large structural changes.

The bioinformatics step that compares aligned reads with the reference genome and decides the genotype at each position, using tools such as GATK or DeepVariant.

A variant without enough evidence to call it either disease-causing or harmless. A VUS should not be used for medical decisions. Many are reclassified, most often to benign, as data accumulates.

The standard text format for variants. Each row gives the chromosome, position, rsID, reference and alternate alleles, quality and your genotype (e.g. 0/1 = one reference and one alternate allele). A gVCF also records the positions where you match the reference.

A cobalt-containing vitamin from animal foods, needed for nerve function, red blood cells and methylation. Methionine synthase (MTR) uses B12 to move a methyl group from methylfolate to homocysteine, and MTRR keeps the B12 in that enzyme active. Without enough B12, folate gets stuck as methylfolate (the “folate trap”).

Vitamin D is made in skin from UVB light and converted in the liver and kidney to its active hormone form, calcitriol. Calcitriol acts through the vitamin D receptor (VDR) to control calcium absorption, bone health and immune function. VDR variants (FokI, BsmI, TaqI, Cdx2) have been studied for bone density and vitamin D response. GC and CYP2R1 variants affect blood 25(OH)D levels.

The gene for the protein warfarin blocks to prevent clotting (it recycles vitamin K). The −1639G>A variant (rs9923231) lowers expression, so carriers need lower warfarin doses.

The highest rate at which your body can take in and use oxygen during all-out exercise, measured in millilitres per kilogram of body weight per minute (mL/kg/min). It is one of the best markers of aerobic fitness and one of the strongest predictors of long-term health.

It is measured with a graded treadmill or bike test while breathing into a gas analyser. Wearables estimate it from heart rate. VO2 max falls with age and rises with endurance and interval training. Both its baseline and how much it improves with training are substantially heritable.

Sequencing only the exons (protein-coding parts) of genes, about 1–2% of the genome. Cheaper than WGS but blind to most regulatory and intronic variants, and coverage is less even.

Reading essentially all 3.1 billion base pairs of your genome rather than a pre-selected subset. Each position is read many times over, about 30 times at the usual “30x” depth. WGS finds rare and novel variants, indels and many structural variants that microarrays can’t.

The typical, most common or reference form of a gene. In pharmacogenomics the default *1 allele plays this role.

Inheritance of a gene on the X chromosome. Males have one X, so a single altered copy usually affects them, while females with one copy are usually carriers (sometimes with milder signs). Fathers cannot pass X-linked conditions to sons. Examples: G6PD deficiency, hemophilia, Fabry disease. MAOA and the androgen receptor gene are also on the X.

The enzyme that converts testosterone into the more potent DHT in skin, hair follicles and the prostate. DHT drives male pattern hair loss, prostate growth and sebum production. Finasteride and dutasteride block it.