Weight, Energy, Mood, and Your DNA: How Hormones Are Linked to Genetics

Fatigue that doesn't go away after the weekend. Weight that reacts to everything except effort. Mood that constantly changes. Behind all these symptoms is the hormonal system. And the reason may partly lie in genetics, which determines the peculiarities of the work of this system in your body.

Hormones are first produced, then released into the bloodstream, then bound to cell receptors, and only then do they trigger the appropriate responses. Each of these steps is linked to hereditary characteristics. How much of a hormone is produced or activated, how efficiently it is transported, and how sensitive the receptors are to it all vary from person to person. And it's all written into DNA.

If you are interested in knowing how a genetic test differs from a regular blood test, – DNA test and blood test: what's the difference?

Same complaints – different reasons

Problems related to the hormonal system are very common and can affect various aspects of health. Fatigue that does not go away after rest. Weight that does not respond to changes in diet. Mood swings for no apparent reason. Feeling cold when others are warm. Poor concentration in the morning.

Most people with such symptoms sooner or later get hormone tests done. And often get results within the reference range.

Unfortunately, this does not always mean that all is well. Reference values ​​are a statistical range for a population, andnot an individual normTwo people can have the same level of a hormone in their blood, but experience its effects completely differently. The reason is usually in how their hormonal system is arranged at the DNA level. 

This is where genetics begins.GWAS (Genome-Wide Association Study) allows to identify genetic variants associated with various physiological states and features of the organism, including the functioning of the hormonal system. Based on hundreds and thousands of such variants, they calculate Polygenic Risk Score (or PRS) – it summarizes genetic markers and allows you to assess the hereditary characteristics of a particular person without a blood test and without a diagnosis. It is important that PRS does not determine the current level of hormones and is not a diagnosis, but helps to assess the genetic predisposition to certain features of hormonal regulation.

How genetics are related to the hormonal system

Hormones are not just numbers in a blood test. Their effects on the body are determined by a complex system of synthesis, transport, recognition by cells, and subsequent signal transmission. Genetic variants can alter the functioning of individual components of this system.

Genetic variants can affect how much of the hormone is produced, how efficiently it is transported, and how sensitive cell receptors are to it. The result: two people with the same hormone levels in their blood can feel very different and require different approaches to treatment.

Here is a specific example. A person takes a test: TSH is normal, T4 is normal. But he wakes up exhausted despite a full night's sleep, is freezing in a warm room, notices that his thoughts "get stuck" in the morning. Even with normal levels of hormones in the blood, genetic characteristics can affect how effectively cells perceive and use their signals. The test showed the norm. Genetics explains why this norm does not feel like it.

Cortisol: why stress affects weight differently

Cortisol is a stress response hormone. It’s neither bad nor good in itself: it’s needed by the body to mobilize energy in difficult situations. The problem arises when stress becomes chronic and cortisol remains elevated for longer than necessary.

Genetics influence the intensity and duration of the cortisol response. In some people, cortisol levels quickly return to normal after stress. In others, it remains elevated for hours. And this second option, as a rule, is not about “weak nerves”, but about hereditary features of regulation.

What is behind this mechanism?

BigGWAS meta-analysis of the CORNET consortium (Crawford et al., Journal of Human Genetics, 2021), which included 25,314 individuals in 17 population cohorts, revealed the key role of the locus SERPINA6/SERPINA1 in the regulation of cortisol levels in the blood. GenesSERPINA6andSERPINA1encodes corticosteroid-binding globulin, which determines the bioavailability of cortisol to tissues. Variants at this locus are associated with how much cortisol actually "gets" to cells and how the body responds to stress. Additionally, the study showed an association of these variants with cardiovascular disease risk, highlighting the importance of cortisol regulation far beyond stress itself.

A separate mechanism is related to the gene FKBP5 Its polymorphisms affect the sensitivity of glucocorticoid receptors and determine how effectively the body "turns off" the stress response after the acute situation has passed.

Why is this important for weight and energy? Chronically elevated cortisol raises blood glucose levels and promotes the accumulation of fat tissue, especially in the abdominal area. It also disrupts sleep and reduces insulin sensitivity. A person can eat a balanced diet and exercise regularly, but if their cortisol response is genetically enhanced, the results will be much less noticeable than they expect.

Estrogen, androgen and their relationship to genetics

Estrogen is often perceived as a purely “female” hormone, and androgen as a “male” one. In fact, both hormones are present in every person’s body and are important for the normal functioning of the body.

Genetic variants affect the synthesis of these hormones and the sensitivity of receptors to them. That is why the same level of estrogen in the blood can be accompanied by completely different symptoms in different women. One does not notice anything special, another experiences pronounced mood swings, fluid retention and sleep disturbances with the same indicator in the analysis.

A large-scale study using data from All of Us and UK Biobank (over 200,000 participants) has identified a locus in the gene associated with the risk of depression ESR1, encoding estrogen receptor alpha, and confirmed that this association is sex-specific (Shojaie et al.,Genet Epidemiol, 2025). A 2022 meta-analysis also showed that polymorphisms in genes ESR1 and ESR2 are associated with women's susceptibility to depressive episodes, with certain alleles increasing the relative risk by 1.35–1.62 times compared to controls (Li et al., Frontiers in Genetics, 2022).

These genetically determined characteristics – in particular, variants in genes that affect estrogen synthesis and receptor sensitivity – remain stable throughout life. At the same time, understanding your predisposition allows you to more consciously approach monitoring your mood, regimen and, if necessary, talking to a doctor.

The same goes for androgen. Genetically determined receptor sensitivity explains why in some people even small fluctuations in androgen levels have a noticeable effect on energy, libido, and muscle tone.

Thyroid gland and basal metabolism

The thyroid gland is closely related tobasal metabolism– and regulates how much energy the body uses at rest. Its hormones affect body temperature, heart rate, the rate at which fats and carbohydrates are broken down, as well as brain function and mood.

The genetics of thyroid function are well understood. A large GWAS meta-analysis (Nature Communications, 2023) of 119,715 individuals identified 74 genetic loci associated with TSH levels, 28 of which were described for the first time. A later, larger analysis of the same group(Sterenborg et al.,Nature Communications, 2023) on 271,040 individuals found that independently associated variants explained 14.1% of the variability in TSH and 6% of the variability in free T4 between individuals. This is important: even within the “normal” TSH range, each individual has their own genetically determined equilibrium point, which may differ significantly from the population average.

The largest modern study of hypothyroidism(Sinnott-Armstrong et al., Nature Genetics, 2025) included over 113,000 cases and over a million controls and identified 350 loci associated with the disease. Based on these data, a polygenic risk score (PRS) was developed, which allows assessing the predisposition to hypothyroidism even before the onset of clinical symptoms.

A genetic predisposition to hypothyroidism does not mean that a person is already sick or will definitely get sick. It means that their system may be more vulnerable to factors that reduce thyroid function, such as iodine deficiency, chronic stress, or certain infections. Knowing about this predisposition in advance is useful: a person can proactively pay attention to nutrition, regularly monitor indicators, and at the first symptoms do not wait until they become pronounced.

Learn about the genetic features of the thyroid gland and metabolismsubstances → Genetic blood biomarker test 

What does understanding your hormonal profile at the DNA level give you?

Genetic testing of hormonal biomarkers is not a substitute for blood testing. Genetic testing results are not intended to diagnose or prescribe treatment. But this information provides something that standard biochemistry cannot show – an understanding of how your hormonal system works, not just what is happening in it right now.

A person who knows their hormonal profile comes to the doctor withother questionsNot “something is wrong with me,” but “I have a genetically enhanced cortisol response – what indicators should I monitor additionally?” or “I have a genetic predisposition to hypothyroidism – should I regularly check TSH, T3 and T4, even if there are no symptoms yet?”.

What does a person who has their genetic hormonal profile analyzed get:

• assessing susceptibility to altered cortisol response to stress and its impact on weight and sleep

• analysis of genetic variants associated with estrogen and androgen receptor sensitivity

• polygenic indicator of predisposition to thyroid dysfunction

• specific monitoring and lifestyle recommendations tied to the individual profile

This knowledge changes the decision-making approach and allows us to act preventively rather than waiting for symptoms to appear.

If you are interested in learning what genetics say about your hormonal profile, → Genetic blood biomarker test 

Hormone control is not just about blood tests

The hormonal system is more complex than the numbers in the lab results. Behind each indicator is a chain of processes that are influenced by genetics. Cortisol, estrogen, androgen, thyroid hormones - each of them has a genetic dimension that is not visible in standard analysis. Understanding your hormonal profile at the DNA level does not eliminate the need to take tests. But it provides a context that makes the results of these tests more informative.

 Genetic test results are not a diagnosis and are not a substitute for a doctor's consultation. The Apixmed Prism report provides genetic context that complements the results of the tests and helps you make decisions together with your doctor.

Sources:

1. Crawford AA, Bankier S, Altmaier E, et al. Variation in the SERPINA6/SERPINA1 locus alters morning plasma cortisol, hepatic corticosteroid binding globulin expression, gene expression in peripheral tissues, and risk of cardiovascular disease. J Hum Genet. 2021;66(6):625–636. https://doi.org/10.1038/s10038-020-00895-6

2. Li C, Xie M, Wang W, et al. Association between polymorphisms in estrogen receptor genes and depression in women: a meta-analysis. Front Genet. 2022;13:936296. https://doi.org/10.3389/fgene.2022.936296

3. Shojaie M, Kwon E, et al. Sex-specific association between polymorphisms in estrogen receptor alpha gene (ESR1) and depression: a genome-wide association study of All of Us and UK Biobank data. Genet Epidemiol. 2025. https://doi.org/10.1002/gepi.70004

4. Sterenborg RBTM, Galesloot TE, Deelen J, et al. GWAS of thyroid stimulating hormone highlights pleiotropic effects and inverse association with thyroid cancer. Nat Commun. 2020;11:4564. https://doi.org/10.1038/s41467-020-17718-z

5. Sterenborg RBTM, Galesloot TE, et al. Genome-wide association study of thyroid-stimulating hormone highlights new genes, pathways and associations with thyroid disease. Nat Commun. 2023;14:6713. https://doi.org/10.1038/s41467-023-42284-5

6. Sterenborg RBTM, et al. Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications. Nat Commun. 2024. https://doi.org/10.1038/s41467-024-44701-9

7. Sinnott-Armstrong N, et al. Genome-wide association study and polygenic risk prediction of hypothyroidism. Nat Genet. 2025. https://doi.org/10.1038/s41588-025-02410-z