Total Testosterone Level and Your Genetics

Written by Scott Peeples, BS Biomedical Sciences · ExomeDNA Founder Reviewed by ExomeDNA Editorial Process Last reviewed: May 26, 2026

Total testosterone — the standard clinical measurement of all circulating testosterone, including both free and protein-bound fractions — is one of the most extensively studied hormonal traits in human genetics. Multiple large genome-wide studies have established a robust genetic architecture for total testosterone levels, with Mendelian randomization analyses revealing sex-specific causal effects on health outcomes including type 2 diabetes, polycystic ovary syndrome susceptibility, and cardiovascular traits.^[1][3] Below: the genetic basis of total testosterone, what population studies and ancestry-specific research reveal about health impacts of androgen variation, and what the evidence means in practice.

What is total testosterone?

Total testosterone is the sum of all circulating testosterone forms: free testosterone (biologically active, ~2%), albumin-bound testosterone (loosely bound, partially bioavailable, ~38%), and sex hormone-binding globulin-bound testosterone (tightly bound, biologically inactive at tissue level, ~60%). Standard clinical testosterone assays measure this combined total and are the most widely used clinical test for androgen status.

Total testosterone differs from bioavailable testosterone, which excludes the SHBG-bound fraction and more closely reflects androgen activity at tissue level. For many clinical and research purposes, total testosterone serves as the practical standard — but its interpretation requires consideration of SHBG levels, which vary with age, body weight, liver function, and other hormonal factors that can shift the bound-to-free ratio without changing total values.

Genetically, total testosterone levels are substantially heritable — twin studies estimate 40–60% of variation is inherited. The specific variants responsible span multiple biological systems: hormone synthesis, SHBG production, hepatic processing, adenylyl cyclase signaling in gonadal cells, and blood group glycoprotein biology all contribute signals to the genetic landscape.

The genetics of total testosterone levels

The genetic architecture of total testosterone is highly polygenic and demonstrates striking sex-specificity. Large-scale genome-wide and ancestry-specific analyses have mapped hundreds of loci contributing to testosterone variation, with different patterns emerging for men versus women and across ancestral backgrounds.^[2][4]

157 significant genetic variants for testosterone were identified in a Million Veteran Program analysis of men across multiple ancestral backgrounds, with 22 novel associations — including ancestry-specific variants not detected in prior European-ancestry studies — implicating liver function genes and pathways regulating gonadal steroidogenesis.^[4]

Among the notable signals in total testosterone GWAS: the ABO locus — encoding the glycosyltransferase responsible for ABO blood type — appears as a genetic signal. ABO variants influence glycoprotein processing in the liver, and SHBG is a glycoprotein whose circulating levels are partly shaped by this hepatic glycosylation biology. ADCY6 and ADCY9 — adenylyl cyclase genes — appear in total testosterone GWAS, reflecting the critical role of cAMP signaling in LH signal transduction in gonadal cells: LH binds to its receptor, activates adenylyl cyclase, raises cAMP, and triggers the steroidogenic acute regulatory (StAR) protein to initiate androgen synthesis. Variants in adenylyl cyclase isoforms can subtly alter the gain of this LH-to-testosterone signaling pathway.

In 625,650 participants from UK Biobank and FinnGen, genetic analysis of testosterone found pronounced causal effects on sex-specific traits — particularly female reproductive health including PCOS-related traits such as hirsutism — while causal effects on most other health outcomes were modest, suggesting normal testosterone variation has a targeted rather than broad impact on disease risk.^[3]

ABCA8 and ABCC10 — ATP-binding cassette transporters — appear in this trait's genetic landscape, reflecting the broader membrane transport and cellular metabolism biology that in aggregate shapes hormone levels in large population analyses. Their presence alongside mechanistically specific signals like ADCY6/9 and ABO illustrates how GWAS captures both direct biological contributors and indirect metabolic correlates of testosterone variation.

What the research says

Research base: Robust. Total testosterone genetics is supported by multiple large independent genome-wide studies, Mendelian randomization analyses, and ancestry-diverse analyses spanning European, African-ancestry, and multi-ancestry cohorts.^[1][2][3][4] Causal relationships between testosterone variation and specific health outcomes have been tested across large UK Biobank, FinnGen, and Million Veteran Program cohorts. The body of evidence distinguishes between correlational and causal associations, providing one of the more rigorously characterized genetic architectures among sex hormone traits. See our methodology page for how we evaluate and apply genetic evidence in your ExomeDNA profile.

An important interpretive note: Mendelian randomization findings show that causal effects of testosterone are strongly sex-specific — effects documented in men do not apply to women and vice versa. The context-dependent nature of this trait's health implications means that directionality of any genetic tendency must be interpreted in the context of sex and individual hormonal profile.

How total testosterone genetics affects your health

The causal health effects of testosterone variation differ substantially between men and women — a consistent finding across multiple large Mendelian randomization studies. In women, genetically elevated testosterone is causally associated with higher type 2 diabetes risk and PCOS-related traits; in men, genetically elevated testosterone is associated with reduced type 2 diabetes risk and protective effects on several cardiometabolic outcomes.^[1][4]

In men, the MVP analysis found that those with higher testosterone genetic scores had lower odds of type 2 diabetes, hyperlipidemia, gout, and cardiac disorders — consistent with the protective cardiometabolic role of normal-range testosterone in male physiology. The liver function genes (SHBG, SERPINF2, PRPF8, PRMT6) implicated in the MVP ancestry analysis reflect how hepatic biology shapes the testosterone distribution and its downstream consequences.

For female reproductive health, the FinnGen and UK Biobank analysis found testosterone's strongest causal effects in the domain of sex-specific traits — particularly PCOS-related phenotypes including hirsutism and menstrual irregularity. Outside of sex-specific conditions, the causal impact of normal testosterone variation on most other health outcomes is modest. This nuanced finding — pronounced reproductive effects, limited broad disease effects — is important context for interpreting a total testosterone genetic result.

Bone density, muscle mass, and body composition all show testosterone associations in population studies; how much of this is causal versus confounded by other genetic and environmental factors varies by outcome and remains an active research area.

Working with your total testosterone result

What research suggests about testosterone-influencing lifestyle factors

• Resistance training is the most evidence-backed modifiable factor for testosterone in men, and supports favorable androgen signaling in women — exercise directly stimulates the HPG axis and androgen production.^[1]
• Body weight management: adiposity influences aromatase activity, converting androgens to estrogens; for men with higher body fat this substantially reduces testosterone. Weight management is among the most impactful modifiable factors for total testosterone in overweight individuals.
• Sleep quality and duration: testosterone production follows a circadian rhythm with peak secretion during sleep. Chronic sleep restriction measurably reduces morning total testosterone in men.
• Metabolic health: insulin sensitivity, liver function, and glycemic regulation all intersect with testosterone biology through the SHBG, ABO/glycoprotein, and hepatic clearance signals in this trait's genetic landscape.
• Alcohol moderation: alcohol suppresses HPG-axis signaling through hypothalamic and hepatic effects, reducing testosterone production in men particularly at higher consumption levels.
• Serum testosterone testing provides the clinical picture that genetic estimates complement — total testosterone and SHBG together give a complete picture of androgen status that genetics alone cannot supply.

Related traits and genes

Total testosterone connects to a rich network of related traits in your ExomeDNA profile. Bioavailable Testosterone covers the active fraction — the non-SHBG-bound portion tissues can actually use — which can diverge significantly from total testosterone when SHBG is elevated or depressed. SHBG Levels is mechanistically central: SHBG variants are the strongest genetic signals for total testosterone levels and the primary determinant of how total converts to bioavailable. Low Testosterone Risk focuses specifically on susceptibility to falling below clinical androgen thresholds in men.

Within metabolism, Type 2 Diabetes Risk is directly connected through Mendelian randomization evidence showing sex-specific causal effects of testosterone on metabolic risk. PCOS Risk is the key female-specific downstream trait — genetically elevated testosterone causally contributes to PCOS phenotypes. Lean Muscle Mass and Bone Density are both downstream androgen-sensitive tissues where total testosterone genetics exerts population-level effects.

Frequently asked questions

What is the difference between total and free testosterone?

Total testosterone measures all circulating testosterone including the roughly 60% tightly bound to sex hormone-binding globulin (biologically inactive), roughly 38% loosely bound to albumin (partially bioavailable), and roughly 2% free. Free testosterone is the unbound fraction; bioavailable testosterone combines the free and albumin-bound fractions. Total testosterone is the standard clinical measurement because free and bioavailable assays are technically less reliable, but SHBG levels must be considered to interpret total testosterone meaningfully.

Do testosterone genetics affect men and women differently?

Yes, substantially and in opposite directions for some outcomes. Mendelian randomization studies show that genetically elevated testosterone reduces type 2 diabetes risk in men but increases it in women. In women, genetically elevated testosterone is causally linked to PCOS-related traits including hirsutism. Outside of sex-specific conditions, the causal impact of normal testosterone variation on most outcomes is modest in both sexes. This sex-specificity means the same genetic variant can have health implications that differ in direction between sexes.

What does the ABO gene have to do with testosterone?

The ABO gene encodes a glycosyltransferase responsible for adding carbohydrate structures to cell surface and circulating proteins. Sex hormone-binding globulin, the primary testosterone transport protein, is a glycoprotein whose circulating concentrations are partly shaped by hepatic glycoprotein processing. Variants in the ABO locus that alter glycoprotein biology in the liver can influence SHBG levels and therefore total testosterone — illustrating how testosterone GWAS captures indirect hepatic contributors alongside direct synthesis and signaling genes.

Why do adenylyl cyclase genes appear in testosterone GWAS?

Adenylyl cyclases convert ATP to cyclic AMP, which is the second messenger for luteinizing hormone (LH) signaling in gonadal cells. When LH binds its receptor in testes or ovaries, it activates adenylyl cyclase, raises cAMP, and triggers steroidogenesis. ADCY6 and ADCY9 — the adenylyl cyclase isoforms present in testosterone GWAS — reflect the genetic variation in cAMP signal transduction that subtly alters how efficiently the pituitary LH signal is converted into gonadal testosterone production.

Is a higher total testosterone genetic score always better for health?

No. The health implications are context- and sex-dependent. In men, higher testosterone genetic scores associate with lower odds of certain cardiometabolic conditions in MVP data. In women, genetically elevated testosterone is associated with PCOS risk and increased type 2 diabetes susceptibility. Even within sexes, there is likely an optimal range where health effects are favorable, with very high levels carrying their own risks (prostate cancer associations, estrogen conversion). Total testosterone genetic results should be interpreted in the context of sex, individual health profile, and clinical hormone levels.

References

1. Ruth KS, et al. (2020). Using human genetics to understand the disease impacts of testosterone in men and women. Nat Med. PMID: 32042192. DOI: 10.1038/s41591-020-0751-5.
2. Harrison S, et al. (2021). Testosterone and socioeconomic position: Mendelian randomization in 306,248 men and women in UK Biobank. Sci Adv. PMID: 34321204. DOI: 10.1126/sciadv.abf8257.
3. Leinonen JT, et al. (2023). Genetic analyses implicate complex links between adult testosterone levels and health and disease. Commun Med. PMID: 36653534.
4. Pagadala MS, et al. (2025). Discovery of novel ancestry specific genes for androgens and hypogonadism in Million Veteran Program Men. Nat Commun. PMID: 40316537.

Data sources:

• GWAS Catalog (NHGRI-EBI, accessed 2026-05-26)
• Open Targets Platform (CC0 1.0, accessed 2026-05-26)
• ClinVar (NCBI, accessed 2026-05-26) — entries at ≥2-star review status
• ClinGen Gene-Disease Validity (CC0 1.0, accessed 2026-05-26)

This page is published by the ExomeDNA Research Team. Last reviewed: 2026-05-26.