Rethinking Sex, Gender and Sexuality in Genomic Research

Modern medical research plays a vital role in generating knowledge that can be translated into clinical practice to improve healthcare. Yet despite legislative progress, sex bias persists: male subjects – whether cells, animals or humans – continue to dominate (pre)clinical studies. This imbalance raises critical questions about the validity and applicability of research outcomes for all sexes and genders, particularly regarding women’s health.

Beyond biological sex, every individual embodies a spectrum of complex traits encompassing gender identity, sexual orientation and variations of sex characteristics (VSC). These dimensions shape health trajectories and can also be sites of discrimination. However, their complexity is often oversimplified – or ignored altogether – in research, frequently in the name of reducing variability.

“By failing to include transgender and non-binary individuals in genomic research, science reifies the idea that gender is solely determined by biological markers such as chromosomes, reproductive anatomy or hormone profiles,” said Dr. Emerson Dusic, a postdoctoral research fellow at the University of Michigan. “This narrative is then replicated in public discourse and policy. Exclusion limits recognition of the broad spectrum of gender diversity and reinforces misunderstandings, such as the belief that legitimate gender identities must be supported by ‘objective’ biological evidence, and overlooks the interaction between social, psychological and biological determinants of identity.”

These issues will take center stage during a dedicated symposium at the 2025 American Society of Human Genetics (ASHG) annual meeting in Boston, where experts will explore the clinical and genetic research challenges related to sex, gender and sexuality. Through the lenses of bioethics, advocacy and community engagement, speakers will examine research findings, ethical considerations and practical implications, highlighting the need for more inclusive and representative research practices.

A history of oversight

For decades, biomedical research prioritized male models – both animal and human – under the assumption that findings were broadly generalizable. This neglect has carried real consequences. A notable example is Ambien™ (zolpidem), a widely prescribed sleep medication. Post-market surveillance revealed that women were more likely to experience next-morning impairments in driving and alertness. In 2013, the US Food and Drug Administration (FDA) mandated sex-specific dosing in response.

Regulators and funders have since begun to close these gaps:

• The US National Institutes of Health (NIH) requires investigators to account for sex as a biological variable.
• The FDA has implemented Diversity Action Plans mandating representative enrollment by sex, race and ethnicity in clinical trials.
• The European Commission now requires sex and gender analysis to be integrated into Horizon Europe research projects.

This shift is about more than compliance – it’s about scientific rigor. Sex, gender and sexuality influence biology at every level, from gene expression and pharmacokinetics to clinical outcomes and patient experiences. Ignoring them risks overlooking therapeutic targets, misjudging safety profiles and eroding public trust in science.

Defining the terms clearly

Progress is often hindered by confusion over terminology. “Sex,” “gender” and “sexuality” are frequently used interchangeably, yet they are distinct:

• Sex: Biological attributes such as chromosomes, hormones and reproductive anatomy.
• Gender: Social and cultural constructs – identity, roles and expression – that intersect with health.
• Sexuality: Patterns of attraction, behavior and identity related to sexual orientation.

In 2022, the US National Academies of Sciences, Engineering and Medicine issued consensus recommendations for measuring sex, gender identity and sexual orientation. Their two-step model – asking about sex assigned at birth and current gender identity separately – better captures transgender and non-binary populations. These frameworks, alongside the Sex and Gender Equity in Research guidelines, provide researchers with structured approaches for study design and reporting.

Clear definitions are not a matter of semantics. In clinical trials, misusing variables can obscure meaningful differences. For biopharma, terminological precision shapes market access strategies, labeling requirements and, ultimately, the safety and efficacy of products.

Dr. Kristina Suorsa-Johnson, an assistant professor of pediatrics at the University of Utah School of Medicine, who works in the field of VSC, explained:

“The specific experience of this [VSC] population is often lost because it is simply not accounted for. Participants are often provided only male/female or woman/man options. While more inclusive options exist today, they still don’t necessarily encompass the experience of those with VSC. Additionally, because this population is small, individuals are often integrated into larger groups or excluded from analysis. The unique experiences of those living with a VSC are often missed.”

Why sex differences matter

Sex differences extend far beyond reproductive biology. Genomic studies reveal that sex influences gene expression across nearly all tissues. Analysis from the Genotype-Tissue Expression project showed that over 91% of FDA-approved drug targets exhibit sex-differential expression in at least one tissue.

Drug metabolism is similarly affected. Women typically show higher CYP3A4 activity, accelerating the metabolism of many drugs, but they also face a 1.5–1.7-fold higher risk of adverse drug reactions compared to men.

These biological differences reverberate through drug development. A therapy that appears effective in male-biased preclinical models may fail in women, and vice versa. Without accounting for sex-specific disease pathways, clinical trials risk underestimating benefits or overstating risks for one population.

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Accounting for sex, gender and sexuality in genomic research

At ASHG 2025, researchers will tackle a longstanding gap in genomics: the oversimplification and exclusion of sex, gender and sexuality. Biological sex differences are deeply embedded in genomic and epigenomic variation – from chromosomal content and gene regulation to methylation patterns and chromatin states. Hormonal environments further shape these patterns, meaning analyses that combine sexes risk masking meaningful biological signals.

These differences extend to genotype–phenotype relationships, where allelic effects, penetrance and trait architectures can vary by sex. Some loci even exhibit interaction effects, where the impact of a genetic variant depends on sex. Failing to account for these differences can lead to false negatives or positives in association studies.

Distinguishing between sex and gender is equally critical. Many studies label samples as “male” or “female” without clarifying whether this refers to sex assigned at birth, self-identified gender or phenotype. Gendered differences in stress, environmental exposures, medical care and lifestyle can all alter gene expression profiles, introducing bias if unaddressed. Additionally, X and Y chromosomes require tailored analytical approaches to account for dosage compensation, X-inactivation, hemizygosity and sex-specific demographic patterns.

Dusic emphasized that meaningful change in genomics research requires a fundamental shift toward greater inclusivity and ethical responsibility. They explained: “Research studies involving transgender and non-binary individuals should undergo rigorous, anticipatory risk analysis in collaboration with trans community members, who should be involved in all research stages. This analysis should consider the political and social context in which the research occurs and utilize advanced privacy protections that account for specific vulnerabilities trans individuals face.”

They continued: “As a part of this, transgender and non-binary participants need to be given authority over how their data is used and shared. We also must move away from frameworks that require ‘proof’ of gender identity through genetics and promote transgender and non-binary individuals’ rights to autonomy and self-determination. Ethical frameworks should instead emphasize the social context of genomics, recognize the fluidity of gender identity and guide researchers to avoid reductionist or deterministic interpretations of their work.”

Incorporating sex, gender and sexuality into genomic research enhances precision, power and equity. It leads to more accurate genotype–phenotype mapping, improves risk prediction models and supports targeted therapies that reflect both biological and social realities. Crucially, it ensures genomic discoveries benefit all populations equitably, strengthening the impact of precision medicine.

As Suorsa-Johnson concluded: “Over the next decade, I hope that community-engaged research becomes the norm rather than the exception. This will allow us as researchers and clinicians to transition from ‘examining’ a population to working collaboratively with them to solve patient-centered problems.”

Disclaimer: Dr. Emerson Dusic stated, “the views in this interview are my own and do not necessarily reflect the University of Michigan”.