Paper reading: Genome-wide study association of sexlessness

#paper information

Title: Genome-wide association study of sexlessness Journal: PNAS 2025 Vol. 122 No. 38 DOI: https://doi.org/10.1073/pnas.2418257122 Research Number: e2418257122

Research background

This study examines the genetic and environmental correlates of lifelong sexlessness. The study used large-scale data from UK Biobank to analyze genotypic and phenotypic profiles of more than 400,000 participants.

Main findings

1. Relationship between regional factors and Sexlessness

Sex Ratio

• Sex ratio at birthplace: no significant association with sexlessness
• Gender ratio in current place of residence:
  • Males showed a small but significant negative correlation (r = -0.07, P = 0.0004)
  • Areas with fewer women have higher rates of male sexlessness

Income Inequality via Gini Coefficient

Income inequality based on current place of residence is significantly and positively related to sexlessness:

• Male: r = 0.09, P = 2.8 × 10⁻¹⁵
• Female: r = 0.14, P = 3.6 × 10⁻⁶
• Overall: r = 0.15, P = 9.5 × 10⁻¹³

Explanation: Areas with higher income inequality also have higher rates of sexlessness

2. Genome-wide association study (GWAS) results

Samples and methods

• Number of participants: 404,470 people of European ancestry
• Sexless individuals: 3,897 people (~1%)
• Number of SNPs: 10.6 million single nucleotide polymorphisms

Main findings

• Significant site: A site on chromosome 1 (top SNP: rs912773)
  • This site is located in an intergenic region, the nearest gene is LOC107984933
  • Single SNP effect size is extremely small

SNP-based Heritability

IMPORTANT OBSERVATION:

• Genetic correlation between males and females is 0.56 (SE = 0.17, P = 0.0007) -Suggests that SNP associations are directionally consistent between men and women but only partially overlap

Evolutionary evidence

The study examined changes in allele frequency of rs4654352, one of two genome-wide significant SNPs, in the Ancient DNA Database (AADR):

• Time Span: Past 12,000 years
• Sample: 3,458 ancient individuals from Europe
• Trend: A continued decrease in frequency of the A allele associated with higher sexlessness
  • 10,000-12,000 years ago: 87%
  • 0-2,000 years ago: 56%

Conclusion: Consistent with negative selection pressure targeting sexlessness-related alleles

3. Polygenic Score (PGS) analysis

UK Biobank Internal Validation

• PGS significantly predicted sexlessness in an independent sibling sample (Beta = 0.016, SE = 0.005, P = 0.002)
• Gene-Environment Correlation Test:
  • Only 7.4% of the effect can be attributed to gene-environment correlations among families
  • This compares to 49% for education, 48% for IQ, and 15% for BMI
  • Conclusion: GWAS signals are minimally affected by gene-environment correlations

Australian independent sample verification

PGS was significantly associated with multiple relevant phenotypes in Australian samples (N = 1,354-13,532):

Religious Impact (N = 6,764):

• Religious people are more likely to have no sexual experience in their lives (P < 0.0001)
• Gender analysis: significant for women (P = 0.002), not significant for men (P = 0.06)

4. Genetic overlap with other complex traits

Genetic correlation with childlessness

Showing high genetic overlap between sexlessness and childlessness

Other important genetic correlates

Positive correlation (genes associated with sexlessness are also associated with the following traits):

• Cognitive and Socioeconomic Status:
  • Child vs. Adult IQ
  • Education level
  • Income and socioeconomic status
• Mental Illness:
  • Autism Spectrum Disorder
  • Anorexia
• Lifestyle:
  • Less substance use (alcohol, cigarettes, marijuana)

Negative correlation:

• Mental Illness: -ADHD
  • Post-traumatic stress disorder
• Psychosocial Traits:
  • Extraversion
  • Relationships with friends and family -Subjective well-being

Phenotypic correlation analysis

Mental health indicators (especially men)

Sexless men were significantly more likely to:

• Suffering from neurosis
• feel unhappy
• feeling lonely
• Believe that life lacks meaning

Social Links

• More likely to live alone
• Social visits are less frequent
• Lack of intimacy or someone to confide in

Physical characteristics

• MEN: Lower grip strength and lean body mass (arm muscle mass)
• Overall: Start wearing glasses earlier

Substance Use

Associated with less use of:

• alcohol
• cigarettes
• Marijuana

Education and socioeconomic status

• Phenotype related: -Positively associated with higher educational attainment (for both men and women)
  • Negatively associated with lower household income
  • Place of residence with high levels of economic deprivation (Townsend index)
• Genetic correlation (opposite direction):
  • Positive genetic correlation (~0.5) with higher IQ, education, income, and socioeconomic status

Research limitations and precautions (Box 1: Cautionary Notes)

1. Culture Specificity

• The association between genetics and behavior reflects the interaction between genetics and the environment within a specific cultural context
• Findings from contemporary Western societies should not be generalized to other ancestries or cultural backgrounds

2. Individual results cannot be predicted

• Polygenic scores are not suitable for predicting sexlessness at the individual level
• Approximations based on large samples and small effects
• It is inevitable that there will be people with high scores but low phenotypes, and vice versa

3. Complexity

• Heredity is just one aspect of a complex network that influences behavior
• Environmental, social, cultural and personal factors all play an important role
• This study explores correlation, not causation

4. Measurement Error

-Sexlessness is a self-report variable

• There may be under-reporting or over-reporting, leading to classification errors
• Social norms may influence reporting behavior (men may over-report, women may under-report)

Discussion and Interpretation

1. **Scientific evidence for the “nerd” stereotype? **

The study found a combination of characteristics that closely aligned with the “nerd” stereotype:

• Introversion
• Wearing glasses when young
• Smart and academically successful
• Physically weak
• Social isolation, loneliness
• Higher autism spectrum traits
• Nervous
• Less use of drugs and alcohol

2. Complexity of Causal Direction

• Sexual inexperience → Mental health issues: Sex is a basic human drive, and its lack may affect happiness
• Mental Health Issues → Sexual Inexperience: Psychological issues may make it more difficult to approach or attract a partner
• Third Variable: Other factors may increase the likelihood of both

Genetic correlations provide some clues:

• The genetic correlation between sexlessness and depression, anxiety, and loneliness is negative (not positive)
• But there is a positive genetic correlation with autism spectrum disorder, consistent with the characteristics of interpersonal difficulties

3. The Paradox of Intelligence and Reproductive Success

• Evolutionary Expectation: Intelligence and resources should be attractive traits
• Research Finding: Positive genetic correlation (~0.5) with higher IQ, education, and socioeconomic status

Possible explanation:

• Young adults with high educational/socioeconomic potential may avoid intimate relationships in order to pursue career plans
• This pattern may continue into later life

Challenges to the Sexual Selection Hypothesis:

• The sexual selection hypothesis of human intelligence proposes that intelligence evolves due to its contribution to mating success.
• This study finds that intelligence is positively related to sexlessness, strengthening the evidence against this hypothesis

4. Sexlessness vs. Asexuality

-Asexuals account for about 1% (similar to the sexless proportion in this study)

• But more than half of asexuals are not virgins
• Asexuals have lower average education and socioeconomic status (contrary to this study’s findings)
• The correlation between male sexlessness and regional female scarcity & income inequality difficult to explain by asexuality

Conclusion: Asexuality may contribute to part of the phenotype, but it is not the main factor

Evolutionary meaning

1. Sexlessness as a fitness proxy variable

• Significant SNP heritability allows genetic correlation analysis
• Significant negative genetic correlation with number of heterosexual sexual partners and number of children
• May be a more “pure” ancestral fitness surrogate than other variables
  • Less affected by social sexual orientation, pickiness in mate selection, family planning, career orientation, etc.

2. Selected Evidence from Ancient DNA

• The A allele (associated with sexlessness) has continued to decline over the past 12,000 years
• Expected negative selection pressure
• but need to be interpreted with caution:
  • The exact function of this variant is unknown
  • Observed effect sizes are small

3. Maintenance of genetic variation

Genetic variation may be maintained through mutation-selection balance:

• Negative selection acts on this trait
• New mutations continue to arise in the population

Methodological Highlights

1. Large-Scale GWAS

• 404,470 participants, 10.6 million SNPs
• Corrected genetic correlation matrix and 25 genetic principal components using linear mixed models

2. Multi-sample verification

• UK Biobank internal validation of sibling samples
• External verification by Australian independent samples

3. Gene-Environment Correlation Test

• Comparison of within-family vs. between-family effects
• Only 7.4% can be attributed to family-level gene-environment correlations (much lower than the 49% for educational attainment)

4. Ancient DNA Integration

• Allen Ancient DNA Resource (AADR) v62.0
• 3,458 ancient European individuals
• A time span of 12,000 years

Policy and Practical Implications

1. Public Health

• Sexless individuals, especially men, may face higher mental health risks
• Need targeted mental health support

2. Education

• Understand the complex interactions of genetic and environmental factors
• Avoid the misunderstanding of genetic determinism

3. Research Direction

• Need more detailed information on the causes of sexlessness
• Distinguish between “inability to attract a partner” vs. “lack of sexual desire”
• Triangular validation of different methodologies (e.g. Mendelian randomization)

Personal reflections and comments

Research Advantages

1. Large sample size and strong statistical testing power
2. Multi-level analysis: phenotype, GWAS, PGS, genetic correlation, ancient DNA
3. High transparency: clearly state limitations and precautions (Box 1)
4. Cross-sample validation: Increase the reliability of findings

Research Limitations

1. Limited Causal Inference: Only correlation can be described, and it is difficult to establish the direction of causation.
2. Culture Specificity: Findings may not generalize to non-Western societies
3. Self-reporting bias: Sexlessness is a sensitive issue and there may be reporting bias.
4. Heterosexuality: sexlessness may include many different causes (asexuality, social difficulties, religion, etc.)

Future research directions

1. Mendelian Randomization: Unraveling Causal Complexity in Larger Samples
2. Longitudinal Study: Tracking the Development of Sexlessness
3. Cross-Cultural Research: Test whether the findings are generalizable
4. Mechanism Research: In-depth exploration of the biological and social mechanisms related to intelligence-sexlessness

Key data summary table

GWAS samples and heritability

Environmental factor correlation

My understanding

After reading this paper, I think the most interesting thing is that it uses large-scale genetic data to explore a phenomenon that is rarely studied in science-lifelong sexual inexperience. This may have been dismissed as purely a matter of personal choice or luck in the past, but this paper tells us that there are actually more complex biological and social factors at work.

First, genetics does play a role. Although the effects of individual genes are small, combined, approximately 12-17% of the variation can be explained by heritability. This does not mean that “having a certain gene will make you single all your life.” It means that some genetic tendencies may affect your social skills and personality traits, which in turn indirectly affects your chances of establishing an intimate relationship.

What impressed me most was the discovery of the “nerd” characteristic group - smart, introverted, wearing glasses when he was young, relatively weak, not very likely to drink or smoke, and prone to nervousness and loneliness. These characteristics are statistically related to a lifetime of sexual inexperience. This is really similar to the stereotypes we see in pop culture, but I didn’t expect it to be supported by scientific evidence.

Even more counterintuitive is the matter of intelligence. It stands to reason that smart people should be more attractive and resourceful, but this study found that at the genetic level, genetic variations related to sexlessness are actually related to higher IQ and higher education. This is really contradictory! One explanation proposed by the researchers is that perhaps smart young people focus more on career development and postpone their love life. However, once this pattern is formed, it may continue for the rest of life.

Another discovery that I found really cool was the analysis of ancient DNA. They found that the frequency of genetic variants associated with sexlessness has been declining over the past 10,000 years. This fits with the predictions of evolutionary theory - if a gene makes it harder for you to reproduce, it should be eliminated. It’s really amazing to be able to verify this trend in ancient human bones.

Of course, this study also has many limitations. It can only tell us “correlation” and cannot prove causation. Moreover, all data come from the United Kingdom, and the cultural background is very specific, and may not be applicable to other societies. In addition, the phenomenon of “lifelong sexual inexperience” is complex in itself - it may be asexuality, it may be social difficulties, it may be religious choice, it may even be just bad luck. Mixing all these different causes into one analysis may obscure some important details.

Overall, I think the greatest value of this study is that it opens a new research perspective. It tells us that human intimacy and sexual behavior are not only the product of culture or personal choice, but also the interaction of multiple factors such as genetics, environment, and socioeconomic factors. This complexity is the most fascinating part of human behavior.

Further reading

1. Sexual Selection and Intelligence: Miller, G. F. (2000). The Mating Mind
2. Behavioral Genetics Methods: Visscher et al. (2017). 10 Years of GWAS Discovery
3. Gene-Environment Interaction: Dick (2011). Gene-Environment Interaction in Psychological Traits and Disorders
4. Evolutionary Psychology: Buss, D. M. (2015). Evolutionary Psychology: The New Science of the Mind

Reading date: 2025-11-20 Notes organized: Dylan Chiang