Rare genetic variants linked to lower cognitive test scores in expanded analysis

by Wellcome Trust Sanger Institute

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The largest genetic study of cognition to date has been published, involving nearly half a million people of European ancestry. This provides a new understanding of the genetic factors that shape cognitive differences and can help us better understand certain health conditions, including neurodevelopmental conditions.

Researchers at the Wellcome Sanger Institute, Amsterdam University Medical Center and their collaborators built on previous studies by statistically estimating problem-solving test scores for UK Biobank participants who never completed the test.

This reduced the bias that comes from analyzing only the people who chose to take the test and increased the number of people included from around 270,000 to more than 455,000.

This study, published today (Oct. 5) in Nature Genetics, found that adding the estimated scores increased the number of common DNA changes associated with differences in test scores from 390 to 550, a 40% increase.

The gain was even larger for rare genetic variants. The number of genes in which rare genetic changes are linked to differences in cognitive ability rose from five to 26. These include 14 that were already known to play a role in neurodevelopmental conditions.

It was well established before this study that genes influence cognitive ability, alongside environmental factors. This study helps identify some of the genes involved to help us better understand these factors and their impact.

Bias from missing test scores

UK Biobank is a large research resource of biological, health and lifestyle information, containing data from around half a million people in the U.K. Among other things, the participants were asked to complete a problem-solving test called the verbal numerical reasoning test. However, around 40% of its participants never completed this test, and those who did were more likely to have higher education credentials.

This bias in the sample population, known as ascertainment bias, can lead to problems in downstream genetic studies.

To increase the size and representativeness of the data set for studying cognition, the researchers used other information about these participants, including health, behavior and socioeconomic measures, to statistically estimate the likely test scores.

Rare variants linked to lower scores

They then analyzed the larger data set to understand more about how genetic changes may influence cognition. In total, the team identified 550 common genetic variants, each with a very small effect on test scores. They also found rarer genetic differences that can have much larger effects, pinpointing 26 genes, all associated with lower test scores. Fourteen of these genes are already known to cause neurodevelopmental conditions, and four had previously been linked to measured cognitive test scores or education in UK Biobank.

The remaining eight had no strong previous evidence linking them to cognition or neurodevelopmental conditions. However, the team showed that in patients with neurodevelopmental conditions, these genes had a higher frequency of genetic changes, implying that they probably do contribute to risk.

Most people carrying these rare variants in UK Biobank do not have a diagnosis of a neurodevelopmental disorder. This suggests these rare genetic effects can influence cognition even without causing people to reach a clinical threshold for diagnosis.

Group findings, not individual predictions

This research adds to the wider understanding of how genetic changes influence cognition and could provide insights into neurodevelopmental conditions. The researchers stress that the results are strictly to improve the scientific understanding of cognition at a group level, not to make individual predictions about cognitive ability.

The estimated scores should not be treated as equivalent to directly measured intelligence, and the researchers emphasize that better measurement of cognition in large studies remains the most robust way forward.

"The challenge was making sure the estimated scores still captured cognitive ability, rather than simply reflecting the other information we used to calculate them. We tested that extensively. Through this approach of statistically guessing unmeasured scores, we were able to expand the study to nearly half a million people, making it the largest study of its kind to date. These results will help us learn more about how cognition relates to social and health inequalities," said Dr. Abdel Abdellaoui, co-senior author at Amsterdam University Medical Center.

"The findings from genetic studies can be biased if they are based on a nonrandom subset of people. In this case, we were able to include information from over 170,000 additional participants to give a more representative picture of how genetics influences cognition scores and to uncover rare DNA differences linked to cognition that we previously did not have enough statistical power to find," said Dr. Daniel Malawsky, co-first author at the Wellcome Sanger Institute.

"By mapping genetic variants across nearly half a million people, we've shown that damaging DNA differences in the same genes that cause severe neurodevelopmental conditions can also affect cognitive traits across the wider population.

"Learning more about these impacted genes could help us better understand how the brain develops and why DNA changes in these genes lead to neurodevelopmental conditions in some people but not others," said Dr. Hilary Martin, co-senior author at the Wellcome Sanger Institute.

Publication details

David M. van den Berg et al, Imputation of fluid intelligence scores reduces ascertainment bias and increases power for analyses of common and rare variants, Nature Genetics (2026). DOI: 10.1038/s41588-026-02787-5

Journal information: Nature Genetics

Key medical concepts

cognitive abilityNeurodevelopmental Disorders

Clinical categories

Clinical geneticsNeurology Provided by Wellcome Trust Sanger Institute Who's behind this story?

Swati Mestri

Swati Mestri holds a bachelor's degree in Electronics Engineering and has worked as a content editor since 2019. She has experience editing research documents across technology, health care, and materials science, and has a particular interest in technology and space. Full profile →

Robert Egan

Bachelor's in mathematical biology, Master's in creative writing. Well-traveled with unique perspectives on science and language. Full profile →

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