Zhu et al., Proceedings of the National Academy of Sciences - Genome-wide studies of schizophrenia and other psychiatric disorders find hundreds of hits, yet those hits barely clear the significance threshold and tend to be common variants, unlike traits such as LDL cholesterol. This study shows that other traits whose heritability is enriched in the central nervous system share the same pattern, that the pattern survives careful matching of statistical power between binary and quantitative traits, and that it is best explained by an evolutionary model in which brain-related traits have very large mutational targets and their variants face stronger selection. Key terms: genetic architecture, natural selection, GWAS, psychiatric genetics, mutational target size.
Study Highlights:
Using stratified LD score regression across 220 cell types, the authors classified 164 traits and found 50 brain-related quantitative traits and four brain-related disorders, all psychiatric, among 151 UK Biobank traits and 13 diseases. Schizophrenia hits had a narrower spread of z-scores and higher minor allele frequencies than LDL or coronary artery disease hits, and the difference remained after downsampling the other GWAS to the effective sample size of the schizophrenia study. Fitting a pleiotropic stabilizing selection model, they inferred a selection distribution shifted toward stronger selection for brain-related traits and a median mutational target of about 1.32% of the genome, against 0.27% for other traits. Simulations showed that stronger selection, once GWAS ascertainment is applied, enriches hits for common variants, and rare loss-of-function burden tests showed that highly constrained genes have larger effects on brain-related traits than on other traits.
Conclusion:
Traits mediated by the central nervous system share a distinct genetic architecture of many small, relatively common effects, which the authors attribute to large mutational target sizes and stronger selection on brain-relevant variants and genes. The brain-related traits studied act as proxies for the processes under selection, so the specific targets of selection cannot be identified, and confounding was not fully excluded because family-based GWAS remain underpowered.
Article title:
Genetic architectures of brain-related traits are shaped by strong selective constraints
First author:
Zhu
Journal:
Proceedings of the National Academy of Sciences
DOI:
10.1073/pnas.2609814123
Reference:
Zhu, H., Simons, Y. B., Spence, J. P., Sella, G., and Pritchard, J. K. (2026). Genetic architectures of brain-related traits are shaped by strong selective constraints. Proceedings of the National Academy of Sciences 123(36), e2609814123. https://doi.org/10.1073/pnas.2609814123
License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/
Support:
Base by Base is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming:
❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01
☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00
▶️ Watch with chapters on YouTube: https://www.youtube.com/@basebybase
More at basebybase.com
On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.
Episode link: https://basebybase.com/episodes/brain-traits-strong-selection-genetic-architecture
QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-10-04.
QC Scope:
- article metadata and core scientific claims from the narration
- excludes analog...
Chapters
- (00:00:20) - Introduction: The Loud Room and the Whisper Room
- (00:01:20) - The Puzzle: Weak, Common Hits in Psychiatric Genetics
- (00:02:31) - Study Overview and Research Team
- (00:03:08) - What Is Genetic Architecture and Why It Matters
- (00:04:14) - The Stabilizing Selection Model
- (00:05:30) - Identifying Brain-Related Traits
- (00:06:51) - Comparing Diseases and Traits Fairly
- (00:07:59) - Modeling Selection and Mutational Target
- (00:08:38) - Key Findings: LDL vs Coronary Disease vs Schizophrenia
- (00:09:43) - The Pattern Across Psychiatric and Behavioral Traits
- (00:10:54) - Ruling Out Study Design as the Explanation
- (00:11:32) - Evolutionary Signatures: Stronger Selection, Larger Targets
- (00:12:41) - Why Stronger Selection Produces Common Hits
- (00:13:19) - Independent Evidence from Gene Constraint
- (00:14:22) - Explaining the History of Psychiatric Genetic Discovery
- (00:14:58) - Why the Brain May Face Stronger Selection
- (00:15:35) - Limitations and Caveats
- (00:16:44) - Conclusions and Broader Implications
- (00:17:48) - Closing and Credits
