| Title: | Integration of estimated regional gene expression with neuroimaging and clinical phenotypes at biobank scale |
| Journal: | PLOS Biology |
| Published: | 13 Sep 2024 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/39269986/ |
| DOI: | https://doi.org/10.1371/journal.pbio.3002782 |
Publication 13492
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Abstract
An understanding of human brain individuality requires the integration of data on brain organization across people and brain regions, molecular and systems scales, as well as healthy and clinical states. Here, we help advance this understanding by leveraging methods from computational genomics to integrate large-scale genomic, transcriptomic, neuroimaging, and electronic-health record data sets. We estimated genetically regulated gene expression (gr-expression) of 18,647 genes, across 10 cortical and subcortical regions of 45,549 people from the UK Biobank. First, we showed that patterns of estimated gr-expression reflect known genetic-ancestry relationships, regional identities, as well as inter-regional correlation structure of directly assayed gene expression. Second, we performed transcriptome-wide association studies (TWAS) to discover 1,065 associations between individual variation in gr-expression and gray-matter volumes across people and brain regions. We benchmarked these associations against results from genome-wide association studies (GWAS) of the same sample and found hundreds of novel associations relative to these GWAS. Third, we integrated our results with clinical associations of gr-expression from the Vanderbilt Biobank. This integration allowed us to link genes, via gr-expression, to neuroimaging and clinical phenotypes. Fourth, we identified associations of polygenic gr-expression with structural and functional MRI phenotypes in the Human Connectome Project (HCP), a small neuroimaging-genomic data set with high-quality functional imaging data. Finally, we showed that estimates of gr-expression and magnitudes of TWAS were generally replicable and that the p-values of TWAS were replicable in large samples. Collectively, our results provide a powerful new resource for integrating gr-expression with population genetics of brain organization and disease.</p>
16 Keywords
- Aged
- Biological Specimen Banks
- Brain
- Female
- Gene Expression
- Gene Expression Profiling
- Genome-Wide Association Study
- Genomics
- Gray Matter
- Humans
- Male
- Middle Aged
- Neuroimaging
- Phenotype
- Polymorphism, Single Nucleotide
- Transcriptome
13 Authors
- Nhung Hoang
- Neda Sardaripour
- Grace D. Ramey
- Kurt Schilling
- Emily Liao
- Yiting Chen
- Jee Hyun Park
- Xavier Bledsoe
- Bennett A. Landman
- Eric R. Gamazon
- Mary Lauren Benton
- John A. Capra
- Mikail Rubinov
Enabling scientific discoveries that improve human health