Tandem repeat polymorphisms are associated with brain structure: results of two large population-based studies

Area of Science:

• Genetics
• Neuroscience
• Population Genomics

Background:

• Genome-wide association studies (GWAS) have identified genetic variants linked to brain structure, but a significant portion of heritability remains unexplained.
• Short tandem repeats (STRs), a type of repetitive genomic element, are often overlooked in GWAS and may contribute to this missing heritability.
• While pathogenic STR expansions are linked to brain disorders, the role of non-pathogenic STR variations in the general population is largely unknown.

Purpose of the Study:

• To systematically investigate the relationship between short tandem repeat (STR) variations and brain imaging-derived phenotypes in the general adult population.
• To assess the contribution of STRs to inter-individual variation in brain structure.

Main Methods:

• Targeted deep sequencing of approximately 3,000 polymorphic STRs in 2,958 individuals from the population-based Rhineland Study.
• Estimation of STR sizes using ExpansionHunter v5 and acquisition of 45 brain imaging phenotypes from MRI scans.
• Multiple linear regression models to assess associations between STR lengths and neuroimaging phenotypes, with independent validation in the UK Biobank cohort.

Main Results:

• Expansion of an intronic AC repeat in PRR14L associated with larger thalamic volume.
• AATG repeat polymorphisms in NADK linked to reduced subcortical gray matter and thalamic volumes.
• Higher polygenic burden of moderate STR expansions correlated with increased total brain, gray matter, supratentorial, and thalamic volumes.

Conclusions:

• Moderate STR expansions are identified as region-specific determinants of brain morphology.
• STR variability may play a role in neuroanatomical plasticity and cognitive function.
• This study expands the understanding of how repetitive genomic elements contribute to brain structure variation beyond single-nucleotide variations.