Population-scale repeat expansions elucidate disease risk and brain atrophy

Area of Science:

• Genetics
• Neurology
• Genomic Medicine

Background:

• Short tandem repeat (STR) expansions are linked to over 70 neurological disorders.
• Population-level data on pathogenic STR repeat expansions is limited.

Purpose of the Study:

• To conduct a population-scale survey of pathogenic STR repeat expansions.
• To investigate early molecular and imaging biomarkers associated with repeat expansions.

Main Methods:

• Analyzed repeat length in 37 disease-associated STR loci across 1,020,833 samples.
• Utilized short-read sequencing data (whole-exome and whole-genome).
• Correlated repeat length with 7,671 binary traits and neuroimaging data.

Main Results:

• Found pathogenic repeat frequencies higher than disease prevalence for most loci.
• Confirmed known associations (e.g., HTT-Huntington's, DMPK-myotonic disorders).
• Identified associations between repeat expansions and increased neurofilament light chain (NfL) levels and reduced brain volumes (e.g., HTT, CACNA1A) preceding diagnosis.

Conclusions:

• Short-read sequencing effectively characterizes repeat expansions in large cohorts.
• Repeat expansions are linked to neurodegeneration markers (NfL, brain volume loss) earlier than clinical diagnosis.
• This approach has potential for epidemiological studies and clinical biomarker development.