Brain-wide genome-wide colocalization study for integrating genetics, transcriptomics and brain morphometry in...

Area of Science:

• Neuroscience
• Genetics
• Medical Imaging

Background:

• Alzheimer's disease (AD) is a prevalent neurodegenerative disorder with incompletely understood mechanisms, impeding effective therapy development.
• Current research lacks a comprehensive understanding of the interplay between genetic factors, brain structure, and AD pathogenesis.

Purpose of the Study:

• To investigate the underlying neurobiological pathways of Alzheimer's disease by integrating genetic, gene expression, and brain imaging data.
• To identify potential causal links between genetic variations, brain morphology, and AD risk.

Main Methods:

• Utilized UK Biobank data (genotyping, MRI), GWAS summary statistics, and GTEx cis-eQTL data.
• Employed a brain-wide genome-wide colocalization analysis using a Bayes factor framework and mediation analysis across 145 brain regions.
• Performed posthoc functional annotations on 482,831 single nucleotide polymorphisms (SNPs).

Main Results:

• Discovered a potential AD causal pathway involving SNP rs6585827, which upregulates BTBD16 gene expression in oligodendrocytes within the brain cortex.
• This genetic influence was associated with a reduced risk of entorhinal cortex volumetric loss, suggesting a protective effect against AD.
• Findings were corroborated by existing AD literature, linking genetics, molecular signatures, brain morphology, and disease diagnosis.

Conclusions:

• The study provides a systems biology perspective on AD, connecting genetic variations to molecular changes and brain structural endophenotypes.
• Identified a novel protective mechanism against AD, highlighting the role of BTBD16 gene regulation in glial cells.
• Offers valuable insights for future therapeutic target identification and drug discovery in Alzheimer's disease research.