Linking genomic and proteomic signatures to brain amyloid burden: insights from GR@ACE/DEGESCO

Abstract

Alzheimer's disease (AD) is a complex disease with a strong genetic component, yet many genetic risk factors remain unknown. We combined genome-wide association studies (GWAS) on amyloid endophenotypes measured in cerebrospinal fluid (CSF) and positron emission tomography (PET) as surrogates of amyloid pathology, which may provide insights into the underlying biology of the disease. We performed a meta-GWAS of CSF Aβ42 and PET measures combining six independent cohorts (n = 2,076). Given the opposite beta direction of Aβ phenotypes in CSF and PET measures, only genetic signals showing opposite directions were considered for analysis (n = 376,599). We explored the amyloidosis signature in the CSF proteome using SOMAscan proteomics (ACE cohort, n = 1,008), connected it with GWAS loci modulating amyloidosis and performed an enrichment analysis of overlapping hits. Finally, we compared our results with a large meta-analysis using publicly available datasets in CSF (n = 13,409) and PET (n = 13,116). After filtering the meta-GWAS, we observed genome-wide significance in the rs429358-APOE locus and annotated nine suggestive hits. We replicated the APOE loci using the large CSF-PET meta-GWAS, identifying multiple AD-associated genes including the novel GADL1 locus. Additionally, we found 1,387 FDR-significant SOMAscan proteins associated with CSF Aβ42 levels. The overlap among GWAS loci and proteins associated with amyloid burden was minimal (n = 35). The enrichment analysis revealed mechanisms connecting amyloidosis with the plasma membrane's anchored component, synapse physiology and mental disorders that were replicated in the large CSF-PET meta-analysis. Combining CSF and PET amyloid GWAS with CSF proteome analyses may effectively elucidate causative molecular mechanisms behind amyloid mobilization and AD physiopathology.