Multi‐ancestry genome‐wide association study of plasma glial fibrillary acidic protein (GFAP)

Abstract Background Glial fibrillary acidic protein (GFAP) is an astrocytic cytoskeletal protein and a promising blood biomarker for Alzheimer's disease (AD) and other neurodegenerative diseases. To date, the genetic architecture of plasma GFAP has not been characterized. We conducted a multi‐ancestry meta‐analyses of genome‐wide association studies (GWAS) in diverse population‐based cohorts to identify genetic variants associated with plasma levels of GFAP and to investigate their implication for neurological diseases. Methods Circulating GFAP levels were assayed by ultrasensitive single molecule array (Simoa) immunoassay. We performed ancestry‐specific and ancestry‐combined meta‐analyses of GWAS in 17,028 individuals (mean age: 64.5 years; 60% women) of diverse ancestry (African (AA), N=1163; Hispanic (HA), N=7405; European (EA), N=8460) from 12 community‐based cohorts. Results In the combined sample, we identified 7 loci associated with plasma GFAP. These were located in or near genes encoding APOE, CAPN1, CAPN2, GFAP, TMEM106B, PPP1R3C, and LOC105375672. The strongest association was with the APOE4 variant rs429358 (P=2.6x10 ‐40 ). However, this association was heterogeneous by ancestry, with stronger effects in EA, weaker in HA, and no association in AA. Ancestry‐specific meta‐analyses identified additional loci, including ZFAND3 in EA (Figure 1) and CAPN2 in HA (Figure 2), which were not observed in the other ancestries. No locus reached genome‐wide significance in AA. Using fine‐mapping methods incorporating functional annotation, gene expression, and linkage disequilibrium, we further prioritized potential causal variants and genes at the identified loci and investigated their implication for major neurological diseases, including AD. Conclusion Our GWAS of plasma GFAP has identified multiple loci with ancestry‐specific or cross‐ancestry effects. Our multi‐ancestry, integrative approach extends knowledge about the biology of GFAP and its shared genetic architecture with neurological disease.