Novel genomic loci shape two neuroanatomical dimensions of AD in non‐demented populations

Abstract

AbstractBackgroundArtificial intelligence has been in burgeoning demand to be applied to magnetic imaging resonance (MRI) data to parse the neuroanatomical heterogeneity of Alzheimer’s disease (AD) and/or mild cognitive impairment (MCI) (Wen et al., 2021a, 2021b; Yang et al., 2021). However, the genetic heterogeneity leading to this neuroanatomical heterogeneity, especially at the early asymptomatic stages, is not fully elucidated.MethodA deep semi‐supervised representation learning method, called Surreal‐GAN (Yang et al., 2022), was applied to T1‐weighted MRI from AD/MCI patients from ADNI to define the two neuroanatomical dimensions of AD at the symptomatic stages. The R1 dimension was characterized by widespread brain atrophy without an exclusive focus on the medial temporal lobe, whereas the R2 dimension showed focal medial temporal lobe atrophy (Wen et al., 2022). We then applied the trained model to 33,540 non‐demented individuals from UK Biobank. Imputed genotyping data were analyzed in genome‐wide association studies (GWAS). We performed multiple linear regressions controlling for confounding factors (e.g., age) via Plink (Purcell et al., 2007). We defined a genomic locus (represented by the top lead SNP) considering linkage disequilibrium. Finally, we manually queried all leading SNPs on GWAS Catalog (Buniello et al., 2019) to determine if the genomic loci were novel, provided they were not previously associated with any clinical traits.ResultGWAS discovered 24 genomic loci, of which 7 were novel for R1 and R2, respectively (Fig. 1). For R1, 8 mapped genes, based on physical positions, eQTL, and chromatin interactions, were associated with AD‐related traits in the literature. For example, the KDM2B gene from the genomic locus (rs9795600, P‐value = 1.13e‐08) was previously associated with AD (Gouveia et al., 2022). For R2, 13 mapped genes were associated with AD‐related traits. For example, the TESC gene from the genomic locus (rs77956314, P‐value = 9.99e‐29) was associated with neurofibrillary tangles measurement, which is formed by hyperphosphorylation of a microtubule‐associated protein known as tau in AD (Wang et al., 2020).ConclusionOur results confirmed genetic variants previously associated with AD and identified novel genomic loci contributing to this neuroanatomical heterogeneity. Further research is needed to understand these novel loci’s biological pathways and functional consequences.