ESTABLISHING THE EFFECT OF CODING VARIANTS ON ALZHEIMER’S DISEASE RELATED ENDOPHENOTYPES

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To discover novel genetic factors contributing to AD pathogenesis, we focused on the genetics of AD-relevant endophenotypes. This strategy assumes that measurable biological properties are more strongly related to the underlying AD pathogenesis than the diagnostic classification, and therefore will have stronger effect sizes, allowing to perform genetic analyses with lower sample sizes. By using an AD cohort with detailed endophenotypic data on CSF biomarkers, MRI images and neuropsychological tests, we aim to establish novel genetic factors that contribute to AD. The Amsterdam Dementia cohort harbors a collection of individuals diagnosed with AD, mild cognitive impairment (MCI) or subjective cognitive decline. A total of 1281 patients were genotyped using the Illumina neuroX exome array, which is enriched for rare coding variants as it consists of ∼240,000 variants of the Illumina HumanExome array v1.1. Additionally, a custom content of ∼25,000 neurodegenerative specific variants were included. To perform single-marker and gene-based association analyses we used PLINK [1] and MAGMA [2], respectively. As anticipated, a strong genetic influence was observed for the well-established APOE locus on amyloid beta and (phosphorylated) tau CSF protein levels. We furthermore observed a close to significant association to the MRI-phenotype posterior cortical atrophy for SNCA (coding for alpha-synuclein), a GWAS locus highly associated to Parkinson's disease. The gene-based association analysis to Ab42/Tau ratio revealed, besides the genes within the APOE locus, a strong and novel association for FZD1, a gene coding for a receptor of Wnt signalling proteins which has been suggested to regulate adult hippocampal neurogenesis [3]. Multiple independent variants and genes show a significant association to AD-related endophenotypes. After replication of these genetic factors in a second independent genetic dataset, future functional follow up experiments will further elucidate their specific role in AD pathogenesis.