Investigating the genetic relationship between depression symptoms and Alzheimer’s Disease in clinically diagnosed and proxy cases

Depression is a risk factor for Alzheimer’s disease (AD), but evidence for their genetic relationship is mixed. Assessing depression symptom specific genetic associations may better clarify this relationship. Using data from the UK Biobank, the GLAD Study and PROTECT, we performed the largest genome-wide meta-analyses (GWAS) of the nine depression symptom items, plus their sum score, on the Patient Health Questionnaire (PHQ-9) (GWAS equivalent N: 224,535—308,421). We assessed global/local genetic correlations and statistical colocalisation between depression phenotypes and AD across six AD GWAS with varying proportions of clinical and proxy (family history) case ascertainment. We assessed bi-directional causal associations using Mendelian randomisation (MR) and the predictiveness of depression phenotype polygenic risk scores (PRS) for AD case/control status in three clinical AD cohorts. Our GWAS meta-analyses identified 37 genomic risk loci across the ten depression symptom phenotypes. Of the 72 global genetic correlation tests conducted between depression/depression symptoms and AD, 20 were significant at p FDR ≤ 0.05. Only one significant genetic correlation was identified with AD GWAS containing clinical-only cases. Colocalisation was not identified at loci contains local genetic correlation but was identified in the region of transmembrane protein 106B (TMEM106B) between multiple depression phenotypes and both clinical-only and clinical+proxy AD. MR and PRS analyses did not yield statistically significant results. Our findings do not demonstrate a causal role of depression/depression symptoms on AD and suggest that previous evidence of their genetic overlap may be driven by the inclusion of proxy cases/controls. However, the identification of colocalisation at TMEM106B warrants further investigation.