Epidemiological studies have consistently shown that chronic kidney disease is associated with increased Alzheimer disease risk. However, the underlying genetic architecture connecting these two condi Show more
Epidemiological studies have consistently shown that chronic kidney disease is associated with increased Alzheimer disease risk. However, the underlying genetic architecture connecting these two conditions remains largely unexplored beyond genome-wide correlation analyses. Here, we conducted the first comprehensive, multi-ancestry, large-scale genetic investigation to identify shared genetic components between kidney function and Alzheimer disease. We leveraged large-scale genome-wide association study summary statistics for estimated glomerular filtration rate (N≈1.5 million European, N≈145,000 African ancestry) and late-onset Alzheimer disease (N=63,926 and N=398,058 in two European cohorts; N=9,168 in African ancestry) corrected for competing risk bias. We deployed a novel analytical framework integrating linkage disequilibrium score regression and polygenic risk score analysis, local analysis of [co]variant association, conjunctional false discovery rate analysis with Bayesian colocalization and fine-mapping, and bidirectional cis-Mendelian randomization to identify vertical pleiotropy. Despite the absence of genome-wide genetic correlation (r Show less
Genome-wide association studies (GWAS) have successfully identified genetic loci associated with major depressive disorder (MDD), yet the complex gene networks underpinning this polygenic risk remain Show more
Genome-wide association studies (GWAS) have successfully identified genetic loci associated with major depressive disorder (MDD), yet the complex gene networks underpinning this polygenic risk remain largely uncharacterised. Here, we elucidate the neurobiological mechanisms of MDD by analyzing co-expression networks of 94 risk genes in the human prefrontal cortex. By linking these networks to individual symptoms, we identify the FADS1 (fatty acid desaturase 1) network as a central integrator across symptom clusters. We find that the FADS1 network functions primarily in astrocytes to regulate fatty acid metabolism and influence oligodendrocyte-related cell states. Furthermore, we identify FGF2 as a synaptic effector of this pathway and highlight PPARα (peroxisome proliferator-activated receptor alpha) as a putative therapeutic target. These results establish astrocyte fatty acid metabolism as a critical mechanistic contributor to MDD and a promising avenue for treatment. Show less
Basal bodies (BBs) are microtubule-based organelles that act as a template for and stabilize cilia at the cell surface. Centrins ubiquitously associate with BBs and function in BB assembly, maturation Show more
Basal bodies (BBs) are microtubule-based organelles that act as a template for and stabilize cilia at the cell surface. Centrins ubiquitously associate with BBs and function in BB assembly, maturation and stability. Human POC5 (hPOC5) is a highly conserved centrin-binding protein that binds centrins through Sfi1p-like repeats and is required for building full-length, mature centrioles. Here, we use the BB-rich cytoskeleton of Show less